·MONOGRAPHIS OF THE PHYSIOLOGICAL SOCIETY
Aumber 1
EC
L E Bayliss
Feldberg A
Holghen

·SYMPATHETIC CONTROL
OF HUMAN BLOOD
VESSELS
by
H BARCROFT
на у бу PP
PROFESSOR OP PEYSTLODY BT THOMAS 8 (9PITAL
MEDICAL SCHOOL LONDY
FRMERLE DUVILLE PROTSES OR PUYOL
U EENS UNIVERSITY BFLY T
and
HJCSAV
PH DI BS WRT
TORMEELK LECTURER IV PHYSIOLO X TTI
TAH PITAL
EDI AL arxagt LIND
RESEAR ASSOCIAT XAYO CLIN ROCK
SER UN
LONDON
EDI APÐ APNOID CO

·Copyright in all countres
Signatory to the Berne Cortention
First mblished 1953
то
OG FDHOI M
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tan by Btler & Tn Lid Fome ni London

·FOREWORD this topic The role of the sympathetic nens es in the control of the blood resels has been the object of intestigation of many physiolo gists from the pioneer worh of Cashell Langley and Elliot in this country In recent years interest in the nature of the chemical transmitter of the simpathetic nerves has widened the topic It appears to us opportune to describe the symp? thetic control of certain blood vessels in man and to comment on the function of the sympathetic hormones-adrenaline and noradrenaline This worh has been written primarily on the basis of studies on the circulation in the extremities but we feel that the responses have a more general application to the function and behaviour of blood ven els in other parts of the body We have described certain fundamental experiments in some detail in order to impress their true importance on the reader In many aspects however omissions will be readily evident both in problems still to be solved and in ob ervations of others on But we do not regard a review of the subject as our present task our object is to present the concept of the control of the blood vessels from the vien point of the inies tigator in this special field It is a great pleasure to acknowledge our gratitude to Dr O G Edholm Director of the Division of Human Phys ology of the National Institute for Medical Research who collaborated with one of us in the work described in the early chapters Without his wise counsel and outstanding experi mental shill this book would never hase been written The investigations on sympathectomized subjects were made posible by the kindness of Vr Hedley Atkins Viss Diana Bech Vr P Fitzgerald Vr Ian Frazer Vr J B hinmonth Professor Sir James Learmonth Vr J S Loughridge VIr Peter Martin Vr DHC Yorthfield the late Vr GRB Purce Profeo C G Rob and Sir James Paterson Ross The experi ments on fainting were begun with Professor J VcVlichael and Profesor E P Sharper Schafer To all of these se espress our deepest gratitude Once more tre should be to think all those who have gui en ·vi Foreu ord up their time to act 13 subjects In particular the members of the Belfast Medical Students Association and the students of St Thomiss Hospital Medical School lle are grateful to Professor 1 G Barnard Dean of St Thomas s Hospital Medical School for the provision of many facilities to the St Thomas s Hospital Endowment Fund for 1 grant towards the expenses of one of us and to the Medical Research Council for financial assistance lle also wish to than) Dr L E Bayliss Dr A C Dornhorst Dr O G Edholm Dr W Feldberg Dr P Gasl ell Professor E P Sharpey Schafer and Dr R F Whelin for reading all or part of the manuscript and for valuable criticism We are indebted to Dr Aziz Ahmad for the preparation of tho index to Miss L Stol es for chocking tho referencos to Mrs D Lyddon for drawing many of the figures to Mr AL Wooding for photographic 1991stinco and to Mr G T Haley for technical assistance For permission to quote passages or reproduco figures from bools and journals we express our thanks to the following American Journal of Physiology Fig 76 top left and right Association for Research in Nervous and Mental Desca504 hig 711 British Vedical Journal Fig 112 Cambridge University Press quotation from Tosters Lectures on tho History of Physiology (linical Science Figs 41 43 and 75 Ilcart Fig Ap 4 Journal of Physiology quotation from Brodic and Russell x article and Figy 12 21 22 23 32 34 35 37 38 39 425 56 57 63 64 65 77 81 82 83 93 10 1 10 3 10 4 and 123 Lancel Tigs 78 70 7 10 10 G 12 I and 122 Zeitschrift für kreislaufforschung Frge 12 4 and 12 5 Vacmillan Fig 12 2 (and legend) Pfingers Archa Fig 5 10 St Thomas llospital Reports 72 73 and 74 Sur gery Cynecology and Obstetnes Fig Ap I (and legend) In each instanco tho author of the article from which the figuro was borrowed has been mentioned in the legend Finally we are most grateful to tho I ditorial Committee of the l'hycological Societs for sponsoring the publicition of thuy booh HB 11 JCS 6th August 19 ·CONTFNIS Pue 1 07 30 36 ار Chafer I Sympathetic Visoconstrictor nerves to sholetal muscle 2 Sympathetic vasodilator neries to skeletal muscle 3 The action of acrtnalıne on the circulation in sheletal muscle * The action of noradrenaline on the circulation in sl eletal muscle ✓ The circulation in sheletal muscle during exercise 6 The action of sympathetic neries on the circulation in skeletal muscle during exercise Sympathetie denervation 8 The action of adren sline and noradrenaline on the circulation in the skin 9 The action of adrenaline and noradrenaline on the general circulation 10 Adrenergic blockade J1 Phonochrome tumout's 19 The also vagal syndromo Appendix Plethsamography Author Incies 58 79 68 126 239 163 Subject Indes 157 It

·No text on this page.

·CHAITFR 1 SYMPATHFTIC VASOCOVSTRICTOR NFPUIS TO SKELETAL MUSCLE In 1941 VIchce Bonnar obtained the VD of the Queens Unnersity of Belfast with Gold Vedal for a thesis entitled The action of the sympathetic on the blood vessels of humın sheletal muscle In this chapter with special reference to Bonnars thesis some evidence will be given that the blood vessels of human skeletal muscle are supplied by sympathetic vasoconstrictor fibres and subjected to ners ous i asoconstrictor tone At the time the worh was done a great deal was known about the action of the sympathetic on the blood vessels in the muscles of animals Section was generally followed by vasodilatation due to relense of constrictor tone strong stimulation caused Vasoconstriction or weah vasodilation (Baetjer 1930 Burn 1932 Gilding 1932 Anrep Blalock and Samian 1934 Bulbring and Burn 1930 1937) Vasoconstrictor fibres were found in the muscles of all animals examined but vasodilator fibres in some species only (Bulbring and Burn) Very little was known about the sympathetic innervation of the vessels of human muscles Some thonght that it w 28 constrictor and advised sympathectomy for intermittent claudication others believed that it was dilator (Finch 1914) and others considered it to be of very little significance (Abrimson Zazecla Marrus 1939 Grant and Holling 1938 Prinzmetal and Wilson 1936 Woollard and Phillips 1932) It w 18 not concerned with vasodilatation in erercise which was caused by metabolites (Grant 1938) Barcroft Bonnic Edholm and Effron (1943) noticed that warming the body caused a conspicuous increase in the blood flox in a very muscular part of the body tho forearm (Fig 11 top plethysmographic method see Appendix) This was of nervous origin mediated by the sympathetic since it was abolished by sympathectomy (Fig 11 bottom left) It occurred after adrenaline had been introduced into the BC IT DV 1 * ·2 Sympathetic zasoconstrictor neries to skeletal muscle forearm skın by clectrophoresis to suppress the circulation (Fig 11 bottom right Ing 12) To see if it was due to the release of sympathetic i asoconstrictor tone in the muscles the median radial and ulnar nerves the motor nerves of the forearm which would be expected to convey any sympithetic fibres to the muscles (Gilding 1932) were blocked by norocuno NORMAL FOREARM 10 (3) Feet Heated o BLOOD FLOW (ml/100 ml/mis) SYMPATHECTOMIZED FOREARM BLANCHED FOREARM Feet Heated Feet Heated (3) 0 35 75 O 35 75 Minutes HIR 11 Ipper ments l w ng sympathetic entre of the 11x1 in humen skeletal musc! Top 1 ss I lotati n in the forearm after imm nng the feet n wir water But m rust It can be in luc d whn to skin vessel a o an gly* #tri teil by acanal in introducellyel troph rel) It is aly 1 p on the shan in the sk letal muscles sh h make up 60 p r cent ftir mani Morion IR Thellutatio Al liszp] ly sympat! mi IL 4 mrelate! 1) sympath fibres kurri glorl CRACIA hare tilly in the skel tal marine Israel rep It Sumbet ( m )rts in i nickets Il t) in iph wat bath temperatute 3 fiue

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·1 Sympathetic i asoconstrictor neries to skeletal muscle on one side of the body (Fig 13) and the circulation in the two forearms was compared The blood flow was approximately doubled on the side of the nerve blocks (Figs 14 and 15 Table 1) Before concluding that this hyperaemia was due to release of sympathetic tone in the muscles other possibilities had to be considered Median Radial Ulnar Fig 13 S tes for blocking the deep ners en supplying the skeletal mu el of the forearm (1) The nerve blochs had all been done on the left foreurm It was concen able that the normal circulation on the left side was faster than that on the right Comparison of the blood flows on the two sides showed that the rates are approximately cqual (Fig 14 top right) (2) A small area of foreirm shin about one third generally became anaesthetized due to unavoidable diffusion of local anaesthetic outwards to the cutaneous nerves The symp? thetic supply to this skin must have been bloched and the increase in forearm blood flow might have been due to relense of tone in the cutaneous vessels The effect of blocking the Fug 1 4 Results showing sympathetic ya ncon tr tor tor on the sease? in human skeletal mus le Top left W7 en the deep nerves (conta ning sympathetic) to th left fure arm mus les are blurked the blood flow (cir le ani broken lin ) us about double that it the opposite normal forcara (dots and continuous line) Top rigit Thi4 is not du to any inhen nt d ffertne in the secularity of the two ley (control 1) Middle Or to una ord at le blocking of the sympathetic supply t of the forearm Akin (control ) Dottom 1 Or to rem sal of the mechanical hin Irun o of the tn traction of tho kk 1 tal muscles (control 3) Bottom gli Or to parsive increase in fw thre ugh th furcamm skin following release of an motor tone leep in the arterial tree (control +) Conclus on It must be lue to the relase of sympathetic anxint tor tone in the blor i senele shich are prot at ly on the kel tal mus len T ·NORMAL - DEEP NERVES BLOCKED • }NORMAL 0-- 10 10 (25) 5 5 (6) (8) (6) NORMAL --- NERVES TO V3 FOREARM SKIN BLOCKED FOREARM BLOOD FLOW (ml /100 ml/min) (6) (6) NORMAL 0-SYMPATHECTOMIZED - DEEP NERVES BLOCKED CONTROL 0 OBLANCHED IO DEEP NERVES BLOCKED 10 (2) 5 (2) 5 (2) 10 20 30 40 10 20 Minutes F18 14 ·6 Sympathetic tacoconstrictor nerics to skeletal muscle cutaneous neries of the forearm on the foreirm circulation was therefore tested (radial mediın and ulnır antebrichın nerves focalized by the method of Trotter and Davies (1909)) and found to increase the foreirm blood flow on the average by -5 с T ИЛЛИИ 5 Fig 15 Simultancou recorls of I loo 1 flow in the normal forearm ( ) and in the opposite forearm in which the deep neri ex wero blocke I (T) Tho rate of the I lood flow in the nerve blocke 1 forearm is ineren od owing to th relca of tone in the mu le blo les elis Recorded at the Cambri Ige meeting of the Physiologi al Sx sety Oct 111 Temperaturo «f plethysmograph waterbath 3. C Calabratu nin millilitre Vo timo tracing wag ma le TABLE 1 Sutct Blood flow ml per 100 ml forearm per min Rght Left Diffrence L-R Prentag Difference 1 - 1 x 100 69 +1 13+ + 21 +3 749 1 + 9 HB 1 B 1 B J SL D ( 11 1 ASF +0) IX 20) 3. 103 6. 8 81 4 ,9 98 +29 -30 66 + 103 7161 + 19 > + 206 Average 38 +39 +105 24 per cent Annesthesia of one third of the forenrm rkin would hue increised the flow by only 8 per cent (Hug 14 muddle) This could not explain the far freiter increase in flou found after blocking the deep nersen (10) por cont) (3) Blocking the deep nerses paralysed the forearm mu cles ·Sympathetic ta soronstriclor nenes to sheletal muscle 7 Concen ably the hyperaemia was due to abolition of muscular tone and decrease of mechanical hindrance to the circulation However similar blocks performed on sympathectomized limbs did not increase the flow (Fig 14 bottom left) (4) Claude Bernard (1876) observed a rise of 2 -60 mm Hg in the central end of the labial artery of the horse following section of the cervical sympathetic Conceivably the hyper aemia in the forearm after deep neri e bloch was caused by release of tone in the arterial tree beneath the deep fascia and passive increase in the cutaneous circulation This was tested by observing the effect of deep nerve block on the forearm circulation after blınching the skin with adrenaline Table II TABLE II Protocol Subject OL Lying on couch I lethysmograph diaphragms fitted to loth forearing but plethysmograph not put on till liter Tmo in Minutes 0-15 Reet Forearms kept warm under blankets 15–20 Cottonwool pad bandaged round both forearms between the diaphragms Electrole put on ench pad Left pad Roaked in adrenalino solution at room temperature right one ponheci in saline at the same temperature "0–30 Flectrophoresis 33-37 Pads off 90of shin of left forearm intensely blanched with marhed gooseſlech 35-40 Deep nerves blocked in the left forearm (blanche 1) 40-45 Plethysmographs put on Wrist cuffs put on (till 60th min) and inflated to 200 mm Hg to present blood from the hands from affecting the temperature of the forearms 15-53 Blool flows recorded simultaneou ly in both forearms at 2 min intervals 6 sets obtained for everaging Results left forearm (blanched deep nerves bloched) 2 1 ml right forearm (normal) 0 4 ml 53-55 Votor movements tester! Complete paralysis of tho e medı ated by the radial and ulnar nerves 11eahening of those mediated by the median 57-60 Calibration 60-61 Cuffs and plethysmographs taken off Intense blanching of shin on left si le 61-64 Circulation in botlı firearms arrested for 5 min After relea e flu lung of the shin of the right forearm and of the left above and blow but not in the blinched area 7. 74 Shin tenperatures taken Left forearm (blanched, sleep nerses bl ched) 26 9 ( Right firearm (nornal) 291 C In accorlance with reluct on of the cutaneous blool flow on the left side ·8 Sympathetic zasoconstrctor neries to sheletal muscle is the protocol of a typical experiment Fig 1 4 (bottom right) shows the results The blood flow W 75 small because the fore arms were cooled to make the blanching more effective The important point is that it was trebled in the blanched forearm in which the deep nerves had been blocked Control experi ments showed that adrenaline alone caused construction The vasodilatation must have been cuused by the nerve blocks and it could not have been in the skin The whole series of experiments may be summarized as follows --After deep nerve block the blood flow in the left forearm is about double that in the right This is not due to an inherent difference in the vascularity of the two sides (control 1) or to release of vasoconstrictor tone in the shin (control 2) or to the removal of the mechanical hindrance of tonic muscular contraction (control 3) or to a passivo increrse in flow through the forearm shin following relerse of tono deep in the arterial tree (control 4) It must be due to the release of sympathetic i asoconstrictor tone in the blood vessels in the sheletal muscles REFI RLICIS Ibram DI Lazeela Handl Marrus J (1939) Imer llcar J 17 206 Anrep GY Blaloch Anu Samaan 1 (1031) Proc roy S CD 114 293 Baetjer AVI (1930) Imer J Phy:10l 93 41 Barcroft and I clim () ( (1943) J Ihysiol 102, Barcroft H Bonnar Vieh Felholm () Ganil I ffron IS (1)13) J Phys. 102 21 Bernard C (1876) Leçons sur la chaleur animale Paris Bullere 13 nnar 11 Vch (1941) VD Thesis Queen Univer its Belfast Bulbring and Bum JH (193) Jihyol 83 83 (113) J Physiol 88 311 Burn J JE (1932) J I hatol 75 144 Finch II (1944) Surs ry of xlern lirf tre 3ndlu II I finburgh Iivingstone (uding I (1932) J I hol 74 34 rant RT (1938) Clin cu 3 1,7 (rant RT And Holling I } (1938) Clin Sci 3 ? 3 I rizinetaly anit son C (1036) Join Intest 15 (3 Trotter 11 ani Davey 1 11 (2009) Jin 1 38 131 Woollani II H And Phill R (193) 1 Inat Loul 67 18 p1 ·CHAPTER 2 SYMPATHETIC I ASODILATOR XFRIES TO SAFI ETAI MUSCI E The discovery of simpathetic vasodilator fibres to human muscle vessels was made accidentally during the war at the British Postgraduate Medical School (Barcroft Edholm VcVichael Sharpey Schifer 1944) During an experiment on haemorrhage one of the subjects (a Friends Ambulance Unit volunteer) fainted and the tracing of the forcarm blood flow shown in Fig 21 was recorded The faint began soon after the twentieth minute and was fully der eloped by the twenty fifth The increase in the forenrm blood flow during the faint was unexpected for Lewis (1932) and Wallace and Sharpey Schafer (1941) had shown tha the arterial blood pressure falls precipitously The increase must therefore have been due to decreased vascular tone The circulatory changes in 9 faints are shown in Fig 22 and the averaged blood flow results in Fig 23 (top left) They leave no doubt of the increase in fore arm blood flow or of the decrease in the tone of the forearm vessels Whereabouts in the forearm was the decrease in tone It was unlikely to be in the skin--the face went deadly pale-or in the relatively nascular bones and was probably in the muscles which make up the bulk of the forearm tissue (Abram son and Ferns 1940) This was confirmed by the observation r10 171 20 29 sec Fig.1 Pl thy Amogr phir tre ings of t} forcarm blood iw recorded by Dr OC Flholm 1 ig tlefrt exper m nt on pithaemorrhag efnt ing Tu er aoin du ng the faint Fount ng began in fter th Othmwuto and was hlly do elopel at the oth m nute th til of th erre iment Aro shown in kg 1 No 1 (Ba oft and E lholm 194 )

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·Sympathetic ia sodilator neries to skeletal muscle that during the faint the blood flou through the hand wach contuns only a small amount of muscle decreased (Fig 23 top right) (Barcroft and Edholm 3945) It * 79 non necessary to find out if possible the cause of the Isodsattson as it nervous or hormonal It might harc been due to the vasomotor centre (Chapter I) or to the action of adrenaline for Cunt and Pearson (1938) bad shown that small doses of adrenaline cansed tsodilatation in humin muscle This could be decided by experiments on sympithecto mized subjects If the 17sochlatation did not occur during the fant in sympathectomuzed subjects it would be because the Visomotor centre could not dire the mnscle vessels If 20 sid occur it would be due to the action of a hormone The results of the crperiments on the sympathectomized subjects are shown in Fig 23 (bottom left) During the faint forearm blood flow decreased the increase recorded in the forearms of normal subjects must have been due to the action of the vasomotor centre Was the increased rate of blood flow due to release of tone in the muscle vessels or to the excitation of actne rasochilata tion as well! This might be settled by comparing the blood Bow in normal and recently sympathectomized forearms during the faint If it was greater in the normal one there must be active vasodilatation as well us release of constrictor tone It would not be possible to use for thts comparison the results obtained on the sympathectomized patients Osing to the return of tone in the first few weeks after operation (see Chap ter 7) the blood flou in their limbs would be far less than that in freshly simpathectomized ones Normal forearm would have to be used in which the pathway from the 180 motor centre to the ressels was cutely interrupted by neri e blochs (see Chapter 1) Fig 23 (bottom right) shows the results obtained in subjects Expe m nts ahon ng that wasrullatat æ takes place m the forearm turung nducet P me rhag < fasting Whate efnpl i en 18 to 1 about th ghet iran ahol 77X) ni tlne I in the 1 beta til 30 Paz tg10g ren ne tun B keisesti ali na fantly diel ? tte olt! el pre Lonec se o'13 oth 5 nnal farrarm mt 1119m! ren nu T me in mnt (H! ſtan! F thoien 194 ) sim HL ·NORMAL FOREARM NORMAL HAND (9) (6) ml/100 m LIMB/min ml/100 ml LIMB/ min SYMPATHECTOMIZED FOREARM NERVE BLOCK FOREARM (6) (6) 50 0 50 Minutes lig - 3 Results showing that the a4 x latation in th forcarm during induce I posthaemorrhagic fainting 19 meiliate l by the sympathetic innersation of the skeletal muscl es els Brohen vert cal line faint fully develope Top left Increas in hloo l flow in the n mmal rearm during fainting A prag resilts of experim nts slown in FiR Top r gli Deerearo in fion in the han I during faunting The increase in flw in the forear (tıp left) teref ro probably in the skel tal mu elu Bitom | Decrease in sy in the sym; atl ectomized for urin duru fainting The in rease in flow in the normal forearm (top I ft) mu t be 110 to thoa ti n of the sympathetic innersation of the skel til mu | Mottom right Decrease in Hood flow in the forearm Tirr g fanting aſtr acute i neration of the muscle by herse block T1 resulta shown this figure were Unt to deri te wheth the in reame in Ayin normal for are 14 en merely t the relei of sympath to AM pritrt ne or it allation tacne vare i latation exifeslls sympatheti in Itlat * For further letails are 11%. + Iverageul results Sumber of utjecte intrachets (Har ft at } ih im 1940) ·Sympathetic ensodilator neries to sheletal nusele 13 funted after deep nerve blocks There was a large resting blood flow due to the release of vasoconstrictor tone During the faint the flow decreased passively with the fall in arterial blood pressure The results obtuned on the normal forearms (Fig 23 top left) and in the forearms after deep nerve blocks NORMAL FOREARM a- DEEP NERVES BLOCKED 10 ml /oo ml/min BLOOD FLOW 25 SO Minutes Fg 4 Pesults showing that the blo le 1 in hu nan mus le ao Alpp) d with sympath te vas dilator fbre In th 4 figure the re ult, seen in Fig - 3 (top 1 ft an 1 1 ottom rigłt) la o hen ure mpad When th fa nt was fully des lope 1 (brok n vert call ne) t blood flow in the pormal fu earm wag con d rably the greater Thi pri ! ably explan lly act ve sasod latat on in the normal torearm ex ted by sympa thet tod lator fib (Fig 23 bottom right) are shown superimposed in Fig 24 When the funt was fully dereloped the blood flow in the normal forevms was considerably greater than that in the nerve blocked forearms This must have been due to active viso dilatation mediated by sympathetic vasodılator nerve fibres

·14
Sympathetic zasodilator neries to skeletal muscle
]
RFFIRI VOI
Abramson DI and Herrt B (1910) 4mer Heart J 19 5+1
Barcroft H Bonnar 11 Vick I dholm 0 ( and 1 ffron AS
(1943) J Physiol 102 21
Barcroft H and Edholm 0 ( (1945) J I hysiol 104 101
Barcroft H 1 dl olm
( Melichael J and Sharpey Schafer
LP
(1944) Lancet 1 489
Tbert R1 and Stend EA (1940) J Clin Inzest 19 561
Grant RT and Pearson RS B
(1938) Clin Sci 3 119
Lewis T (1932) Brit med J 1 873
1l Allace J and Sharper Schafer IP (1941) Iancet 2 393

·CHAPTER 3
THE ACTION OF ADRENALINF ON THE
CIRCULATIO IN SE FLETAL VIUSCLF
In the previous chapters we were concerned with the action
of sympathetic neries on the circulation in the skeletal muscles
It is convenient to turn non to the changes caused in the muscle
vessels by the action of adrenaline
The first relevant observations in man were made by Grant
and Pearson in 1938 They found as shown in Fig 31 that
the intravenous injection of small doses of adrenaline caused a
great increase in the calf blood flow as metsured with the
plethysmograph However in a later paper not directly con
cerned with the subject Holling (1939) pointed out that if
adrenaline is given as a continuous infusion the dilatation is
not maintained
MI
6
CALF BLOOD FLOW
(ml/100 ml/min)
49
33 35
39 41
43 45 47
Minutes
Fg 31 pl thy mo graph c results ołtan 1 'y Gant an! Pearson
showing od letat on in the all following each of four au # Te intravenoun
nje tons of 1 ug of a lrenal ne
Sunce adrenalin always cat seul vasocont tion in the ska thy on
lu led that t mu t hase & va oil lator a tion on the floo 11eeel nth calf
mu 19 (Crant an! Parson 1939)

·INTRAVENOUS ADRENALINE 10 ug/min BLOOD PRESSURE 25 mm Hg 100 75: 80 HEART RATE 70 Beats/min 10H 50 - FOREARM BLOOD FLOW ml/100 ml/min 0 20 30 50 Minutes Fig 3. Results showing that matrasonous a lrenal no a large transient followed Iva Amell rou tel u latit ositt? f natin The transi nt 34 litatation is dit al mrt act nofa in nal ne on skeletal muscle sen! TI tain valur te dire tal if we in eth rhum ral mut taice Average results of experiment on 6 mujort (11 7 Pirrit Im 1916 ) ·Action of adrenaline on skeletal muscle tessels 17 Allen Burcroft and Edholm (1946) investigated the problem in some detail also using the plethysmograph They confirmed Kolling s finding observing a large transient dilatation in the forearm duning intravenous mfusions This did not last longer than 2 min after which the flon subsided to about double its initial value Fig 32 18 tahen from their piper It wil be convenient non to follok first the inte tigations on the cause of the transient sasodilatation and then to pass on to those on the subsequent sustainer! Tasodilatation THE TRANSIENT I ASODILATATION The problem whih mterested Allen et al concerned the nature of the initial transient dilatation It was not due to emotional changes for it did not occur m experiments in which the subjects thought they were recen ing adrenaline when in fact they were not Also sery small closes of adrenaline Fig 33 Photograph of the infu n apparatus made by PT Machell n the Radot) er jy Work lop St Thomas & Hosp tal By alternate me of tt Ting & co itin 20H Infus on of salme 4 kept up through an expe in nt at alatt 4 ml mnt AN IA yt nga in ne Iris emptv the a lapt ir on t1 t fang la ng to ir reelle is pulled off the zzle and perheel on the so fe of the otte The P99 13. mSA 19 then rensed reflied and replaced Arenal re allait to ty sal 8 and wh n reqused (Duft J Phy ol)

·18 Achon of adrenaline on skeletal muscle tessels
insufficient to cause symptoms frequently caused the transient
dilatation without the subjects knowledge
The sılıne containing the adrenaline could not have caused
it for it was infused at a constant rate during the whole of every
INTRAVENOUS
ADRENALINE
\Bug/min
10
SYMPATHECTOMIZED
FOREARM
FOREARM BLOOD FLOW
(ml/100 ml/min)
man
Minutes
Fig 14 Result showing that intravenous a lrenalınc cau ca a transi nt
va olslutat n in the sympathectomized forearm
The tasollalat on is not materi ty tha ympathetic supply to t1
skeletal mu cle resacl (Allen Barcroft and film 1040 )
Fig 33
experiment the adrenalıne way merely added to it
shows an infusion apparatus
The effect could not be a passise one due to increase in
arterial blood pressure
Careful cramination of the records
showed that the transient increase in flow often coinculed with
a transient fall in the blood preseure I or a simple increase in
pressure to cause the increase in flow the mean arterial preugure
would have to esceed 100 mm Hg

·This sug To put Action of adrenaline on skeletal muscle tessels 19 Fig 3 2 shows that there was a transient change in the heart rate rather like that in the blood flow Atropine was given to paralyse the vagal nerve endings adrenaline was then infused intravenously as before The transient heart rate change was abolished but the transient pasodilatation persisted They were not cause and effect Could at have been due to activity of the vasomotor centre This seemed unlikely for if the forearm and calf blood flows were measured simultaneously the transient vasodilatation appeared in the forearm before it did in the calf gested that the dilatations were due to the local action of adrenaline reaching the forearm first and the calf later the matter to a more direct test intravenous infusions of adrenaline were given to subjects who had undergone sympa thectomy Fig 3 4 shows a typical result It was clearly not dependent upon the presence of the vasomotor nerves Finally Allen et al showed that intra arterial adrenaline caused the transient vasodilatation (Fig 35) It must have been due to the direct action of adrenaline on the vessels of the limb The whereabouts of the transient vasodilatation was then considered Since at the beginning of the infusion the shin alwaye paled it was probably in the muscles To test this observations were made on the circulation in the hand which contains relatively much less muscle and relatively much more skin than the forearm (Abramson and Ferrie 1940) If the transient dilatation was in the muscles then it would be less conspicuous in the hand than in the forearm If it was in the skin it would be more conspicuous in the hand The results showed that it was much less evident in the hand so the dilata tion in the forearm wis in the muscle vessels The possibility that it was due to opening of the vessels in the muscles followed almost immediately by closing of those in the skin was considered and had to be rejected for the follow ing reason Before the beginning of the infusion the cutaneous blood flow could not exceed the total forearm blood flow 1e about 3 ml/min (Fig 32) Closing the cutaneous vessels could not reduce the flow by more than that amount Yet the decrease in flow immediately after the peak of the initial transient Fasodilatation exceeded it and amounted to ml/min (Fig 32) Therefore both the initial dilatation

·20 Achon of adrenaline on skeletal muscle i essels
and the subsequent abrupt decrease took place in the same
vascular bed ie that in the muscles
There is a certain amount of information relevant to tho
whereabouts of the vasodılatation in the muscle vessels Dile
INTRA-ARTERIAL
ADRENALINE
3ug /min
150
mog
ARTERIAL BP
HEART RATE
of 아
CALF BLOOD FLOW
(mi/100 ml/min)
15
Minutes
og 3 Ryult showing that an intra arter al infu un of a lrenalinn
cau49 & tran nt sa natation the cuf
The vasollatation is due to & Birect local att of the a in nalne in the
shel tal muscle tool sess] (Allen Barcroft & Ilm 1.4)
and Richards (1918) concluded from the analogy of their find
inge with acetylcholine and histamine that adrenaline citised
dilntation of capillaries but a constriction of arterioles
Hartmın Fians and Walker (1928) confirmed this

·chon of adrenaline on keletal muscle tessels 21 An explanation of the transient resodilatation in man on the basis of capillary vasochlatation followed by arteriolar con strictions presents some difficulty For erample Fig 32 shows that at the beginning of the drenaline infusion the blood flow increused fourfold That is to say the resistance in the muscle circulation must have decreased to 1 quarter of its resting amount If this was due to capillary vasodilatation then before the infusion at least three quarters of the total resistance ADRENALINE 1-8 ug/min S ایران ادامه 85 98 105 Minutes mg 36 Results showing the effct on the calf blood Bow af stepwise $1 tage I the intra arte 1infunon of atirenal ne fora ? to 8 ug mn T20 t las diletetott oc urrect whenes er the rate of afu n in reave? During th most rap d afunon afttrans tesor Intation there was &$c 9 Ktson must have been in the capilartes and must hare been abolished by the arrival of the adrenalme It is conceix able that this may be so but it has never been demonstrated and seems unlikely Bloreover the explanation of the effect of adrenaline must account for the fact that during a contiudus infusion successive increases in its rite truse successi e transient rasochlatations as shown in Fig 3 6 (Allen 1946 Stead 1990 Swan 1951) and for the fact that during intravenous infusions at rates ranging ·22 Action of adrenaline on skeletal muscle tessels fiom the minimum to be effectiic (11g, min ) to tho maximum that can be tolerated without discomfort (20-30 Mo /min ) both dilator and constrictor phases of the transient dilatation are present the two cannot be dissociated as one would supposc might happen if the adrenaline hrd independent actions on two distinct parts of the vascular bed According to Zweifach (1949) the anatomical arrangement of the vessels in sheletal muscles is more compler than is com monly supposed He describes arterio venous anastomoses thoroughfare channels precipill iry sphincters and true capil laries If this is confirmed the interpretation of the transient vasodilatation becomes more difficult It may be that when adrenaline reiches the periphery it causes the momentary liberation of a vasodilator substanco from the arterioles which 19 swept on ind tause, trinsent dilatation of the precapillary sphincters Or it may bo that it has a durl action on the arterioles--first dilatation and then constriction Many substances have a paradoxical action-- that of nicotine on the ganglia is a good example--concevably while adrenaline begins to pass across the membrane of the smooth muscle cell normal function is temporarily inhibited and vasodilntation occurs and when equilibrium is reached the vessels return to a state of tonus governed by other factors rither of the mechanisms if they existed could explain why successive transient vasodilatations occur in response to succes 811e increases in the rate of a continuous infusion The fundamental cause of the transient vasodilator action of adrenaline is complex in the extreme and more precise state ments on the causation are not at present possible THE SUSTIIVED VASODILATATION At the beginning of this chapter it was shown that intra venous infusion of adrenaline caused a transient vasodilatation in the forearm followed by a smaller sustained one (Fig 32) This was confirmed by Duff and Swan (19,1 Table III) Similar sustained vasodilatation follow 9 transient vasodinta tion in the calf (Duff and Swan 191 lig 37) The aus tained vasodilatation 19 of singular interest as it probnbly represents tho repon. c of human inuscle blood sexuels to the natural phı siological secretion of the suprarenal glands ·1ction of adrenaline on skeletal muscle vessels 23 TABLE III Changes in furiarm Word flou in normal and in sympal ectm el limbs during intravenous infusions of adrenaline and en normal limbs during intra arterial infusions of adrenaline Blood flow in ml/min/100 ml t198ue (Duff anl Suan 19.1) Blood & Blood pressure B-% No (y ) B-A 4 Norm 1 3 +33 7 8 Age Se B A B Condit on D (Norm I forearm atrapet us adrenalin 10 48 /min 1 18 MI 34 56 + 2 +65 128,80 160/65 Normal 19 DI 3 4 64 +30 +88 116 85 140/80 Norrt 1 3 18 M 34 77 +43 +1 7 135 80 165/65 Nrra! 19 DI 46 + 6 +130 135/80 155/70 5 19 +08 135/80 150/7 Normal 6 19 17 39 + 2 2 + 130 Norm 1 19 M 54 +19 +5+ 134,80 160 6 Nor 1 33 M 19 47 + S +167 Ν ΓΙτι , J 33 M 18 42 +24 + 133 Nrmal Ay 6 51 +24 +101 (b) Symp th tomed forearm int nous adr abn 10 vg/mu BE 31 39 +08 +26 12 /76 140/78 Hype hd oels BI 40 35 -0-5 -13 130/74 156/00 Causalga 7 M 46 55 +09 +19 Hyperhidros 6 44 +18 +89 148/74 Raynaud disease 4 M 69 2 -07 1 110'68 140/64 Causalg 4 29 M 67 59 -08 Causalg F 5 +19 +76 112/70 140/89 Raynaud dware 18 AY 42 47 + 0-5 +2 / (Normel forearme ntra arterial adrenalin tugman. 1 22 M 30 +01 +3 Norvet 29 M 87 38 - 49 -56 Norm 1 3 21 M 19 17 Normal 4 21 M 60 63 +0-3 +5 Nr 1 20 M 60 70 +10 +17 Norm 1 6 20 M 53 60 +07 +13 Norm 1 Av 5 47 -05 A=m nduri gtb 4 m pno to th start fth sdren line B=mean d ring the last 4 min. of th adre aline i fusio D=durat n of ymp thectomy in months 118/9 -10 The explanation of the sustained vasodilatation is still unl nown The search for it has been narrowed down by Duff and Swan (1951) and by Whelan (1952) Arterial hypertension accompanying the intravenous adrena line does not seem to be responsible Mean pressure is raised by only 10 mm Hg whereas the blood flow in the forearm 15 doubled In individual experiments the changes in pressure and flow often seem to be quite unrelated The sustained vasodilatation does not appear to be due to a direct action of adrenaline on the muscle blood vessels Duff and Swan found that during intra arterial infu ions of small ·24 Action of adrenaline on skeletal muscle tessels amounts of adrenaline the blood flow in the calf and forearm after the initial transient sasodilatation returns to tho initial level (calf 1 ng/min foreirm gmin see Fig 37 and Table III) A larger amount (2/g/min) caused constriction in the calf ADRENALINE Normal .v (12) - Normal IA (6) Sympath iv (6) 300 CALF BLOOD FLOWS Percentage of average 200 100 0 30 10 20 Minutes Fig 37 Result of experiments on th sui tains 1 latat on Duer! cause! Iy intravene us a Irenaline Clon ou lone Intras enous a Irenal ne uues trans nt an 1 ku ta i aulilatations in the calf (10 48 /min) Dont tous lte Intre artcrul adni nalme catree transtva oil 1 ta ton onls The u ta ned vasohil tation cannt be lu to the direct local action of a Irenalino on the skel tal mu cle sparels (1 HRmin) Dolled Intr venons Adrenaline cause trin it asox latatı n only in chronicallt sympatheet mizel limbs (10 ug/mi) In acutels sympathertom z vl ones lower the mi ta x sax I lntation 14 pruunt (Hug 3) Åscagni mwults of exp r nett inlxr of ut tm A ket (DIT ani Swan 1931) ·Action of adrenaline on sheletal muscle ressels 25 Whelan thought that the failure to find any direct vaso dilator action might have been because the rates of adrenaline infusion were too great For the intra brachial infusions Swan and Duff had used a rate of ug/min Whelan thought that the amount of adrenaline entering the forearm during an intravenous infusion at 10 ug/min would be about to pg/min and might be very much less if adrenaline left the circulation or was destroyed on its way round He therefore investigated the effect of intra brachial infusions ranging from io to stao ug /min In all these after the initial transient vaso dilatation the flow was unchanged or very slightly increased There was no sustained vasodilatation in any way comparable to that during 10 ug /min intravenous infusions Both Swan and Duff and Whelan are agreed that the sustained vaso dilatation cannot be due to a direct local action of the adrena line (11 helan s estimate that not more than it ug adr /min would enter the forearm during a 10 ug /min intravenous infusion was made as follows forearm volume 1000 ml resting blood flow 5 ml /100 ml forearm/min Therefore for whole forearm 50 ml /min cardiac output 5 ltres There fore fraction reaching forearm is tão fraction of 10 ug is to ng ) Swan and Duff thought that the sustained vasodilatation was mediated by the empathetic because it was unobt unable in chronically sympathectomized limbs (Fig 3 7 and Table III) However Whelan observed it in the nerve blocked forearm His results are shown in Figs 38 and 39 Returning to the sympathectomized limb he showed that the sustained vaso dilatation was present a few hours after operation but that it grew less as hours passed between operation and the time of testing (changes in other vascular responses following sympa thectomy are described in Chapter 7) This explained why Duff and Swan had not been able to find it The results of Whelan s experiments on one of his three sympathectomized subjects are shown in Figs 3 10 It appears then that the sustained vasodilatation is definitely not mediated by the sympathetic The only other explanation left for it is that it is due to the direct action on the muscle blood vessels of some humorul sub stance other than adrenaline This substance might be formed SUHBV B ·26 Action of adrenaline on skeletal muscle ressels from adrenaline itself during its passage from the venous to the arterial side or it might be released by adrenaline in some other part of the body Staub (1946) found that intravenous infusion of adrenaline released histamine but Mongar and Whelan (1952) have not been able to confirm this The sus INTRAVENOUS ADRENALINE 10 ug/min 18- 16 DEEP NERVES BLOCKED 14! FOREARM BLOOD FLOW (ml/100 ml/min) NORMAL TO 25 20 Minutes Fig 38 Re ults ot exper ments on the busta nod vasodilatat on in mulo caused by intravenous adrenaline Owing to the releaso of sa oconstrictor tone resting blood flow in the nere I locked forearm is about doubled Apart from the difference in the g nemal Jovela tho behaviour of the blood flows during the alrenalino infu in Toke! very much alike 1 or better compariwon the bloo 1 flows have been graph ! in t 8 3 9 after subtraction of the respective resting raten Average mult of 10 in UK A on fi pul je to I lethy mg ni wat temperature 3+ 3 C (Whelan 19 ) tained vasodilatation is not likely to bo duc to the rolenso of Iustamine At present the nature of thun substance remains unknown Before leaving the subject of adrenalino and tho blood flow in human muscles mention must be made of a curious napon which I helan (192) described and which 19 ween when the simpathetic supply is bloche or sovered After stopping an ·Achon of adrenaline on sheleltl muscle 1e8eele 27 intravenous adrenalinc infusion the blood flow instead of gradually subsiding to the resting level subsides for a short time and then shows a well marhel secondary increase Thug 19 seen in the nerve blocked forearm in Figs 38 and 39 in the acutely sympathectomized forearm in Fig 3 10 though not 7 hours after operation in this subject and in the clironi cally sympathectomized calf in Fig 37 It was recorded in a forearm which had been completels denervated by avulsion INTRAVENOUS ADRENALINE Opg/min BLOOD FLOW ABOVE RESTING LEVEL mi/100 ml/mn) 10 15 20 Mntps Fig 39 I xperim nt n thru tain A* 1 lataton n mill caused by introvenou Alrenaln Re uits , en in Fg 38 graphed after pul t act or of tho re pectyc re ting bl flow Tran ent par dilatat on was followel by su ta nel va ol latat on in b th normal an i nerve blocked forearms The sustain vaso blatat on cannot be med ated y the sympathetic nne surply to the sk I tal mus le seguels (Wh lan 19 ) of the brachial plexis (Whelan 19,2) Its significance 19 not et known Finally it 13 of interest to compare the action of adrenaline on human muscle vessels with its action on those of the cat In the animal muscle blood flow can be recorded by more direct and satisfying methods In studies of muscle bloost flow in the intact cat however adrenaline has usually been given by intravenous injection The obeered blood flow changes huve therefore been limited to those which correspond in time to the transient vasodilatation in man

·INTRAVENOUS
ADRENALINE
54g/MIN
30
20
FOREARM BLOOD FLOW
(Ml/100M/MIN)
10
0
15
25
MINUTES
Fig 3 10 xperiments on to sustained varodilatation cattered l ytra
icno i adrenal ne
Results showing the elf et festmavenous a Irenaline on the forenrin I loou
flow : lays bef re (lots) en 1 7 hours (triangi) 9+ r (errel) an 1 4 days
(crowne) After sympat) e tomy
Trang ent and eastatel an dilatation am cone CUOI IN the acut ly
Aymputerta miza lim (triangles)
The mil ta nel 1axxlilatatin ann t be melatert is the sympathetc
nero supply to the muscle sexeet
After symp stectomy na uma pax thea tainel sasa lutation Iwan ili
It is nint en cronk ally sympati ectomized I mbx (118 37) (151 lan JOS)

·Action of adrenaline on skeletal muscle tessels 29 In this respect there is good agreement between the findings in the two species Hoskins Gunning and Berry (1910) and Gruber (1929) found that small intravenous doses of adrenaline caused active vasodilatation in feline muscle and Clark (1933) and Follow Frost and Uvnas (1948) showed by intra arterial injection that this was by virtue of its direct action on the muscle 1 essels REFERENCES Abrangon D I and Ferris E B (1940) dmer Heart J 19 541 Allen J (1946) MD Thesis Queens University Belfast Allen WJ Barcroft Hand Edholm OG (1946) J Physiol 105 255 Clark ("A (1933) J Physın 80 429 Dale H H and Richards AN (1918) J Physiol 52 110 Duff RS and Swan HJC (1951) J Physiol 114 41 Folkow B Frost J and Uvna B (1918) Acta physol Scand 15 412 Grant R T and Pearson RS B (1938) Clin Sci 3 119 Gruber CM (1929) Amer J Ph294 89 650 Hartman FA Faris J I and Walher HG (1928) Amer J Physiol 85 91 Holling LE (1939) Clin Sci 4 103 Hoskins R G Gunning REI and Berry EL (1916) Amer J Physiol 41 513 Mongar J L and Whelan RF (190-) J Physiol Staub H (1946) Schuer med Wachr 76 818 Stead E A (1950) Personal communcation Swan H J C (1951) Unpublished observations Whelan RF (195) J Phyrol Zweifach B (1949) Factors Pegulating Blod Pressure Josiah Macy Foundation Caldwell NJ Progre 8 Associates In the press In the press e ·CHAPTER 4 THL ACTION OF MORADRENALINE ON THE CIRCULATION IN SKELETAL MUSCLL The sus In 1910 Burger and Dale observed that the substanco we now call noradrenaline caused responses more like those of sympathetic nerve stimulation than did adrenaline gestion by Bacq (1934) that noradrenaline might in fact be the mediator of excitatory sympathetic nerve impulses was not finally accepted until 1946 when von Euler identified it in extracts of organs and neri es His discovery was the starting point of numerous investigations on its action in different organs In this chapter we shall be concerned with its effect on the circulation in human muscle which as we shall seo differs from that of adrenaline The first observations in man on the effect of noradrenalino on the blood flow in muscle were communicated to the Annual Meeting of the American Physiological Society at Detroit in 1949 by Duncinson Stewart and Tdholm An abstract of their paper appeared in the Federation Proceedinys of the anmo yeir They found that intravenous infusions clused a slight decrense in forearm blood flow Their finding was later con firmed both in the forearm and calf (Swan 1919 Barcroft and honzett 19491 h de Largy Greenfield Melorry and Whelan 190) Barnett Blacket Depoorter Sanderson and 11 ilson 1910) Fig 4 1 18 from the paper by the last nimed authors Although Burcroft and honzett did not obscrvo any initial transient vasodilatation during intravenous infusions at 10 mg 'min a small one often occurs at the beginning of 20/8 min infusions after which the blood flow in the forcarm returns to about the resting rte (11 helin and Houng 19:-) Oning to the presence of both skin and muscle in the plethos mograph and to the fact that noradrenaline constricts cutaneous vessels as 19 evidenced by pallor of the shin it is difficult to tell with assurance from the experiments just described whether on the si erage it caused any change in the calibre of the musclo Icecela 30 ·Action of noradrenaline on skeletal muscle tessels 31 Barcroft and honzett (1949) and Swan (1951) investigated the direct action of noradrenaline on the circulation in the calf Fig 42 shows at the top the results of short intra arterial infusions In all cases L noradrenaline caused a simple decrease in the calf blood flow in some the flow was reduced by 75 per cent Since skin forms only a small proportion of INTRAVENOUS NORADRENALINE 20ugim BLOOD PRESSURE 130 DO 100 50 HEART RATE 190 8 t/m 70 FOREARM BLOOD FLOW SO mt/100 ml/m - 20 JO 40 IO M tes Ig 41 Results show ng the a ton of an intravenous infus on of nor adrenali on the for arm blood flow (Barnett Blacket Depoo ter Sande & n and Waleon 1350) the calf they thought it reasonable to conclude that it must have had a direct constrictor action on the muscle vessels He must non briefly compare the actions of adrenaline and noradrenaline The most striking difference is the absence of the transient vasodilatation in the calf during intra arterial infusions of noradrenaline Fig 42 shows clearly that the transient v zsodilatation only occurs with adrenaline Barcroft ·32 Achon of noradrenaline on skeletal muscle ressels and Konzett (1949b) found that the transiont vasodilatation also occurred with isopropyl noradrenaline which has two methyl groups It is of some interest too to compare the actions of the two substances from the point of view of deciding which of NORADRENALINE 25 ADRENALINE CALF BLOOD FLOW (ml/100 ml call/min) W Fig + Kesulta honing the action of intra arter al norn Irenaline on the circulation in human mus le Absence of th transient sasodilatation during intra arterial nora Irenaline Snce the skin forma only a small proportion of the calf and nora Irenaline mluced the call blood flow by as murh as 75 per cent it is nauonal in to supporo that it had a direct vasoconstrictor action on th muscle I londela The figure un ler th top margin of each d agram is the rate of infu son int the femoral artery in g/min Air filled plethy mograph (Harcmft an honzett 1949) them 19 likely to be the transmitter at the sympathetic sayo constrictor Derve endings The following points are reles ant i Noradrenaline causes simple i asoconstriction This action 19 manifest during intrafemoral arterial infusion, at ny low a rite 05 ng per minute (Swan 19) ·Achon of noradrenaline on sheletal muscle zessels 33 2 The local action of adrenaline depends upon the rate of Infusion In tho calf rates of 1 16 per minuto cluse transient vasodilatation with 1 return of the blood flow to approximately the initial level Only when the adrenaline enters the femoral artery at a greater mte does constriction tahe place (see Chapter 3 Table III) On the by no means certain supposition that the effects of intra arterial infusions are compirable with those of continuous liberation at nerve endings we can speculate on the probable transmitter substance If it were adrenaline a vasodilatation would have to precede any vasoconstriction also considerable amounts of adrenaline would have to be liberated to cause vaso constriction This would not seem to be the most economical way to cause constriction In contrast noradrenaline in very small doses causes constriction without iny vasodilatation and at appears very much more likely that this substance is the meditor of the sympathetic nerve impulses to the muscle vessels Now let us consider the effect of a circulating mediator in distinction to that liber ited at the nerve endings It is un likely that in natural conditions the circulation would contain only drenaline or only noradrenaline a mixture of very small amounts of both would be expected The question of which of them in a mixture will have the predominant action was one which interested de Largy Greenfield McCorry and Whelan (1950) They recorded the blood flow in six subjects during intravenous infusions of mixtures at the rate of 8-10 g per minute lasting for 5 minutes Fig 43 shows the averaged results Beginning at the top on the left the noradrenaline contents of the mixtures in the six groups of experiments were 18 33 53 75 89 and 100 per cent The figure shows that the effect of adrenaline predominated in mixtures containing as much as 75 per cent noradrenaline This indicates that it is likely that noradrenaline predominates overwhelmingly at the nerve ending In conclusion there appears to be a difference in the action of intravenous noradrenaline in man and the cat We have seen that in man intravenous infusions usually cause vaso constriction in the forearm and calf (Fig 41) however intra Venous injections cause vasodilatation in the cat s leg The SCIE ·34 Action of noradrenalıne on skeletal muscle cessels observations on the cat were carefully made by Meier (ross and Eichenberger (1949) and by Cobbold and 154 (192) Cobbold and lass haic shown that this vasodilatation is in the vessels supplying leg muscles and that it is only transient for in intravenous infusions it soon gives place to sustuned constriction The initial vasodilatation appears to be duc to the A85 NIS O A 64 N 31 43 N 47 AO9 N73 CALF BLOOD FLOW (ml/100 ml/min) NBO on IS +3 Pesults showing the eff on the calf bloul An of intraven infu ons of adrenal e noradrenalina mixture containing 18 33 37 7 89 and 100 per cent n adrenal ne re pretirely The tran sent aux tator act on if a lrenaline wa proportion of nora Irenaline wa en pou till the mre than u per cent Averignul result of BIT exprime it mit infu von Black re fang! adrenaline Hat hn re tangle mora Irenaline McCorry anWh lan 19 0 ) (le Largy (reill abrupt rise in blood pressure and the subsequent constriction to the more gradual de clopment of the constrictor action of nordrenaline on the muscle vessels I he prevention of the rre in blood pressure by a compensator abolishes the initial sasoclılatation and only the subscquent constriction n soen In the cat as in man in all effective intra arterial doxes It lias a direct vasoconstrictor action upon the muscle ren ek (Cross 1919 Follow Frost and Uynas 1948)

·Achon of noradrenaline on skeletal muscle ressels
3
RI TIPICIS
Baca LM (1931) Ann Ihysiol Il yaic 11 brol 10 467
Barcroft Hand honzett H (19491) Hell phyeu hermacol
Acta 7 C+
(1949b) J_Physicl 110 194
Birger G and Dale HI H (1910) J Physiol 41 19
Birnett AJ Blacket RB Deporter A E Sanderern PH
and Wilson GM (1970) Clin Sci 9 151
Cobbold AF and 1894 CCV (1952) Plyszol
In the presa
Duncangon D Stewart Tan 1 Edlıolm O G (1949) Fell I ror
8 37
Fuler US von (1946) Actu physırl 8 and 12 73
Follow B Erot J and Uinis B (1948) leta pkystol send
15 419
Gross F (1949) Hell physiol pharmacol Acta 7 C 43
Larsy (de Greenfiel ADM McCorry R L And Whelan RF
(1350) Clin Set 9 71
Aleier RGP F and richenberger I (1919)
Hell phys: 1
pharmar l Acta 7230
Sw án H ) ( (1049) Lan et 2 08
(1951) Unpubli hel ob ervations
Whelan RJ and Young I V (1952) Brit J Ilarmac/ in
the press

·CHAPER 5 THE CIRCULATION IN SKELETAI MUSCI E DURING EXERCISE It is generally believed that sympathetic neries and hormones perform important functions during stress Their action upon the circulation in actise muscle is therefore of special interest But before discussing this it will be convenient to describe some experiments on the effect of exercise on muscle blood flow These cın be divided into two groups--those on the effect of sustained and those on the effect of rhythmic contraction SUSTAINED CO TRACTION In 1877(a b) Gaskell established by experiments on the dog and frog that the two most important vascular changes taking place in skeletal muscle during sustained contraction are vaso dilatation and opposed to this mechanical compression Later the relative importance of the vasodilatation and of the com pression became the subject of an interesting rontrou ersy between Anrep s and Reins laboratories In man the existence of these factors had been recognized (Lindhard 1920a b) but there was some difference of opinion as to their significance Dolgin and Lehmann (1930) compared the times for which graded strengths of hand grip could be maintained sath and wsthout previous circulatory arrest in the upper arm The duration of the weak grips was sliortened by the arrest but that of the strong ones was not affected They concluded that in strong gripe the circulation had been arrested in the muscles Handell Henderson and his nguey (1936) studied the effect of contraction of the calf muscles on the intramuscular pressure as recorded by a necdle and water manometer As strong contractions only caused a very small rise in intramusculur pressure they concluded that there could not be much resistance to the blood flow Grant (1938) 140d the plethysmograph to record the changes in forearm blood flow during strong hand grips He found a slight rise in flow durino the contraction and a largo one immediately after He con 36 ·Circulation in skeletal muscle during exercise 37 cluded that vasodilatation occurred during sustained contrac tion but was restricted Barcroft and Alllen (1939) also studied the behaviour of the blood flow during sustained contraction The principle of their method was as follows Bluscle temperature was recorded thermoelectrically By immersing a limb in hot or cold water for an hour or more a constant difference in temperature could be achieved between a muscle and the blood entering it (at approximately body temperature) Sustained contraction was then performed Hyperaemia could be inferred if hot muscle cooled and if cold muscle became warmer and if these tem perature changes were abolished by previous circulatory arrest The muscles used were those in the calf of the leg Details of the self retaining thermojunction and of its insertion into the calf muscles will be found in the original paper Four different strengths of contraction were studied namely 0 05 01 02 and 0 3 maximal (According to lleber (1816) koster (1868) Hermann (1898) and Peys (1915) the limiting load on the ball of the foot is about 225 kg and the pull on the Achilles tendon about 675 kg - more than half a ton ) To perform any one of the three weaker contractions the subject sat with one leg in a waterbath (a dustbın) and keeping his knee straight exerted a steady pressure with the ball of the foot on a stirrup attached to a suitably weighted lever To perform the strongest the 03 maximal he stood on tiptoe with the knee straight on the leg in the waterbith The two strongest contractions and all the contractions performed during pret sous circulatory arrest in the thigh were maintained till discomfort became intolerable The two weaker ones were given up after a quarter and half an hour respectively and no acute discomfort was felt The results obtained in the weakest contraction are shown in Fig 51 The upper curve on the left hand side shows that the temperature of the warmed muscle fell during exercise the curve immediately below it shows that the temperature of the cooled muscle rose It tended to approach the tem pernture of the blood entering it This suggested hyperaemia The results obtuned when the exercises were performed during urculitory arrest are shown on the right hand side They were quite different there was a slight rise in the temperature of ·38 Circulation in shcletal muscle during exercise both the warmed and the cooled muscle which could have been due to metabolic heat production The comergence of the temperature towards body temperature ob ersed when the circulation was free was not seen and must huic been due to hyperremia In this experiment the clercise performed with free circula tion listed half an hour and could have been kept up for longer O 05 MAXIMAL CONTRACTION °C 40 36 A 35- 55 1 34 0 70 0 Minutes Fix Result showing that weak su tain eri tracti n of the An ga troremiu kelei mu le Hompany hyt ri mi Hatephath tmperatum ( { 10 4) Iriar latert th tem muture 11 me! lintala mtaa mnxunul itrin 41 metar ile Axial tih L Turther wnlm fut tempa mtur Shi cua titi yra mi 1 gl C nfirme!! Alfth tmpernture ch grigex trie prrform with Arnel pirulition 1 Air

·O MAXIMAL CONTRACTION
40
394
MUSCLE TEMPERATURE
35
34
0
60 O
50
Minutes
turte
Ig Re ults show ng that weak sız tajn d cont action of the 1 uman
ga troen mjus gol us m 1s le 9 accompanied by hyperaem a
Upper cu se Waterbath tempe ature 4 C hot mu cle
Love
Wate bath temperature 3) C cold mus 1
Hatch d rectangle 0 max mal contraction
Sol i rectang ulat on arre
in th th gh
Lt D
трех c14e the temperature of th murele approa h I bloor!
tmpe atu e Th coul I have been due to hyperaem a
Pight Confirm 1 by ahsen e of the t mperature change dur ng exerci e
pe form wth arre tre latin

·Circulation in skeletal musule during exercise
When done with the circulation arrested however it had to
be stopped after about 10 minutes becouse of unendurablo
discomfort The absence of fatigue in the free circulation
experiment w is consistent with the conclusion that the muscle
was receiving an adequate supply of blood
O2 MAXIMAL CONTRACTION
40H
MUSCLE TEMPERATURE
muw
O
400
50
Minutes
Hug 53 Result showing that strong su tained contraction of the gastru
cnemiu xolcus mu le schermic
Uprer cure Waterbath temperature - C hot mue le
Lower curte Waterbath temperature 3 с Colt Inurcle
Hatched rectangle 05 maximal entrartion
Soli rectangle circulati n arested in the th gh
During exercise the temperature of both hot en 1 cold
unereased shen circulation free an when it wa arreste! There 11 not
have been any appreciat le lowl ffw through tho mucle in either case
Hyperemiy also of functional signific ince occurred too
during the 01 maximal contrations as will be seen from
FIL 12
the behaviour of the circulation (Iuring the stronger con
tractions WAY altogether different F16 13 Ahows the result

·Circulation in skeletal muscle during exercise 11 of the 02 maximal one During contraction the temperature of both hot and cold muscle increased In the absence of any sign of approximation of the temperature of the hot muscle to that of the blood it was difficult to believe that there could have been hyperaemia Indeed the striking similarity between the temperature changes recorded while the circulation was free and those obtained during circulatory arrest strongly suggested that there could hue been no circulation in either case This could easily be expl zined on the grounds that the intramuscular tension had overcome the arterial blood pressure and occluded the vessels supplying the muscle Moreover the duration of the exercise performed with free circulation and maintuned for as long as possible was no longer than that in the corresponding circulatory arrest experiment Such a result would be expected if there was no circulation through the muscle in either case The temperature changes relaxation are also instructive Fig 5 3 shows that the temperatures of the hot and of the cold muscle changed abruptly in the direction of that of the blood This and the delay of similar temperature changes in the circu latory arrest experiment till after the circulation had been released signifies that they were caused by marked hyperaemia Marhed hyperaemia would be expected after release of the circulation to potentially widely dilated vessels The results of the strongest contraction the 03 maximal tiptoe standing on one leg shown in Fig 54 were similar as also was the inference that mechanic il compression had arrested the circulation through potentially dilated muscle vessels A number of interesting points need discussion Perhaps the most striking finding is the suddenness of the change from hyperaemia to i chaemia with increasing strength of contrac tion After relaxation of the 01 maximal contraction the blood flow apparently began to subside almost at once there was no evidence of the removal of any mechanical obstruction Yet 1 10 per cent increase in the strength of contraction changed the whole picture to one of ischaemia On the one hand the exerere wis gnen up voluntarily after 1 quarter of an hour and on the other it becrme intolerable in less than 5 minutes It seems that the circulation through the calf muscle must have been very free below a critical strength of

·12 Circulation in skeletal muscle during exercise
contraction (between 0 1 and 0 2 muximal) and neirly or qunte
obstructed above the critical point
Mirschak (1931) found that strenuous contriction of the
forcırm muscles could obliter ite the ridial pulo
gests that ischaemia of the calf muscles could conceivably huo
been due to nipping of the main artery or vun This would
reconcile Hendersons (1936) finding of low intramusculur
This sug
03 MAXIMAL CONTRACTION
C
40
39
HEL
MUSCLE TEMPERATURE
3S
34
45 0
50
Minutes
big 56 Renta showing that trong xu tan el contractinif the guin
cenu 4 muscle 1 marhaemir
llallathe mox ratu 4 C
1 warrim late lath temi rat in 3 ( III)
fateh al retargi +7 ITAYIN ntra i 1
Shring urruletin Arrutelu tgh
1) rus xorn the tempraturr of both t AT MIL
in ravxl wlei (in ulat n free ani whest if na armuel Throllnt
I Air Any af prey able tlonul 4 tirigh the mic! Inter

·Circulation in skeletal muscle during EterCZYA pressure with our finding of ischaemia It would be interesting to repeat ius experiment It will be remembered that (rant (1938) concluded that strong sustainel contraction of the forearm muscles dut not present hyperaemia but restricted it This was because there was a slight increase in forearm blood flox dunng contraction and a large increase after There may have been a email increise in flow not shown by our method during the two strongest contractions Another interpretation of Grants results scems possible During contraction there may have been ischaemia in most muscles and hyperaemii in fen The hyperaemia might account for the small increase in flou found during the contractions After reliration the rush of blood through the previously scheme muscles could explain the conscious increase in flow It 18 mteresting to recall that Goshell (18771) found that the blood flow grudurlly increased during tetanic stimulation of the do, sextensor muscles Similar results have been obtainer for the dogs gastrocnemius even during strong stimulation (Pein Mertens and Schneider 1935 hramer ind Quense! 1937 Bulbring and Bumn 1939 The incrense 19 manifest alter 1 minutes contraction But there was no sign of this during our two stronger contractions which lasted still longer This is probably explained by the fact that the dog 8 muscle may have been contracting weahly csen though strongly stimulated The importance of the tension developed in the muscle does not seem to have been appreciated hramer und Quense) do not mention the strength of their contractions Rein et al apprrently tied the Achilles tendon to a 1 bg weight fo that the tension developed could not have exceeded that amount Bulbring and Burn recorded tensions of about 18 kg but these soon fell to 5 hg let the maximum strength of contriction of the cat & gastrocnemius 19 12 5 hg (Eccles and Sherrington 1930) and by analogy that of the dog should be about 3 hg The reason why strong stimulation apparently elicited werk contraction in the dog 19 not clear 111 ME SELF Puri Before check-in, the behaviour of the blood flow through rhythmically contracting muscle a fex words must be aud on ·44 Cuculation in sheletal muscle during exercise the subject of the muscle pump Its action in man has been demonstrated by Smırh (1936) who recorded the pressure in a iern in the dorsum of the foot of a subject standing upright Marhed fall in pressure occurred when the subject raised and lowered his heels rhythmically due to emptying of the leg veins by the pumping action of the muscles Further interesting work along these lines has appeared by Pollack Taylor Myers and Wood (1949) and by Walker and Longlind (1990) The action of the muscle pump can very ensily be showni with the plethysmograph (Barcroft and Dornhorst 19191) Fig 55 is from an experiment in which calf volume was 50 mi V ng 55 Plethysmographic recor i of the volume of the calf of leg Shri ak age denoted by downward movement of writing point Results showing shrinkage in calf volume during rhythmic exerci o due to the action of the E pedal pressed down on e a second for 10 sec Rrest for 10 sec CP cuff just abose knee inflated to 90 mm Hg till en 1 of record ng and Dornhorst 1948 ) (Barcroft muscle pump recorded with the plethysmograph in a subject lying down Periods of 10 sec of Alexion and extension of the foot alternated with periods of 10 sec rest During exercise pressure was exerted about once a second to the sound of a metronome with the ball of the foot on a suitably weighted pedal Calf volume decreased at the beginning of the exercise as the blood in the reins was pumped out (Fig 55) Increase took place at the beginning of each rest period as they refilled The muscle pump has considerable power When the venous pressure was rused to 90 mm Hg by inflation of a cuff above the knee the volume of the calf still shrank at the beginning of exercises The contractions had forced the blood out under the cuff ·Circulation in skeletal muscle during exercise RUTIIVIC COTR 10110 The experiments on static contraction sucoest that there would be free hypertenna in muscle during gentle rhythmic contractions During strong ones however an intermittent flow would be expected stasis during contraction and free flow through widely dilated vessels during relaxation This had not been studied plethysmographically in man as it had been assumed that the to and fro movements of the muscles would interfere with recording Thanks to the ingenuity of Dr AC Dornhorst it has now been done Details of the method are given in the orginal paper (Barcroft and Dorn horst 1949b) and shown in Fig 5 6 Calf volume was recorded with the plethysmograph in the supine subject as in the previous experiment on the muscle pump The subject pressed the pedal once a second to the sound of a metronome relaxing as completely as possible after each contraction After the initial pump out of the venous blood the record usually showed very even up and down movements of the recorder due to the to and fro movement of the calf muscles This may be seen in Fig 57 Inflation of the thigh cuff to a pressure of about 90 mm Hg was usually followed by a regular upward trend of the oscillations from which the inflow could easily be esti mated Houever this was only the apparent inflow for some blood was usually forced out under the cuff by the muscle pump To estimate the rate of blood loss the inflow was arrested by digital compression of the femoral artery in the groin There was usually a regular downward trend of the oscillations from which the outflow could easily be estimated (Fig 57) This figure was added to the apprrent inflow Το see whether arterial compression had succeeded in arresting the inflow the subject then stopped exercise I cape of blood from the calf was presented by the venous occlusion cuff If the inflow had ceased the recorder drew a horizontal straight lino In some subjects though there were no pulsations tho line sloped gently upwards due to una oidable inflow from collateral venecls A small allowance was made for this in tlio calculation Fig 58 shows the blood flow results obtained before during and after six minutes of strong rhythmic exercise Flie blood

·c.
(A)
(13)
Fig. 56
Ippuratu u dn the experiment on the I loft win the end
during rhythmic exere se
The plethysm graph ling a 1 ounter TH A # iglt (1) lectung (ufr
on the lower part of the thigh anklo cuff for arresting the circulation in
the foot
heels rest nt on fivel upports feet on pelaleh rizontal ans
at right angleg t) pe lats
ça h 18 p soto le parat ly where pe la! an 1 / er
wcig) ta on lar: fralja ting work dono ponter actuatel by me
ment of pe lat an l bar on right side (B) stop at heal en 1 of 1 ar one ir
taking we ght off pedal luring relaxati n the other to pr sent mov mit
of yw inter beyon 1 ent of cal (!) metronome (D)
strap Pts
suljects sh uld rs (4)
ontrollarl or enlif kym graph toll (1)
Tirsutist HI kng at the monter (Barcroft al Doilrt 1917)
join

·70 1 FO 14 7 Tracing of calf olume changes during rhythmie erer 18e showing roced, res for determin ng the er rei eft At CP a colleting rres ure of 0 mm Hg was appled 78 later at 10 th femoral artery was occluld Aft r a furthe 3 sex at the subj ct relared for 6 sec (Barcroft ant Dorntoret 1949) 40 RHYTHMIC EXERCISE 30- ml / 100 ml / min CALF FLOW 10 16 Minutes Fig 68 Results hwrgthellau of the !! IA als lu ng ythm c exe Biak lots man rate of ffw Mi at n reas n I loo if w Cre entra ate of Aw { ung Afw con lsr liut n Rap Iblo I flow ate of fw I rng a fw eron! tt ta jetont act on Sightly nexxx! A w 11 n6 is alt 18 ·48 Crrculation in skeletal muscle luring exercise flow increased both during the eycicise and immediately after This proves that it was obstructed mechanically There is no alternativo explınation for the sudden increase in the flow immediately afterwards But the obstruction did not present hypernemia The blood must have been flowing in spurts its progress being obstructed during contraction and free through widely dilated vessels during relaxation Fig 58 shons further evidence to the same effect The exercise u as interrupted eight 40 RHYTHMIC EXERCISE uw/W001/ CALF | FLOW t 10 16 18 Minutes Fig 9 Dagrammatic representation of change in Hood flow in the call during strong rhythm c contraction times for a few seconds each time four times to ni cord blood flons during sustained pressure on the pedal and four times while the subject relaxed the calf muscles as completely ns possible The results shox as would be expected, restricted flow during sustained contraction (circles) and free flon during relaxation (crosses) This is seen diagrammatically in Fug 59 It 19 interesting to compare the results obtained in our experiments (Fig 5 8) with those obtained on the dog e gastro cnemius by hramer Obil and Quensel (1937) and shoun in ·Circulation in skeletal muscle during exercise 49 Fig 5 10 They are vers alike Their interpretation too 19 the same as ours The experiments Just described show that the circulation in calf muscles during strong rhythmic contraction is affected by three factors local vasodilatation mechanical obstruction and the muscle pump They enable us to visualise the spurting blood flow the overall hyperaemia the forceable return of blood to the heart the shrunhen eins and paradoxically the redistribution of blood from the calf to other parts of the Vascular system EXERCISE 160 BLOOD FLOW (ml/min) 2 4 6 Minutes Fg 5 10 Expe ment showing the effect of rhythmic exerci e on the Flood flow through the chlo alosed dog 8 gastrocnem us mus 1 The changes 8 st kingly toke those re ord d in man Fg 58 (hrame Obal and Quem el 1337) REFFRE\CFS Barcroft Hand Dornhorst AC (1949) J Plynol 108 39P — (1949) JP/yool 109 402 Barcroft Hand Millen J L E (1939) J Phyrol 97 17 Bulbring F and Burn JH (1939) J Phyn i 95 203 Dolgin P and Lehmann ( (1930) Arbeitsphynologre 2 248 Eccles Jian1 Sherrington CS (1930) Proc roy SoC B 106 3.6 Ga hell W H (18* a) J 4nat 11 360 (181.b) J Anat 11 720 Grant R T (1938) Clin Sci 3 157

·50 Circulation in skeletal muscle during exercise
Henderson I Å Oughterson A 14 Greenberg LA and Searle
CP (1936) 4iner J Physiol 114 201
Hermann L (1898) Pfug Arch ges Physiol 73 429
Koster 11 (1868) Ted Arch Cenees Natuurkunde 3 37
kramer I Obal t and Quenel !! (1937) Plug Arch ges
Physil 239 670
Lindhard J (1920) Shand Arch Physiol 40 145
(1920b)
Shand Arch Physiol 40 106
Varschal M (1931) Arbertsphysrologie 4 I
Pollack A A Taylor B E Visers TT and Ilood EH (1945)
J clin Iniest 28 59
Rein Hertens and Schneider MI (1935) PAug (rch 0.8
Physiol 236 636
Rejs J HO (1915) Pflug Arch ges I hysol 160 193
Smirk FH (1036) Clin Sci 2 317
Walker AJ and Longland CJ (190) Clin 9101
Weber E (2846) Ilagner & Handu orterbuch d Physiol 3 89

·CHAPTEP 6
THE ACTION OF SYMPATHETIC VEPIES O
THE CIRCULATION IV SKELETAL MUSCLE
DURING EXERCISE
In Chapter 1 it was shown that the vasomotor centre main
tains vasoconstrictor tone in the blood vessels of skeletal
muscle It was natural to wonder whether this was released
in exercise and if so to what extent it was responsible for the
20!
FOREARMS
Normal
Sympathectomized
BLOOD FLOW (ml/100 ml/min)
IO
Minutes after exercise
Fig 61 Results show ng acord latat on n sympathectomi ed muscle
aftet ex C4 Axe ag l re ults of experiment on one subj ct ( rant
1939)
increase in blood flow through the active muscles It will be
remembered that (rant (1938) had found that during exercise
the vasodilatation in normal and sympathectomized limbs was
similar and concluded that it was due in the main to the action
of metabolites This may be seen in Fig 61 which has been
drawn from his results However athletes find that they run
51

·52 Action of sympathetic muscle tessels in exercise better if they Harm up before a race and the explanation of warming up might be that the rise in body temperature caused the vasomotor centre to release the constrictor tone in their muscle and so potentiated the vasodilator action of the metabolites This possibility was investigated by Barcroft Dornhorst FOREARMS Before heating During heating $ o 20L BLOOD FLOW (ml/100 ml/min) EXERCISE 5 Minutes Mnutes after exercise Fig 6 Results showing the effect of relea4ing sympathetic vaso constrictor tone in musele on the rating and post exercise blood flow in the forearm Apart from an increase in the general les el of blood flow the post ever 180 changes look alike To enable more accurate comparison they have been superimpo ed and graphed in Fig 83 Each ubject did 3 rhythmic exercises lagting 3 to 4 minutes before and after relea o of vasoconstrictor tone Tone released by immersion of fet in water at 45 C Plethysmograph water filled temperature 3-3 C Averag d result on 4 subjects McClatchey and Tunner (1951) The general plan of their experiments was as follows If release of constrictor tone speeded up the circulation in working muscles the rate of accumulation of metabolites should be retarded At the end of the exercise the hypertemia and blood debt should be reduced (I ewis and Grant 1925 Freeman 1935 hunkel ·63 Achon of sympathetic muscle regtels in exercise Stend and lleis 1939 Ahranicon hatzen tun and Ferris 1941 Fichni and Itilhing 1011) To see if this kls 80, care fully standardized rhythmic exercises were performed with the forearm or call and the resulting hypertemia and its subsidence were measured with the plethysmograph One or more of the subject s limbs was then immersed in mater at 45 C to raise his body temperature and release his constrictor tone (Bar croft Bonnır and Edholm 1947) The erercisag were then 201 FOREARMS Before heating (4mi Pesting Flow subtracted} During heats (10 7 m1 } BLOOD FLOW Imt/100 ml/ma) 3 Mrutes after exerc se Fig 63 Post exer le bloord Brw changeer orded in the forearm murules krefore and daryg release of sympath tic taso onstructor tone kigo Cephe after subtraction of the re precise post ex Free feating rates To differen in the Fould bts (aceas unde the curses! rty 97 per cent (Barcroft Darah st McCatch y and Tanner ) repented and the ensuing va cular changes recorded and com pared with those pret jously obtained by 6 2 shows the results The resting blood flow was 40 mi per 100 ml forearm per minut after the release of tone it ro o to 10 7 ml Apart from the inrrease in the general tel of the circulation the post extres e changer looked rather alke To compare them more arcurately the respectile rest ing rate 14 subtracted from the post erercise rate in each case and they were graphed as shown in Fig 63 The difference ·Action of sympathetic muscle iessels in exercise in the blood debts ( areas under the curies ) was only 9 7 per cent Further experiments on the calf were done on a much larger number of subjects Fg 64 shows the results of the first series superimposed after subtraction of the respective resting rates There was no difference Fig 65 20 204 CALVES Series I Before heating ( 3 6 mi) During heatingi 78 mi) CALVES Series II Before heating ( 39 mi) O During heating ( 9 1 ml) BLOOD FLOW (ml/100 ml/min) IO 2 Minutes afte exercise Fag o Eigs 0 Post exere se calf blood flos recorded bef re ani dur ng release fympathetic Abo onstrictor tonen the calf muscle Gruphed after ubtraction of the re pe tive po tererci e resting rates Relea ing vasoconstrictor tone scarcely affected the circulatory changes after exercise Fog 64 Averaged results of exper ments on 14 Biljects Fachlid tl and min rhythmic esercise before and during reflex va udal tation 118 65 Ale age I results of experiments on 9 subjects Fach da! 4 and 8 min hythmic exerciso 6 fore and during refler ia dilatation (Barcroft Dornh rt VcClat lay an 1 Tanner 19.) shows the results of a second series the post exercise changes rere the same Considering all theso results on the forcarm and calf there was no reasonable escape from the conclusion that the activity of the 190motor centre hid had no effect on the circulatory changes taking place during or after muscular activity In deed it could hardly have been acting on the sime vessels as the metabolites If so surely there would hue been some ·0- Achon of sympathetic muscle tessels in ererciee INtere relation between the genera) level of the blood flow and the blooil debt To sum up then release of sympathetic i asoconstrictor tone increases the blood flow through muselo (Chapter 1) but eppir ently not through the same vessels as aubserve its metabolo requirements that is tke anatomical basis of this 20. CALVES The facts would be simply Before Adrenaline explained if the vascular (-42 ml) bed contained arterio - During Adrenalne Tenous anastomoses of the (-80 ml) vasomotorcentre regulated them in the general in terests of the circulation and it the capillary led 101 was controlled by metr bolites according to local requirements But the classical descriptions of muscle vessels by Spalte holtz (1889) and Krogh (1022) do not include AI anastomoses et recent observations on Minutes after exercise $199ues by Zweifach (1949) here con inced him that 66 fesuita shows that minute anastomoses or 192reas ng resting mu le blood flow by at al noite infus on of ad ename preferential channels scarcely affected the teviatory exist in many tissues hanges on the calf f flow ng exercise Each ubject Astar 1 thythm including skeletal muscles xercise, Fasting * before and where their presence as Iering the infusion hitherto unsuspected mageal re ulla ex rerum It 24 very important to see if this can be confirmed If so our understanding of the circulation in muscle would be considerably extended It will be recalled that mtrasenous infusions of adrenaline caused a sustained increase in the blood flow in muscle due it was thought to the action of an unknown circulating hormone (Chapter 31 Experiments were therefore done to 60 if the release of vasoconstrictor tone by adrenaline would BLOOD FLOW (m/100 ml/min) Issing ·50 Action of sympathetic muscle tessels in exercise increase the rate of repay mient of the blood debt (Swan and Su in 19,1) During the exercises the blood flow was probably relatively small as the muscles were never relaxed completely Fig 66 shows the results Adrenaline increased the average resting blood flow in the calf from 4 2 to 80 ml per 100 ml per minute The average post erercise blood flows obtained after subtracting the respective resting rates were again similar Although the simulanty is not quite so perfect as that obtained by Barcroft et al It is clear that the difference in post exercise repayment is slight It is worth mentioning that the adrenaline made the exercise more difficult fatigue did not occur to any greater extent but muscular tremor and uncoordination of fine movements impeded the rhythm of action It appears then that increasing the rate of the circu lation in the muscle by adrenaline does not hasten the reply ment of the blood debt and this too suggests that the sessels controlled by the sympathetic may be different from those controlled by the metabolites The existence of two circulations in muscle-nutritive and anastomotica-may explain an important discrepanct between the results of plethysmographic and sodium clearance experi ments The radio active sodium method introduced by hetv (1949) 18 briefly as follows Sodium 24 18 injected into a muscle and is cleared from it at a rate depending on the ability of the local circulation to remove it To determine the clearance counts are made over the muscle with a Geiger Muller counter and plotted semi logarithmically against time A downward sloping line results whose steepness depends upon the rate of the nutritive blood flow and is denoted by a constant Using this method to study circulation in the gastrocnemius McGırr (1952a b) found that the rate of cleirince from the musclo was decrersed during reflex henting Hyman and Morton (1902) observed that tho clearance from the calf muscles was not increased by lumbar sympathetic block These differences from the results of the plethysmo graphic method (Chapter I) would be expluned if the vessels controlled by the sympathetic in muscle were arteriovenous anastomoses Increase in blood flow through anastomotic vessels due to refler heating or lumbar bloc) would not be detected by the sodium clearance method However the Rapaport Saul ·ddion of simpathetic inuscle tessels in exercise difference betueen the resalts of the two methods may well lo due to some other cause and further work is needed to explain it RFFERS CIS Abramson DI hatzenstein FI and Ferri (2011) Amer Heart J 22 329 Barcroft I Bonnar VIch And Extol (6 (194) Ik gerol 106 2+1 Barcroft 1 Domhorst AC VIct latches Hand Tanner JV (1091) J Phyrol 117 391 Frohna L11 and skins R1 (1941) Bull Johny Hapk Hjsp 68 0 reeman F (1935) Amer J Plynol 113 384 (rant R T (1939) Clin Set 3 157 kety s s (1919) Imer Heart J 38 391 Κτης, Α (1922) The Anatom, and I hyrology of the Cupollines Sew Havent Lele University I regg Kunkel P Stead E ! and less 5 (1939) Jchen Inzest 18 220 Lewis T and Crant RT (19.) Heart 12 13 McGuirr 1 (195221 Brut med Bull 8 192 (2002b) Chin Ser 13 9 Rapaport S I Saul A Hyman A and Morton UF (19.2) Circulanon 5593 Spaiteholte u (1898) A daacha ' d 3 189 Vath Phyerk K 14 509 Swan HJC and Swan D (19.1) Inpublished observations 7 wesfu) 13 15 (1949) Factarg R gulanng Blood Pressure Jonah la v Fun dat:41 (ve!! Ir greqi Associated CABY C ·CHAPTER 7 SYMPATHETIC DENERVATION Changes in the behaviour of sympathectomized blood vessels can conveniently be divided into two categories—early and late The early changes have to do with the development of intrinsic tone and the later ones concern the re establishment of connection with the vasomotor centre It will be convenient to describe these separately THE EARLY CHANGES Goltz and Freusberg (1874) seem to have been the first to notice that the vasodilatation following denervation only lasts a short time They found that a freshly denervated dog s leg was warmer than its fellow but that the difference did not persist other observers have confirmed the phenomenon in animals (McDowall 1938) In man the early results appeared to conflict Adson and Brown (1929) found that lumbar sympathectomy caused permanent rise in the temperature of the toes of 12°C On the other hand Lewis and Landis (1929) decluced from spec tion of the skin that the capillary vessels recovered their tone two days after operation and from palpation of the digital arteries that the arteries had contracted considerably by the fourth day more recently a number of observers have shown with the plethysmograph that there is very little difference in the blood flow before and some weeks or months after sympi thectomy (Grayson 1948 Grant and Pearson 1938 Wilking and Eichna 1941) To obtain more quantitative data on the circulatory changes in human vessels following sympathectomy the blood flow in the hand and foot was measured daily with the plethysmo graph before and for some time after nerte section For the in the wards the technique was simplified air filled persper plethysmographs were used and the recording appiratug was mounted on a trolley cupboard Fig 71 shows the apparatus being used to determine the blood flow in the foot Further 58 ·Sympathetic denerzation 59 det uls of the method will be found in the original articles (Bir croft and Walker 1919 Linn and Barcroft 1930 liker Lynn and Barcroft 10 30) Only the results obtained on limby operated upon for excessive sneating or deep venous throm boars will be described here is they alone represent the response or normal human artenal vessels to sympithetic denervation In the case of all of the feet and some of the hands the pre ganglionic fibres were severed in the case of the other hands **?! Smple plethy mograph capparatus fo use the wed {Photo graphed by E in ilmott Postgra luate Vei al School of Lond n in ter the section was predominantly though not entirely through the postganglionic fibres Table 11 and Fig 79 (left) show the effect of Bympathectomy on the circulation in the hands After disconnection of the Tessels from the vasomotor centre and the release of vaso constrictor tone there was an immediate eight ſold increrse in the blood flow Thus hyperaemia subsided quchiy on the sixth day the blood flow has only double the initial rite and on the fourteenth the difference was gtl less The figure shows that the fingers remained warm though unfortunately the temperature records are incomplete ·TABLE IV Blod flow (ml per 100 ml hand or foot) Dgt temperature RE or Lt B fre tron After op at on 150 BC operation After op rat on OP 1 3 ts 1 1> dy a's ? dasa) 4 5 6 14 lays days lays day 1 3 m 2 days d's day 6 7 14 days days 1-3 1108 1 HINDS 1 Rt 11 - 67 92 68 59 F 349 3 Lt 3 1 5 10 9 8 76 08 34 | 9 | 18 4 390 ID 7 5 6 7 10 6 0 1 07 450 534 | 34 89 59 493 77 35 0 3 1 RE 162 300 197 160 VC 08 39 > 3 347 29 5 34 3 LE 9 19 04 07 118 36 3 3 - 10 Lt 3 09 546 30 3 99 84 2 1 181 115 гар 67 52 39 1 38 6 227 167 18 5 144 137 81 34 3 31 7 33 0 FH11 J Rt 1 10 180 10 00 10 70 I 19 68 76 - 66156 15 30 + 390 33 0 Lt 0 15 150 160 14 110 70 781 90 55 953 60 30 0 393 31 7 Rt I 3 3 18 3 08 166 92 F | 13 129 30 66 240 35 33 3 310 31 3 141 1 150 94 13 4 80 BO 90 3 3 0 315 F 30 10 Lt 40 40 128 14 5 0 16 0 130 130 8 295 350 333 30 34 Lt 16 17 80 O 14 5 146 10 6 19 20 3 35 4 337 3 3 & 21 21 165 184 200 149, 105 106 | 851 49 24 2 25 0 327 32 3 321 test Wronta 0 thenod th figure used those ted wthan o 0 two d 37 ·Sympathetic deneriation 61 The results obtained on the feet are also shown in Table IV and in Fig 7 2 In general they resemble those obtained on the hands The maximum flow did not occur till two days after the sympathectomy and was only about half that in the hands The final flow 2-3 months later was about double the preoperative one A large number of toe temperatures were obtained the toes were much warmer after division of their sympathetic nerves and they remained so for 2-3 months HAND FOOT SKIN TEMP 30 Kooi/ ) M014 9007a O 14 14 1 3 Dy befrend after peration Mth Fig 7. Re ults showing the effe t of sympathe tomy on the blood flow in the hand and foot and on the temperature of the dog tal hın The blood flow bubs ded Th dgt era ned warm As raged re ult from Table I (Walker Lynn and Baruroft 1950 ) A number of points need comment It was surprising that the blood fow did not always rise to a marimum at once In three of the five hands the maximum was not reached till the day after the operation Unfortunately the blood flows in four of the feet were not recorded on the day of the operation but in the other two the maximums were recorded on the day after operation in one case and on the second day after in the other This cannot at present be explained The finding that the maximum blood flow in the hand was about double that m the foot (Fig 7 2) which accords with the observations of Greenfield et al (1951) using a different method ·02 Sympathetic deneraton is probably because the circulation in these parts is mainly through the skin and the hand.contains a relatzsely much larger proportion of shin LEFT SYMP Y 50F 40 30 O. HAND BLOOD FLOW ml / 100 ml / min Left • Right O 7 14 24 Days Fig 73 Results showing the effect of unulateral sympathectomy on the circulation in the hands Varked hyperaemia in the palateral han1 To change in the c rculation in the contralateral hand The asodilatation in the ip ilateral han ! cannot be due to any factor connected with the operation other than section of the sympathet catre (llalker Lynn and Barcroft 1920) In several cases of which Fig 73 18 one esample the sympr thetic was cut on one side only and the increase occurred on that side alone this seried as a useful control showing that the hyperiemia was not due to release of metabolites from ·Sympathetic denertalıcn the traumatized tissue or any other factor connected with the operation other than the sympathetic denersation In the case of two of the subjects operated upon for the hands preganglionic section was performed on one side and postganglonıc on the other ganglionectomy) as Fig 74 shows the results did not appear to differ Fie 75 shows that RIGHT PREGANGLIONIC SECTION LEFT GANGLIONECTOMY 1 40 30- 2014- ml / 100 ml hand / min HAND BLOOD FLOW JOH Right + 14 Days before and alter (+) operation 58 74 Changes n blood fow the hands after sympathectomy by preganglione section on one 8 de and I y gangł onectomy on the other The whereabouts of the gyrapatbextemy mate na defteretion to the circu latory change (1) alker Lyna and Barcroft 1950 in muscle sessels too the rate of recovery of tone after pre ganghonic vection appears to be much the same as that after guglonectomy (Duff 1921) Adson and Brown (1999) found that after sympathetio den eru stion the toe were warm for many days this was con firmed by our results (Fig 72) The fact that they remained warm in spite of the subsidence of the hyperaemia in the foot a8 & whole cannot at present be explained The finger tips are known to contain great numbers of Al anastomoses and

·Sympathetic deneration
it may be that these regain relatz: ely less tone than the sequels
generally in the foot Another possibility is that of a greater
heat loss from each millilitre of blood passing through the toes
owing to the increased capacity of the veins after sympathetic
SYMPATHECTOMY
HAND BLOOD FLOW
305
20-
mi/100 ml/min
FOREARM
& BLOOD FLOW
4
8 JO
Days before (-) and after (+) operation
Fig 75 Records of the effect of ympath ctomy on the blood flow in
the forearm and hand
The maximum Now we recor le learl er in the for arm it was smaller and
It Ribsi led more quickly
This may have been due to slight differences in the behaviour of the blood
vessel in muscle and skin (Duff 1921)
denervation (Goetz 1950) Or it may be that the digits remun
warm because they cannot sweat
The vascular response first described in the hand and foot
probably represents essentially the effect of sympathectomy on
the cutaneous Sessels The response of the vessels in the fort
Arm probably that of sheletal muscle blood vesela has been

·Sympathetic denentation craminti with the ple this vinoginph by Duff (191) results out xined on for rms with normal blood puuel art altown in 1, 75 and the figure uso shows the results obtrined simultaneously in the hands of the Brme subjects The general resemblance is clear Duff described the following differences The masalum was retched sooner in the foreirra than in the hand its extent was smaller and the regain of intrinsic tone * 25 quicker The maximum was of the arme order as that recorded after blocking the deep nerves to the forearm muscles (Chapter 1) Simlar results were obtained in the calf by Dornhorst (1951) who found that the marimum calf blood flow occurred on the dry of the operation lle must now turn to the explanation of the return of tone It is generally recognized that after section of a nerve the distal part undergoes in ordered process of destruction hnown 19 Wallerran degeneration These changes take place at much the game rate in all mammals (Young 1950) Cation and Rosenbleuth (1949) have shoun that the consequences of den ervation extend beyond tho distal neurones to the effector cells They do not ce but they undergo Tery fundamental alteratione in their way of life The strated the smooth the cardiac muscle cell and the gland cell are all affected The chief manifestation of this 19 their increased sensitivity to chemical stimulation It holds for ercitation as well as for infubition and it applies to stimulation by the chemical transmitters adrenaline and acetylcholine which act outside the cell and to stimulation by other drugs which only act after penetration Supersensitivity occurs to a less extent of the nerte eupply 19 cut through the penultimate neurone The facts have been aptly summarized by Cannon and Posenbleuth (1949) in the 12 of denertation 1t rang When in a functional chau of neurones one of the elemente 14 det ered the ensuing total or partial denervation of some of the subsequent elements in the chain causes & supersenetty of all the distal elementy Eticluding those not denerated and effectors of present to the excitatory or inhibitory action of chemical agents and nerve impulses the supersensitivity 19 greater for the imks which immediately follow the cut neurones and decreases progresshely for more distint elemente The known changes in the denervated cells which cause the AO HB ·66 Sympathetic denenahon superensitivity are very imperfectly understood They may affect imong other things enzyme systems and the permeability of the cell wall to potassium and phosphorus (Lymin 1942 Friedlander Perlman and Chackoff 1941) ind to Instamine 25 oo A. CS G MEMO E DENAL NE E EC OF DE E ES O SI DECRE 40F 30- 100/ NO 201 HANO FOOT OOD Fig 76 Results showing that the time relations for the devel pment of intrins o tone in the veseels of the han l an ! foot after syropatletom closely re emble those for the dei elopment of a trenaline e ipersen tiity 1 the rabbit ear res els and net tating memt rane Ir trinsie tone les elops at the same time as the phenomena 1 seribral by Cannon an 1 Ronbleuth law of Jeneri ati 1 (7) Ift plumpel 193 Top r ght Le mpre 1941 ) (Cannon and Rosenbleuth 1936) The permeabilty of copil liries muy also be affected (Gabbe 1926 Fngel 1910) Many of these facts hase been established for many years and have been the basis of attempts to explain how tono 18 regained The connection between the law of denervation and the regain of tone appears to us to be still more firmly estab lished by the experiments on the blood flow through the land ·Sympathetic deneriation 67 15d foot For ny klo 7 fi shows the rate of re un of tone 14 w remirkibiy similar to the rite of development of drenaline supersensıtırtı fter comparing tliche Citrus it is difficult to escape the conclusion that the events they represent must be Tery closely related Sympathectomy must start chun of brophysical and biochemical events in smooth muscle which are manifested by supersensitivity and the regain of tone The followmg hypotheses hase been suggested to explun the return of tone (1) It may be due to the arteries becoming supersensitive to circulating adrenaline (Freeman Smithwick and White 1034 Smuthtrach Freeman and White 1931 White Olelberry and Whitelan 1930 Ascroft 1936) (2) It may be due to supersensitivity to an unknown hormone (Grant 1935 LeCompte 1941) (3) It may be the direct effect on the contractile process of intrinsic changes in the smooth muscle (Cannon 3937 Doupe 1913) Those in favour of the adrenaline sensitivity theory have based their ves principally upon experiments shoning that sympathectomized vessels in man and animals are supersensi tive to injected adrenaline and to the secretion of the suprarenal glind when excited by insulin or struggling That they are indeed supersensitive to adrenaline is some subjects has recently been shown with the plethysmograph by Duff (1952) and may be seen in Fig 77 However these findings are in themselves no proof that regain of tone x due to supersensitivity to circulating adrenaline since in the resting state there muy not be sufficient in the blood to cause the sessels to contoret This question might be settled by ascertasning if sessels that had regained tone could be reopened by an adrenergse blocling agent Grant (1035) and Lelompte (1943) showed very clearly how the sympathectanuzed arteries of the rabbit a ent became supersensitive to an unknown constrictor substance not adrenaline or pituutnn since it was secreted in the adrena lectomized and in the hypophy sectomized animal However there is no conclussse epidence for the presence of an active con strictor substance in the blood of a normal resting humın being It was ·70 Sympathetic deneration THE LATE CHANGES Paterson Ross (1916) his stated that the results of a well planned and correctly executed sympathectomy are permanent On the other hand Simmons and Sheehan (1939) and Haxton (1947) found that in many cases vasomotor and sudomotor refleres returned The question of the completeness and permanence of sympathectomy is obuously important in both clinical and research work So we shall now describe tests performed on a large number of sympathectomized arms to 1ssess the completeness of the denervation Altogether 56 were studied (Barcroft and Hamilton 19481 b) Most of them had been operated upon for vascular disease In all cases the sympathetic path was cut through the pregangli onic fibres (Smithwich s operation 1940) The interval be tween the operation and the performance of the test varied from 1 month to 6 years The completeness of the sympathectomy was first assessed with the plethysmograph which gives rather more quantitative information about the blood flow than the finger temperature method used by the previous authors The principle of the test is that in normal subjects warming the body causes a cen tral release of vasomotor tone which 19 manifested by flushing and increased blood flow in the extremities In sympathecto mized ones the circulation in the extremities is not affected (Landis and Gibbon 1933) The test was carried out 15 follows (Fig 78) The blood flow in the hand was recorded at 5 minute inters als for a preliminary control period of half an hour The subject was then covered with two blankets and both his or her feet immersed to well above the ankles at 45°C Recording continued for an hour more Afterwards the blood flow at the end of the period of heating was divided by the initial resting blood flow the result was the heating ratio In the experiment shown in Fig 78 the heating ratio was 6 warming the body had increased the blood flow in the hand sixfold In a completely sympathectomized subject the heating ratio would have been approximately 1 The heating ratios of some normal hands are shown in In all of them warming the body caused a three to firefold increase in the circulation The figure shows also the Fig 79

·bymmlhelic deneriation
71
results obtained on the 50 sympathectomized hands Thest
are arranged from left to right in increasing order of inter al of
time between operation and testing All hands tested within
six months of operation had heating ratios of about le
30
24 cc
( W/P 4W001/
MEATING RATIO
24/426
HAND BLOOD FLOW
FEET AT 45
Mours
Hub 8
#somotor test for simpathetre va omuto 10 sation of the
han
The han i blood fow are orded before and during 1 i mersio 1 of the feet
na warin water to release gympathetic anstrictor ton
the 5 mese in Row
keang ratio taa » hulndex of sympatheter Vinotor actraty
(Barcr it as Haralton 19488 !
reflex heating had no Bynihcant effect on their vessels
contrast to these early results many hands tested between one
and six years after deneri ation had heating ratios considerably
greater than that 19 warming the body had elicited reflex
asoxlilatation

·Sympxhelic dentilation In many cases the test was repeated and instead of warming the body to release the vasoconstrictor tone the deep neries were blocked (radial median and ulnar Chapter 1) The results of the two different methods were similar Fortunately the state of the sympathetic paths could be 1ssessed by another altogether different test a sudomotor test JNORMAL) SYMPATHECTOMIZED 06 MONTHS 16 YEARS 06 MONTHS RETESTED HYRS LATER 1 workout CURRENT DIFFERENCE (A) HEATING RATIOS Fig Results of a motor and udomotor tests performed on Jbl mb after sympathectomy arrange I from left to right in or ler of time interval between operation and testing Hasomotor and sudomotor refie res were absent in mbx testeri 6 months or lesg after operation but present in Imbs teated 1-6 years after operation The results show that the sympathet e re e tablishes connection with the blood vessels and gueat gland in the hand (Barcroft and Hamilt n 1948a b ) The principle of this test is that the resistance to the passage of a current through the body lies almost entirely in the skin and is determined mainly by the activity of the event glands This in turn depends on nerous excitation mediated by the sympathetic (Richter 1946) The apparatus for testing the resistance of the skin consisted of a tf salt battery with one of the poles connected to an indifferent electrode and the other through a mcroimmeter to a brzes applicator with an insulated ·Sympathetic denert attor 73 handle (Harton 1947) The test was carried out as shonn in Fig 1 10 The indifferent electrode was strapped in the artila The skin current over the pulp sprces of the thumb muldle and little finger w 19 mersured at intervals of 5 minutes After a control period of half an hour the subject was warmed to induce maximal activity of the su ent glands and the uintr nerve was blocked with # per cent proemine and adrenaline to present any impulses from reaching the little finger Shan current readings continued for another hour After the test the current that had passed through the little finger (control skın) at the end of the period of body arrming was subtracted from the averge of the currents that had passed through the thumb and middle finger (test skin) The result was the current difference In the experiment shown in Fus 710 ossng to the relatie moisture of the test skin caused by activity of the sympathetic Bulomotor fibres there was 1 current difference of 241 microamps In completely sympi thectomized hands the current difference 19 approxrmately zero since there is no material difference in the amount of sweat in the test and control shin areas The current differences of a number of normal hands are shown in Fig 70 in all of them there were quite large current differences The figure ahows also the results obtained on the 56 sympathectomized hands They are arranged as before in order of increasing interval of time between operation and investigation and vertically below the corresponding results for the vasomotor test The results of the sudomotor test Wthe those of the casomotor one fall into two groups. those obtained on them six months after sympathetic deners ation and those obtained a year or more after All hand, tested within six months had very small current differences Vans of the others however had quite large ones Warming the body had caused sweating Considering the results of both vasomotor and sudomotor tests it was clear that there may no elence of any significant connection between the brain and the hand for ser eral months after sympthectomy However a year or more after opera tion vasomotor and sudomotor referes were often present Finalls sixteen of the feu enteen hands tested within six month of sympathetic denersation were retested 1-1 Tears

·301
UNBLOCKED FINGERS
7-2542 A
20h
CURRENT
DIFFERENCE
O
24'12 A
CURRENT STRENGTH (MA)
ULNARI
NERVE
BLOCK
GBLOCKED FINGERS
000V- kuA
12
Hours
FEET AT 45 C
Fig 7 10 Sudomotor test for sympathetic inners Ation of the han 1
The electrical conductivity 19 mea ured through
(1) The skin of the top of the mid lle finger and thumb in which maximal
Actiity of the sweat gland has been excited by warming the subject The
re ults are averaged (test skin)
() The skin of the tip of the fifth finger which has been deprned of myth
pathetic acts sty by ulnar nere block (control skin)
The differen e between the conductivity of the test and control skine
(current difference 1-?) 18 a useful index of sympathetic nudomotor activity
Barcroft and Hamilton 1949)

·Sympathetic deneriation 75 fater The results seen in Fig 79 shoned that yasomotor and sudomotor refletes had returned to many of these hands A number of points need further comment In the first place the blood vessels of all the hands (seventeen) eramined mithin sit months of operation must have been to all intents ind purpose, completely sympathectomized by cutting the rami communicantes of T2 and T3 and the sympathetic cham Betsseen 13 nnd Tu as was done at operation in every cusc The existence of other paths that would have been left intact by these sections 14 suggested by the work of kuntz Alexander and Furcolo (1938) van Buskirk (1911) highs and huntz (1942) Skoog (1017) Ray and Console (1948) and Boyd and Vonro (1949) Hones er as far as the blood vessels of the hands wo examined are concerned such pnths cannot here boen of much importance We cannot speth with such assur inte about the completeness of the sympathetic denerı atron of the swent glands in the first place our apptratus was not very sensitive and in the second we were concerned only with the glands in the skin of the finger tipe It would be of great interest to know how the new connection established by the symprthetic compares with the original as regards function No doubt there will be great differences from one individual to another It 18 worth examining the meagre data available The figures in Table V suggest that In most subjects the new connection functions poorly he table shows that in years after sympathectomy the hands TABLE Sympatheciomized Final 16 tử và * 30 8 9 Aseruge heating tatt Astraga fand blood fk w during boly HASTSEEK (int per 1(k) mi per mute} Fffect of operation in frequent 1880 pastie attacks curert relesed krelteret 38 + ·76 Sympathetic deneration resembled completely sympithectomized ones rather than normal ones both as regards their heating ratios and blood flows during reflor vasodilatation (Hamilton 1917) This suggests a deficient innervation However it may hue been rather better than would appear from the figures for vascular disease would have slightly restricted the capacity of the vessels to dilate There is another reason for think ing that littlo function returns It concerns the beneficial effect of the sym pathetic denervation on the vascular disorder Of 36 limbs sympathectomized for frequent vasospastic attacks and first seen 1-5 years later 18 had had no re currence since the operation Yet to many of them tho reflexes had returned This too suggests that the re connection was a poor one How the reconnection in the sympathetic path comes F1g 711 Drawing showing how regenerating nerve fibres bridge i 8 gap about cannot at present be of in hi e cat & right cerv cal explained There are tho sympathetic chain The nerve en is o I of the ym possibilities The develop pathetic nerse are slightly thi k ne! ment of a new prth in the and are j inel ky numerou lan 1 1 thyroid gland C common ci ot d rami communicantes above art ry agu nerse (Lee 1930) the level of T2 and regen eration of the cut fibres across a gap of about an inch The former ha; been described in the cut by Geohegan and Aidar (1942) Following interruption of preganglionic pathways to the forepad preganglionic path was developed higher up from roots which normally contribute nothing to the forepid As regards regeneration the powers possessed by the sympathetic in animals at any rate seem to be very much greater than those with which somatic sensory and motor fibres are endowed An experiment of Lees (1930) rrac 1 ·Sympathetic denenation 77 is vorth quoting I re cut a ct s cerykal 4 pathetic 2011 fired the ends so that they were sepunted by an inch of muscle After 27, tlays stimulation of the proximal en crated the typical retraction of the nictitati membrane and enlırgement of the pupil Stimulation of the tissue between the nerve ends showed that the regenerated fibres had then a course partly through the muscle and partly round it Histological sections confirmed that regeneration hd ocenited The results of another of Lees experiments are shown RI FLREVIS Adson 11 A and Erown (P (1929) Surg Gynec Obstet 48 7" Ascroft PB (1936) Bret Surg 24 *8. Barcroft kan! Hamilton GTC (1948) Lancet 1 41 -- (19181) Lancet 2 70 Barcroft Hand Walker J (1919) Lancet 1 103 Boyd JD (10) Personal communication Hoyd D and Honro PSG (3049) Lancet 2 882 Buskırk C van (1941) Arch Surg Chicago 43 44 Cannon 1B (193) Amer Fleart J 14 393 Caxxion Bank Roger bleuth A (1936) Amer I Pk! 116 108 (3949) The Su 8m thua ở tỷ Đem rat d Stractt res Tort Macmillan Dornhorst A ( (19.1) Unpublished at priati ne Doupe J (1913). I Veurol 1 aychrat 6 g Dust RS (1951) Clin Sc2 10 599 w (1952) J Physiol 117 415 Engel D (2010) Ihysiol 99 181 Freeman Smithwick RH and White ) 13934) Amer J Physiol 207 529 Fosedlander H1 D Perlman I and Charko IL (E9+1) J Physiol 132 24 Gabber (19 6) 2 ges xp Ved 53 728 Geohegan WA onil Aslar O'J (1912) Proe Socery Box 50 36 6 Metz R H (1931) (arculation 1 Goltz and Freual erg A (1874) Pflug Arch gs Physiol 9 174 (rant RT (1935) Clin Set 2 1 tant RT And I earson RS B (1938) Clin Set 3 119 (reys y J (1918) VD There Unn ersity of Manchester Greenfell ADV hernohan 6 A Varshall RI Shepherd JT and Whelan R (1951) aprl Physiol 43 Hamilton ( TC UD They Queen slicerssty Belfrat Hengel (11 (1935) mer 17 yetol it 6! Haxton MA Tryf sy 35 09 ffermann Hani Guiran 1 B (1934) Bull Hoxtol teck er 11 391 hin HD an imtz (1919) Arcł Serg Cicago 44 9 ·78 Sympathetic deneriation huntz & Alexander Wand Furcolo L (1938) 11 Sury 107 25 Landhs 1 Y an 1 Gibbon J XI (1933) irch intern Ved 52 185 LeCompte P M (1911) Imer J Ihysiol 135 43 Lee FC (1930) Res Publ 888 ncru ment D1 9 417 Lewis T and Landre F VI (1929) Heart 15 151 Lyman CP (1942) Amer J Physiol 137 392 Lynn RB and Barcroft H (1990) Lancet 1 1105 VicDowall RJS (1938) The Control of the Circulanon of the Blood London I ongmens Ray BS and Console A D (1948) J Neurosurg 5 23 Richter CP (1946) J Neurosurg 3 181 Ross JP (1916) Brit med J 1 1 Simmong HT and Sheehan D (1939) Brit J Surg 27 931 Shoog T (1947) Lancet 2 457 Smithwick RH (1910) Ann Surg 112 1085 Smithwick RH Freeman E and White JC (1931) Arch Surg Chicago 29 759 Telford E D (1935) Brit J Surg 23 448 Walher AJ Lynn RB and Barcroft II (19.0) St Thom Hosp Rep 6 18 White JC Ohelberry A Y and Whitelaw GP (1936) Irch Yeurol Psyrhat Chicago 36 1251 Walking Rand Eichna LW (1941) Bull Johns Hopk Hosp 68 425 Young J Z (1990) Personal communication ·GAMER 8 THE ACTION OF ADRLAALINF AND MORADPENALINE ON THE CIRCULATION IN THE SHIN Both adrenaline and noradrenaline cause pallor of the face in nian This effect is usually attributed to the direct con structor action of the amines on the cutaneous vessels How ever & more detailed study of the problem reveals certain interesting facts in regard to the action of these substances on the vascular system in the skin Although visual inspection of the skin colour may indicate ita vascular state objective studies of the skin surface are unatrefactory if we are attempting to follow rapid changes in skin blood flow Shin temperature measurements are of little use in auch mvestigations because the change in surface tem perature lage behind an alteration in blood flow by an appre cable internal As an extreme example of this it may be shown that when the blood flow in a limb is completely occluded by a pressure cuff there is only a gradual fall in shin tempera ture Also if the blood flou increases from a state of moderate dilatation to one of full dilatation only a small rise of skin temperature occurs whereis changes from moderate dilatation to a lower flou may be accompanied by a considerable fall in skin temperature (Lewis 1927) Heat elimination (Cooper et al 190) 29 also unsatisfactory as it reflects average changes which hase occurred over 1 period of time The use of the hand or foot plethysmograph asords the response lsg and ghen an accurate picture of the variation in flow It has the dis advantage honeser that measurements of blood flow are made on & specialized shin site and on a structure containing some muscle Nevertheless the blood flow changes in the hand and foot reflect predominantly alterations in the skin Sessels (Abramson and Ferris 1940) We will consider in detail the changes in blood flow in the hund during and after infusions of adrenalme or noradrenaline Frecrutions hale to be taken lest the responso is due to chance 79 ·80) dchon of sympathomimetics on skın zessels for the kind blood flow undergoes considerable spont ineous Triation and is also influenced by emotional stimuli (llilkins and Eiclin 1941) THE VASOCONSTRICTOR ACTION OF ADRENALINE AND NORADREVALIVE In order to compare the constrictor properties of these sub stances on the skin blood vessels infusions were made into the brachial artery thus ki olding any central effects which these substances might ciuse Because of the experiences gained in an earlier investigation infusion rates of Hand ng per minute were used Table VI summarizes the find There appears to be httle difference in the constrictor activity of the two substances This is somewhat surprising for the freel pallor caused by drenaline is always more evident than the pallor resulting from a similar amount of noradrenaline Il hat is the explanation of this apparent anomaly ! lle recognize the preponderance of shin over muscle in the tissues of the hand but some muscle is present ings TABLE VI The liant blood fitore response to intri arterial infusions af alrennline and nsradrenaline i Average of 10 subjects Average bl olfi (in! 100 ml min) Doe 8 min Durg idrenaline 120 129 3413 121 96 131 109 109 86 29 Toradrenaline 80) 99 103 11 to 2 13 77 97 1 Intra Arterial infusiong of acirenaline at 1/miti did not cause any esocongtrition in the hand of Duffs experiments Fug 7 in this respect they differ from tho e seen in Table 11 Tira dascojany * probably due to small differences in the asculir response of the suhjects and in the procedures and analytical methods It 14 unlikely that the conclusions of either investigator are incorrect ·Achon of sympathomimetics on skın icarela 81 (Abramson and Fertis 1940) Therefore the blood flow through the hand is the sum of both skin and muscle blood flow Nov in small doses as used in thus study adrenaline cu4e4 a transient dilatation in muscle blood vessels followed by a return to the resting salue wherets noradrenalme causes & pouerful tooconstriction (Chapters 3 and 4) Therefore doses of adrenaline which reduce the blood flow to say 2, per cent of its resting value accomplish this almost entirely by a skin vaaoconstriction while noradrenaline reduces the musclo blood flow in addition to decreraing the shin flow Therefore one can conclude that adrenaline is stronger in constrictor action on skin vessels than noradrenalne which 19 in keeping with the impression gained from visual inspection Tur CENTRAL DILATOX ACTION OF IDREVALISE After intravenous infusions of moderate amounts of adrenn line in mun flushing of the shin of the face frequently occurs This has been attnbuted to serctre hyperaemia following the vasoconstriction caused by the action of adrenalme on the blood vessels It appeared to have its counterpart in the Tessels of the hand for in a small series of subjects it was clear that the hand blood for increased after the intravenous infu sion was discontinued The after dilatation was not seen un sympathectomized kombs nor after intrabrachial infusions in normal ones (Swan 1950) As this seemed to be of some Importance the matter was more carefully examined (Swan 1971) The effect of intravenous infusions of adrenaline and not adrenaline on the hand blood flow was studied using a plethys mograph filled with water at 33 C The room temperature was maintained 10 21 C Under these conditions subjects chosen at random from a class of medical students shoued a surprisingly consistent response to 2018 adrenaline per minute and to 20 sg noradrenaline per minute Istras enous infu 810n9 of either of these substances for 3 minutes caused a decline in blood flow for approximately the duration of the infusion In the case of noradrenaline the blood flow returns to about the previous level after the infusion 19 discontinued 11th adrena line hoxeter the phase of constriction succeeded by an increrse in blood flow which occurs with sufficient frequency

·201
15|
10
BLOOD FLOW ( ml /100 ml hand/min)
V
2221
NSSI
AM
4011
20
10
30 0
30 0
10
20
30
10 20
Minutes
Fig & 1
Rosult showing hyperarm & in the han 1 en 1 fuching of the face
following intraveno 19 infunong of adrenaline
The shaded blocks represent (hall scal) th Ascrage #s recorded in the
perods 0-to and 17- 7 min 3 min nfitions at 20 ug/min The artowe
denote the beginning of flushing (Swan I)

·Table VII gres Adion of sympatkomumetics on skin tessels 83 not to be due to chance Tuele successire experiments in which infusions of 20 yg adrenaline were gsen to normal medical students are depicted in Fig 81 & summary of the findings in a number of these experiments It must be pointed out that in the experiments mentioned abore the adrenaline and noradrenaline affected the tissues besides the vessels in the hand and alterations in cardiac out put blood pressure and heart rate occurred It was therefore decided to carry out a similar series of experiments usung the technque of brachnl artery mlusion and by gising a dose sufficsent to cause a powerful constriction By this method a study of the direct effect of adrenaline and noradrenaline on the vessels of the hand could be made while the central effects were as orded Smaller amounts of adrenaline were used for the drug was not diluted in the general circulation as danng intravenous infusions findings are shown in Fig 82 Duning the period of infusion the hand flow is much reduced Mo after dilatation was observed in these etperi ments or in the experiments described in the first section of thu chapter in which smaller doses were infused intra arterally arefag of t1 TABLE VIL The land blunt for raw ) se to infusi He tauh gn up 11 tes Datterent experi A) gnificance of Iserage blood flow any increaso {m} 100 tol han tan ! Bfter the infice on fure During ormal 1117 1 Intres enous Adrenaline 30 MB B$ 88 P5 28 98 X) ora Irena 83 38 $3 20 g 80 2 Intra arterial renalina 0 Sympati ectomi ert Intrauerous 10 28 - Bujects Aclienalino 0 48 66 53 5 subjects Room temperature 21 C Plethysm graph water temperature 33 C 3 minute infusun 90 PS 10 PR

·200
151
10
5
11
801
122
품
The.
willar
150
20
10
20
30 0
30 0
10
30
10 20
Minutes
Fis 8 1
Results showing hyperaem a n the han i and Aushing of the face
fllowing intras enous infusions of adrenalme
The shaded blocks represent (half scale) the average flows recorded on the
periods 0-10 and 17-7 min 3 min Infustons at 0 75 /min The arrows
denote the beg nning of flushing (Swan 1951)

·Action of sympathirimetics on shan i essels 85 Wuste the noradrenaline flush is of rather 1 dusky tut the Adrenaline fush as bri_ht and intense and is accompanied by a sensation of warmth which spreads over the body--but 19 chieffy eypenenced in the face and hands It is clear that the flushing has its counterpart in the hund blood fon response As se bave pointed out there is a Bigruficant increase in blood flow in the hand following intri venous infusions of 20 g adrenalme per minute for 3 min The changer followin, norrtrenaline and smaller dose of adrenaline are not significant that is the cause of this moreased blood flow A change in blood flow may result from an alteration in the arterial pressure into the organ or from a change in the vascular resistance in the blood vessels themselves Increase in artenal pressure could not account for the increase in blood fon after adrenaline since blood pressure observations make it clerr that there is no increase Moreover the observations of Green et al show that flushing of the face coincides with a phase of hypotenson There fore it is reasonable to consider that there 19 in fact & dilatation of the blood tessels after the termination of the adrenaline Infusion This dilatation might result from the direct action of substances on the blood vessels or it might be due to changes in the nervous influences which regulate the vessels The firyt of these alternatives seemed likely on the grounds that the shin Sessels had been constucted for the duration of the infusion and dilator metabolites might have accumulated locally But this possibility cannot be the explanation for as we have pointed out earlier intra arterial infusions are not followed by dilatation It might be argued that in the intrau enous experiment, the adrenaline liberated a dilator kubetance from some central organ into the general circulation and that the substance was then bome by the blood to the skin where it caused dilatation To test this hypothesis the respon40 to intravenous adrenaline was studied in sympathectomized sul jects Fig & 3 shows that no dilatation followed the infusion By elimination we may conclude that the delatntion which follows intravenou' airesalıne in normal subiecti 29 due to alteration in the nerous control of the bkxxl $£442}4 be more precise for Amnit anul Vacft (1019) have shown that the skin of the little finger dext not contain dittar nerve fibres We may ·80 Action of sympathomimetics on slın iessels It is probable that the whole hand is similar Therefore the adrenaline dilatation is due in fact to an inhibition of sympa thetic constrictor neri e impulses How may this inhibition of constrictor tone come about? It is unlikely to be due to 1 depressor refler because it frequently coincides with a phase of hypotension But there is considerable evidence to show that adrenalıne affects autonomic transmission This has been shown in animals following the injection of sery small doses of 105 TA 20wg/min TA 2018 /min TA 2048mn 80 سمیرم Lusher w/167 4 100g / 105 JAI 104g/m 10ug Im 150 BLOOD FLON (ml /100 mi hand/min) Aluthy j's 1122 2 TA 10 g/m 2 2018 m J140 50 S 10 SI 85 Ils? 72 10 20 30 0 10 20 Minutes 30 O 10 20 30 Fig83 Results showing that intravenous adrenal ne infu song in *ymn pathectomized subjects are not followed by hyperaemia in the band The hyperaemia after intravenous infu song in normally inner sted han! (Fig 81) cannot be due to the liberation of a va odlat sub tan into the general circulation and its subsequent a tion on the han i vensely It is probably due to a central dilator act on of a Irenaline met ateliy the sympatheti and ablished by sympat) ectomy The shaded blocks represent (half scale) the average f we recul I in the period 0-10 and 17-*7 min 3 intravenot infusions The arrow ind cated the time at which the maximal blood pressure given on th lagram The number of limbs sympathectomizal in I ing the test 1 mb 14 shown in the top r ght hand corner (Swan 19 ) min W recorded ·4ction of sympathomimetico on skin tegels 87 adrenaline and after reflex stimulation of the sympathetic supply to the adrenal gland (Marrizzi 19392 Bulbring and Bum 1949 Posternal and Larrebee 19>0) Nemry con clude that the after dilatation seen in normal limbs 3s due to direct depression of vasoconstrictor tone probably in the sympathetic gangha Finally-what is the significance of this mechanism le may consider it esther as part of the emergency reaction (Can non 1929) or as a protective mechanism (Barrazzi 1939b) or 29 a harmful mechanism (Bulbring and Burn 1912) As regards the third we feel that it is unlikely that under normal conditions sufficient amounts of adrenabne are fiberated to crusca hurunful hypotenue state also we consider that adrenaline shock depends on an inability of the blood vessels 10 respond to pressor hormones and thus should not result from ganglione blockade or depression of ners ous vasocon Btructor tone The inhibition of vasomotor tone may on the other hand do much to mitigate against excessive rices of blood pressure thus acting as a protect on rgatnst harmful effects RIFERFICES Abramson D I and Feerie FB (1940) mer Heart J 19 541 Arnott And Vacfie J 1 (1948) 3 hyriol 107 233 I arclay & Coohe Ten hennes RA (1947) mr Il/B20L 151 693 Bullring E and Burn II (1941) I hynol 101 289 Cannon B (1999) Bxrly Changes t1 Pain Hunger Fely and Rage Appleton Cooper he trhy (reenfield A Dy Hamilton and Scarborough X (1950) Clin Sex 8 917 Green DV Johnson AD Lobb A and Curick G (1948) elin Wed 33 332 Hyman A and Vencher (1943) t rol 49 5 Lewis (1927) Blood 1 288 Ls of the Iluman Shir and Their Responses Shaw London Vartazes AS (1939) Scre içe 90 2ui (1939b) Pharıncıcol 65 39 ) osternah 3 and Lartebee 11 ( 119 0) Bull Time Ilapk Woen 87 144 Swan HC (19 () J Py8 ! 111 vi (1031) ✓ Thyrol $12 496 14.1ks R and Lochna H (1943) John H L Hnap But 08 40 ·CHAPTER 9 THE ACTION OF ADRENALINF AND NORADRENALINE ON THE GENERAL CIRCULATION The presence of both adrenaline and nor idrenaline in the human body makes it of great interest to comprre their action on the general circulation The more so since they differ remarhably The effects of intravenous infusions are been studied by Goldenberg Pines Baldwin Greene ind Roh (1948) and by Barcroft and Starr (1951) Small differences in the findings may be explained by the fact that the rates and durations of the infusions differed in the two investigations Both authors recorded the changes in artenal blood pressure and cardiac out put Goldenberg et al used the cardiac catheterization tech nique Barcroft and Starr the ballistocardiograph The effects of infusions at the rate of 10 mg per minuto may be summarized as follows First as regards symptoms and signs With adrenaline an e irly sensation was a curious focling of expect incy with 1 transient mild tingling all over the body Then there followed an increase in depth and rate of respiration and the subjectie symptoms associated with hyperi entilation It was possible to hold a moderate inspiration for only about 10 15 sec About 10 sec after the start of respiratory symp toms the heart rate increased-but this increase might not be noticed by the subject for ses eral seconds Gradually the force of beat increased for a further min After which the rate frequently fell back to a few beats above to resting value The subject remuned aware of the forcefulness of the heart bert Shortly after the start of cardiac symptoms a feeling of fatigue spread into the bach-and into both legs A conrre tremor of the extremities was common After the first two minutes the symptoms diminished rers considerably Tho lith noradrenaline the symptoms were sery different feeling of anxiety or expectancy was absent in most subjects although two subjects reported apprehension with noradrena 88 ·chon of sympatomimetics on general circulation 89 Iine and no psychical sy raptoms with adrenaline Respiration was increased but there was no pulpitation fatigue or muscian tremor Infusion of both amines caused a facial pallor but adrenaline to a greater extent than noradrenaline ADR NOR, { { -- HEART HEART RATE ARTERIAL B (mm Hg) CARDIAC OUTPUT (1/1) *** TOTAL PERIPHERAL RESISTANCE $ $ 40 20 35 Minutes Diagrammar e representation of the effects of intravenor usa song of adrenalino And af soracisenal na on th heart rate arterial bou pressure cardliec output ax total peripheral re infance thential tranvat nt lecrease in the arterial blus pressure wh ch occurs tus ng infuering of adrenaline tag 93) 18 not hown) Other changes are shown ongrammatically in Fg91 Adrenaline caused tachycardia which Ike the palpitations usuallv sub ided though in this 17se not altogether during the course of the infusion (sto also Hume 1933) Noradrenaline ·90 Achon of sympathomimetics on general circulanon on the other hand caused bradycardia Before this curious parador cin be discussed tho other cuculatory changes m Fig 91 must be described Adrenaline did not have much effect on the mean blood pressure it raised the systolic but it either did not affect or lowered the diastolic Noradrenaline had much greater effect because it raised both the systolic and diastolic pressures (see also Burnett et al, 1990) Adrenalin increased the cardiac output wherers noradrenaline either did not affect it (Goldenberg et al) or decreased it (Barcroft and Starr) The changes in the total peripheral resistance were calculated from the cardiac outputs and mean blood pressures Adrenaline decreased the overall resistance whereas noradrena line increased it That is adrenaline acted as an overall vasodilator noradrenaline as an overall asoconstrictor To return to the explanation of the different effects of the two substances on the heart rate Both creito the isolated and atropinized hearts (West 1947 Ahlquist 1948) adrena lıne more so thın noradrenaline But in the human subject this action will be opposed by increased vagni inhibitory tone reflexly excited by the rise in the mean blood pressure This rise is less with adrenaline than with noradrenaline The difference in their actions on the heart rate in man is there fore probably due to the predomination of local ercitation with adrenaline and of reflex inhibition with noradrenaline The different actions of the two substances on the diastolic pressure is probably due to their different effects on the periph eral resistance During infusions of adrenaline in spite of the tachycardia and increased output the blood probably p19409 60 rapidly through the peripheral resistance that there 19 time for the pressure to fall precipitately between two successic heart beats Ilith noradrenaline honei er although there 19 bradycardia and perhaps decreased output the escape of the blood from the constricted arterie4 B slon and the change in pressure during diastole is comparti ely small Studies of the arterial pulse contour changes are in accord with these observations Using a low displacement capacit ance manometer Peterson Duff and Swan (190) recorded the changes in pul e contour during infusions of adrenalıne or noradrenaline Fig 9 2 is typical of their findings In the case of adrenaline it is clear that the increased pulse ·ADRENALINE 10 ug/min MW 100 - Before 1 min after start 100 - Www Just before end of 10 mn nfus on 17 min after end of nf us on NORADRENALINE 10 pg/min www 100 Before 2 mn after start 100 -100 -0 10 mn after start Fag 9. Trac ngs of the arterial blood pressure recorded with a Llly intra art r al capacitance manometer during ntra enou infu tons fadrena lin and noradrenaline Adr nal the increased palm presau e and pulse istegn fy increase n stroke and minute solune the absence of a corresponding rise in the mean blox premure & gnifies pe spheral asod l tat on Voradrenali the d reagel pulpe p er um ani rate s gufy docrease in stroke and minute solum ther pr of mean hlox 1 premature 8 gn fa periph ral Aeron inton ·92 Action of sympathomimelics on general circulation pressure and pulse rate signify increased stroke volume and increased cardiac output and the absence of a corresponding rise in the mean blood pressure signifies peripheral vasodilata tion In the case of noradrenaline the decreased pulse pressure and pulse rate signify decreased stroke output and minute volume, and the rise of the mean blood pressure signifies peripheral vasoconstriction To turn now to the whereabouts in the peripheral vascular system of the vasodilatation caused by adrenalıne In what parts of the body is its action so different from that of the other substance? Evidently not in the skin where both cause pallor Fortunately in man the circulations through most of the internal organs can be studied individually and the results show that the blood flow through the liver kidneys skeletal muscles and brun accounts for most of the output Bearn Billing and Sherlock (1951) have described the effects of the tuo hormones on the hier blood flow They used the bromsulphalein (BSP) dye method The principle is as follows The dye is infused intravenously at a known rate the liver abstracts it from the blood at the same rate and excretes it in the bile The liver flow is calculated on the Fick principle from the rate of hepatic uptake (infusion rate) and the differ ence in the amounts of dye in the blood entering and leaving the liver (estim ited in samples tahen by arterial puncture and by hepatic venous catheterization) (Bradley Ingelfinger Bradley and Curry 1945) Bearn et al found that adrenaline increased the liver blood flow by about 100 per cent adrenaline did not materially alter the liver blood flow The circulatory changes in the hidneys have also been studied Barclay Cooke and henney (1947) measured the renal plasma flow in eight subjects before and during 25-40 minutes intravenous infusion of adrenaline at rates of infusion varying from 0 5 to 10 mg per minute Construction occurred in every subject the average decrease in flon being 40 per cent They were not concerned with the effect of noradrenaline which was examined later by Barnett Blacket De poorter, Sanderson and Tilson (1950) It too caused constriction but apparently not so much as adrenaline since even with more than double the rate of infusion (20 30 yg per minute) the average decrease in flow in sir subjects was only 20 per cent nor ·Action of sympathomimetics on general circulation The blood flow through the skeletal muscles probably accounts for another large fraction of the cardiac output at rest It will be remembered that after the tranflent vaso dilatation in the forcarm had p199cd off the blood flow remained Approximately doubled (Allen et al 1940 Chapter 3) This was due to incrense in blood flow through the muscles which must have been at least doubled In spite of the rise in general blood pressure intravenous infusions of noradrenaline do not increase the blood flow through muscle (Duncınson Stewart and Fdholm 1949 Barcroft and honzett 1919 Barnett et al 19.0) One of the large individual circulations 19 that through the brain The effects on it of adrenaline and of norndrenalino have been studied by hing Sokoloff and Wechsler (19,2) by the nitrous oxide and internal jugular venous blood grmpling method Adrenaline increased the flow by approximately "0 per cent Moradrenaline caused constriction the averago decreare in flow was 10 per cent The changes in the different organs have been collected together in Table Viil and afford independent evidence not inconsistent with the finding4 previously described nimely that adrenaline stimulates the cardiac output whereas nor adren ılınc doce not They show that the overall vnsolilator action of adrenaline 19 essentially due to its effect on the circu lations in tho liver and skeletal muscles TANLE VIII DI 79 B for | A r nal na Norer nola tilrenal Na Irenal, ml /min rilm? ml mn Ingin 1 ng Iron 111cr hiiney Shelctal mi cley Bran luto 100 1000 3000 000) 0 -90 + 1001 - 40 1 100) 190) 90 1900) 1000 07 010 - 10 47.) 6800 10 13, -B ·Action of sympathomimetics on general circulation Finally it is of interest to compare the actions of the two imines on the blood pressure in man the cat the dog and the rabbit It will be seen that differences still need to be ex plained In animal experiments the hormones hare usually been injected and not infused so that the corresponding effects INTRAVENOUS INTRAVENOUS INTRAVENOUS ADR_1018 /mn ADR 10 pg/m ADR 10/g/n 150 100% ITA L II 1 1 L-t INTRAVENOUS AOR 10 g / m INTRAVENOUS ADR 10 g/m LINTRAVENOUS ADR 10 g/m BLOOD PRESSURE (mm Hg) 150 Minutes His 93 Experiments showing that the first effect of intraven us infony of adrenaline on the human arterial blood pressuro is to CAUR A Amall transient decrease The blood pres ure records were made every min by the auscultatory method (Allen Barcroft and I lholm 1948) in man will be those taking place at the very beginning of an infusion before the establishment of equilibrium Careful measurement of the human arterial blood pressure by the auscultatory method usually reseals a small transient decreaso before the sustained rise This may be seen in Fig 93 This transient decrease is readily displayed by the intra arterial manometer (Barnett et al) In this connection it 19 worth noting that infugons of adrenaline into a normal subject ·Achon of sympathomimetics on general circulation 7J never cause a sustained fall in pressure however great the dilution The transient fall in the human blood pressure probably corresponds to the fall seen following the injection of small doses in the cat (Cannon and Lyman 1912) and dog (Hoshins and McClure 1912 Lands Luduena Ananenko and Crant 1950) This is appirently unobtainable in the rabbit (Cannon and Lyman) With noradrenaline the situation 18 different In min the capacitance manometer shows that it causes a simple rise in pressure (Barnett et al) this is so in the cat too (leier Gross and Eichenberger 1949) but oddly enough noradrenaline causes a fall in pressure in the dog (Lands As far as we are aware the response in the rabbit has not been studied The explanation of these differences though of great fundamental interest 19 not at present known et al) REFIRI VCHS Ahlut RP (1918) Ink Jrhjal 1 153 596 Allen J Barcroft H and diem 0 ( (1940) J I hystol 105 2.35 I arclay LA Coke U Tan 1 kenney RA (1047) Amer J Ph/9101 151 691 Barer ft Hand honzett H (1949) J Physiol 110 194 Barcroft Hanil Starr I (1951) Clin Sci 10 995 Barnett AJ Blachet RB Depoorter A F Sanderson PH and Wilson GM (1950) Clin Scr9 151 Bearn IG Billing 13 and Sherloch S (1951) J Physiol 115 430) Bradley SE Ingelfinger 1 J Bra lley Pant Curry JJ (1915) J Clin Incest 24 890 Cannon Bani Lyman H (1912) mer J Physiol 31 316 Duncangon D Stewart 1 and tholm OG (1919) Fed Proc 8 37 Gollenberg V Pines IL Baldwin r de F Greene D G and RCE (1918) Amer J Med 5 799 Hocking RE and McClure ( (1913) Arch intern vel 10 313 Hume 1 (19.) Quart J od 21 459 king D Sokoloff Lani lechsler RL (192) Jchin Intest 31 275 Land AV Luduena FP Ananenho 1 ani (rant JI (1950) Archiz int Pharmacodyn 83 602 Veer R C rog F and Eichenberger E (1919) Helt physiol pharmacol dela 7230 Peterson I H Duff RS and Swan HJC (1950) Unpubli led observations West GB (1947) J I hyun1 106 414 ·CHAPTER 10 ADRENERGIC BLOCKADE In 1906 Dale found that large doses of preparations of ergot of rye paralysed the excitor function of the sympathetic nerves and also of adrenaline These observations were the basis of the considerable volume of work on adrenergic blockade and adrenergic blocking agents which has been carried out since then Adrenergic agents are the natural amines adrenaline and noradrenaline which induce the responses of the great majority of the sympathetically innervated effector cells Adrenergic blocking agents are those substances which specifically inhibit certain effects of adrenaline noradrenaline and sympathetic nerve stimulation The terms sympatho lytic and adrenolytic should not be used for in general neither nerve ending nor mediator nor effector cell is lysed by these agents (Nickerson 1949) It should also be clear that adrenergic blockade refers to an action at the neuro effector junction that is a peripheral effect other actions on the efferent vasomotor pathway are by definition not part of Nevertheless many adrenergic blocking agents cause vascular changes not due to their adrenergic blocking properties and se must endeavour to distinguish between these effects and true adrenergic blochade There are four main groups of adrenergic blocking agents and in this chapter we will consider their action in man so far as it is at present known The effects of the alkaloids of ergot ]] be discussed in rather more detail than the other substances not only because we have iniest gated them to a greater extent than the other agents but also because we may make certain generalizations which are applicable to all adrenergic blocking agents to varying degrees 1 Hydrogenated 4/kalords of the Ergołozıne Group Although the anti adrenaline properties of the ergot extracts Wis recognized in 1906 the toxic effects of a oactise doges presented any serious investigation of the circulatory effects of ergot in man The principle of ergot which possessed the this topic 96 ·Adrenergic blockade 07 freitest vascular activity (ergotoxine) also cau cd the most adverse side effects Stoll anil Hoffman (19431) showed that ergotoxine is made up of three sepurite alkaloids ergocornine ergocristine and ergocryptine The same workers (1943b) found that the lysergic acid molecule which is a component of each alkaloid could be hydrogenated to form nes and stable substances 'These compounds known as dihy droergocornine dihydroergocryptine and dihydroergocristine (the dihydra alkaloids) were much less toxic than the natural alkaloids yet retained certain anti adrenaline properties Because of the diminished toruity the dihydroalhaloids were extensively investigated in man Dihydroergocornine (DHO 180) was studied by Bluntschli and Coetz (1947) Freis Stanton and Wilkins (1948) and others Less attention was glen to the effects of mixtures of the dihydro alkaloids or to the effects of dihy droergocryptine or dihy droergocristine probably because dihydroergocorrine displayed the greatest ascular activity The majority of these investigators made little attempt to interpret the action of the dihydro alkaloids describing many effects as evidence of the sympatholytic or adrenolytic properties of the compounds It is clear that not all of these effects would come within the more rigid definition of adrenergic blockade set out at the beginning of this chapter Barcroft honzett and Swan (1901) investigated the effect of dihydroergocornine and of a mixture of equal parts of the three dihydro alkaloids (Hydergine) on the human peripheral circulation They measured peripheral blood flow with the plethysmograph and found that either dihydroergocornine or Hyderyine infused intravenously caused an increase in the blood flow in the hand and foot in all of ten normal subjects Fig 10 1 19 from their paper This confirmed the observations of Coetz (1949) who measured the finger blood flow and Hayes et al (1949) who measured the blood flow in the whole limb Barcroft et al found little change in the calf blood flow in normal subjects The cause of the dilatation in the hand and foot was con sidered Goetz (1949) had concluded that the dilatation was due to central indubition of sympathetic vasoconstrictor tone and not to peripheral adrenergic blockade but his evidence did not exclude an adrenergic blocking effect Goetz concluded чҫнв;

·98 Adrenergic blochade that the dilat ition seen in normal limbs was due to a central depression of vasoconstrictor tone because sympathec tomized limbs fail to dilate He assumed that if the alkaloids diluted normal sessels by a peripheral action they should also cause dilatation in sympathectomized vessels This does not necessarily follow for a substance which blocks the adrenergic CCK 06 mg ARTERIAL BLOOD PRESSURE * (mm Hg) 120 100 80 60F 80F HEART RATE 60; nonton 201 154 Hand BLOOD FLOW (ml/100 ml limb/min) her Calf within the , 10 30 4043 5053 60 70 80 Minutes Fig 101 Results showing that alkaloi is of the ergotovine gry up at rasdilatation in the han 1 In thu experiment Hyderg ne (CCK) 489 admin trmd ntralenou ly It na mistur nf equal parts of Iths Iroergorom na (DHO) d hydrorgorrist se anel dihydroerg rypt na (Barcroft honzett ant Swan TV1) ·Idrenergic Blackade trinsmitter of sympathetic nerves in normal limbs inight not cuuse vasodilatation in sympathectomized vessels In such limbs i ascular tone may not be due to the action of adrenaline but to that of some quite different mechanism (Chapter 7) Vasodilatation in the hand due to pharmacological agents can result from inhibition of constrictor tone at a number of HIGHER CENTRES VASOMOTOR CENTRE POSTGANGLIONIC FIORE LOCAL ANAESTHETICS SYMPATHETIC GANGLION CELL TEAB C5 C6d - TUSOCURAAINE ADRENERGIC BLOCKADE -BLOOD VESSEL NITAITES DIRECT OILATORS Fog lo PREGANGLIONIC FIBRE Dagrain showing 8 tes of inhit ry act nof Irigs on sympa tor tone tu tic va oo t points along the sympathetic efferent pathway or from a direct effect on the blood vessels This is shown diagrammatically in Fig 102 We do not need to consider activity of dilator nerves--becruse these do not exist in the hand (Arnott and Nacfie 1948) Firstly an attempt was made to see if the dihydro alkaloids had a peripheral action This was done by recording the blood flos in both hands and then infusing the alkaloid directly into ·100 Adrenergic blockade the brachial artery on one side Fig 10 3a shows that the intri arterial infusion of 0 2 mg dihydroergocornine caused an increase in blood flow in the ipsilateral but not in the contra lateral hand A similar response was obtained in ten other subjects This indicates that the dihydro all aloids either 05 CHO DRO 02 mg ghb h 1 ery mph 20 un LIN DHO 0 25 mg 20 nyer Lind Il wip 4 IW COLI) MO11 G0078 Rgh Ad 0 O M Fig 103 Resulta de er bed fully on the text reveal ng two d t net odilator actions of the alkaloids of th ergotosine group on th Ilocxl essels of the han! (1) Low ( n entrations 89 have to he un In Intravenou4 experiment to a1011 toxic effects hase little of the peripheral Ll cking artı n an I rlenme Aympath tic tone by a powerful central indibitory a ton (High concent at on 19 can be 115e«in intrA arterial orper m ntr evert true local a Irenerg c blorking actin anl rel Ase Aympatlitevnen constrictor tone peripherally (Barcroft h nz tt anl Swan 191) ·Adrenergic blockade 101 block the tonic constrictor impulses arriving by way of the sympathetic nerve or otherwise cause a vasodilatation by their direct action on the walls of the blood vessels To decide between these two possibilities we investigated the action of the dihydro alhaloids on sympathectomized limbs for if dilata tion occurred in the sympathectomized limb one could con clude that the alkaloids caused a relaxation of the blood vessels This was not found to be the case While there was no signifi cant change on intravenous administration of the alkaloids in four subjects (Fig 10 3b) intra arterial infusions actually caused a vasoconstriction in two subjects Therefore the vaso dilatation seen on intra arterial infusion of the dihydro alkaloids in normal limbs was due to blocking of the tonis constrictor impulses mediated by the sympathetic nerves true adrenergic blochade It does not necessınly follon however that the vasodilata tion seen after intravenous infusions in normal subjects is due to the same mechanism Although the dihydro compounds are less toxic than the natural alkaloids of ergotovine they still retain certain unpleasant side effects which limit the do e which Barcroft et al were unable to gisa very large doses of the dihydro compounds intravenously and clearly the amounts given intra arterially are much larger than the amount Teaching the hand following intravenous administration The following experiment was therefore devised to see whether central inhibition of vasoconstrictor tone-as suggested by Goetz-way responsible for the peripheral dilatation after Intravenous administration (Fig 10 3c) The resting blood flow was determined in both hands of a normal subject Then the flow in the left hand was occluded by a cuff for 10 minutes after which the resultant period of reactive hyperaemja was recorded After a suitable period of rest the circulation in the left hand was again occluded for 10 minutes but during the first 3 minutes of this period di hydroergocornine was given intrasenously The blood flow in the unoccluded right hand increased in the usual manner Now the dihydroergocornine reached the adrenergic nerve end inge in the rght hand but not in the left hand Pothlin (1917) had observed that in the rabbit 99 per cent of the dihydro alkaloids were removed from the circulation in 5 minutes le can be given ·102 Adrenergic blockade considered that little if any dihydroergocornine would remain in the blood when the circulation in the hand was released On release of the occlusion on the left hand the peak of reictre hyperremia passed off but the blood flow did not return to its previous value there was a persistent vasodilatation of almost the same degree a3 in the right hand This must have ben due to inhibition of sympathetic i asoconstrictor tone centrally The question arises as to whether inhibition could have been caused in the sympathetic ganglia This appears to be un Ithely for konzett and Rothlin (1950) found no such action on the perfused superior ceruical ganglion of the cat Also the occurrence of nausei and vomiting as side effects of the dihydro „ubstances suggest a medullary action Therefore we conclude that the hydrogenated alkaloids of the ergotovino group have an adrenergic blocking action in man when gren in relatively large doses by the intra arteril route When gnen intravenously honever the adrenergic blocking effect is small and the vasodilatation is in the main due to central inhibition of sympathetic asoconstrictor tone as suggested by Goetz (1949) Barcroft et al (1901) then investigated the effects of the alkalords on the response to infusions of adrenaline and nor adrenaline for substances which block sympathetic nerve end ings are said to be more effective agunst circulating sympatho mimetics Fig 10 4 shows an experiment in which short info sions of adrenaline and noradrenaline were nen befure and after the intravenous administration of Hydergine It indi cates that the dihydro alhalords had sery little effect on the arterial blood pressure or he irt rate response to adrenalıne or noradrenaline The constrictor action of adrenaline on the skin vessels and of noradrenaline on the shin and muscle vessels was not affected From this and five other similar expuri ments Barcroft et al concluded that the dihydro compounds had no blocting action on the effects of adrenaline and nor adrenaline In this respect their resulta differed from those of Goetz and hatz (1949) who described reversal of the adrenaline pressor effect after intravenous dihydroergocornine and from those of happert (1949) who concluded that dihydro the constrictor action of adrenaline on the shin vesselsWe are unable to account for these differences ergocornine Tesersed!

·Adr
Nor
10s
Ar!
Normal
CCK
(06 mg)
Ad
ktore
Umi
N
{10,28
Am
HEART RATE ARTERIAL ALOOD PRESSURE (mm Hg)
سليلم
40
1
Hand
(wwqwp wouw) M071 00078
Calt
FE104
0
12 15 23 26
4
56 59
Minute
Results hwt) at a larg stra nous re of hy lmg nated
alkalo ) of the erg tos ng group (lly ferg n } slmost enough to cause tor:
ymptoms fl to Ilo k the AA) on trictor act on of a nal ne anl nor
Allrenal ne in th hand (P& moft korzett and Swan 1911

·104 Adrenergic blochado Adrenaline and nordrenahne given intravenously act upon orgins and structures which are almost unrffected by the direct action of the intravenous dose of the dihydro alkaloids It is therefore difficult to see hop a strong antı adrenaline effect should have been obtained from doses of alhaloid which when given intravenously act in the main centrally Regarding the effect of the dihydro alkaloids on the pressor response to adrenaline Goetz and Katz (1949) reported that adrenaline crused a fall in blood pressure when given after dihydroergocornine But Barcroft et al (1951) were unable to confirm this An explanation of this divergence of responso might be that while in Barcroft et al s experiments the subject lay supine with one pillow under the head the other insesti gitors muy hue placed their subjects in a more upright position If the posture is altered fundamental cardiovascular dynamics are affected and differing results may be obtained This is all the more true when vasodilator substances have been gruen and may be responsible for the fact that Barcroft et al found that the dihydro alkaloids fuled to lower the blood pressure in normal subjects although a hypotension was reported by several other workers Barcroft et al also investigated the effects of Hydergine gren intra arterially on the constrictor response in the foot to adrenaline and noradrenaline The observations made did not indicate any blocking effect to adrenaline or noradrenaline but they thought that the doses of sympathomimetics used might have exceeded the normal physiological range for man Swan (1951a) studied this aspect of the problem in more detail using the hand for his intestigations Definite constriction occurred in most subjects at a dose rate of $ ug adrenaline or noradrenaline per minute when given into the brachial artery Constriction in the hand was also recorded on immersing one foot in water at 12C The cold constrictor response so obtained is mediated by the sympathetic pathway and 19 a convenient way of testing sympathetic constrictor tone Then dihydroergocornine 01 to 0.25 m. was given intra arterially and the ensuing response to intra arterial adrenaline or nor adrenaline or to the cold constrictor test was obseried Fig 10 5 19 an erample in which the constrictor effect of nor adrenaline and of the cold stimulus are compared before and ·Adrenergic blochade 10.) after the dihydro alkaloid It will be seen that the constrictor response to ng noradrenaline and to cold were abolished by the dihydro alkaloide and the response to ng noradrena hne 18 very slightly reduced The same obserı ztions were also made with respect to adrenaline The blockade so produced can be overcome by farger doses of adrenaline or noradrenaline Left hand 201 20 mo 10 BLOOD FLOW (ml/100 ml/mn) IND DHO NI NA NY Right hand Mann the and morn 20 10 25 80 90 TO BO 120 130 Minute Fig 10 Gen intra arter Rlly reach the right hand a h gh concen tration d hydroergocorn {DHO) bl cked the per pheral 1 asoconstr ctor Action of a small dose of noradrenal ft and also that indured reflexly by placing the feet n cold water (between pa rs of ert Cal broke lmesi It has been present up to 30 min after the dihydro alkaloids were given The effect of the dihydro alkaloids on the adrena fine and noradrenaline effect on the muscle blood vessels is variable--but in general the response is unchanged We are not in this worh concerned with the overall effects of the dihydro alkaloids on the circulation An adrenergic blocking action has been concluskely demonstrated--but 18 we have already pointed out the effects observed must be ·106 Adrenergie bloclade critically interpreted The responses in the intact organismi are complex representing the sum of local and general effects At times the local effect may be marked Grayson and Swan (1950) found that local injection of the dihydro alkaloids into human colonic mucosa exposed at colostomy caused a 1980 dilatation Iet when the alkaloids were gi en intravenously 1 vasoconstriction occurred in the colonuc mucosa To summarize the position in regard to the effects of the hydrogenated vikaloids in the human peripheral circulation wo may say that although in large amounts they produce true adrenergic blochade toxic effects permut the general adminis tration of doses which only cause vasodilatation by a central inhibition of sympathetic Soconstrictor tone 2 The Benodioranes Although these blocking agents have a relaticly weak action in comparison to others one of their number is of considerable interest in man--beciuse it is used in the diagnosis of phaeo chromocytoma of the adrenal gland The set eral members of this serie, fall into two different types and are designated by a numeral followed by the letter F (Fourneu--ho synthesized the series) Those substances which are more effective ngunst the effect of sympathetic stimulation than against circulating adrenaline and noradrenaline are typified by the compound 833F while those which ire more effective agunst circulating adrenal hormones are represented by the compound 933F The adrenergic blochade produced by the benzodio ines in animals is welk when compared to other substances There are many aspects of sympathetic and humor i action which are not affected by them Finally these compounds are the only adrenergic blocking agents which accelerate the inactuation of adrenaline (Morrison and Lisenk 1938) In 1917 Goldenberg Snyder and Aranon described the benzodiovane test for phaeochromocy toma In this test 0 25 mg 933F per kilogram bodit weight is injected intraven ously If the arterial blood pressure is clerated due to the presence of circulating pressor hormones then a fall in blood pressure of 10-15 min duration is observed but if the (144 is one of essential or renal los pertension then the bloor! pressure usuallı r es slightis This test is non of proien valto in the diagnosis of phaeoclıromocy toma In their original ·Adrenergic blockade 107 paper Coldenberg et al (1947) reported an ini estigation in which continuous infusions of adrenaline sere gisen to normal subjects When the blood pressure 129 stable 033F 19 Ijected intravenously producing a fall in blood pressure From Goldenberg & experimental results it would appear that 933F was either blocking the augmentor effect of adrenaline on the cardiac output or 39 lowering further the already dimin ushed total peripheral resistance From animal experiments the former possibility apperred unlikely (de Vleeschhouwer 1947) It occurred to Prunty and Stan that plethysmographic determination of limb blood flou might assist in the interpreta tion of the action of 233F on the overall peripheral resistance The latter workers also in estigated the effect of 933F on the hypertension produced by infusions of noradrenaline in normal subjects Prunty and Shan (1950) measured calf and hand blood flow in normal subjects lying supsne sith the head elerated 15 to the horizontal The blood pressure was measured with the sphygmomanometer Continuous infusions of adrenaline or Doradrenalne sere gisen and the vascular response recorded for about 20 minutes by which tsine the circulatory changes had stabilized Then & doue of 0 1 mg 933F per kilogram body weight was slowly injected either directly into the tube through which the adrenaline or noradrenaline infusion was being munt'uned or in some subjecta 129 injected into another suitable en The ensung responses were noted the infusion of adrenaline or noradrenaline being maintained An experiment in which a continuous adrenaline infusson was given 13 shown in Fig 106 The adrenaline infusion increased the systolic blood pressure while the diastolic pressure declined The calf blood flow is increased At the arrow 15 mg 933F was injected over about 90 sec This resulted in a brish Increase in heart rate and in intense flushing of the frice and There was a further increase in calf blood flow The diastolic blood pressure fell further but recovered to its previous Value within a few minutes The Ry stolic pressure also declined shghtly but then rose to i maximum vzlue of 182 mm Hg There as a moderate but gradual fall in blood pressure for the remunder of the adrenaline infusion The subject did not complain of symptoms other than pipitition Vost subjects neck ·108 Adrenergic blockade however experienced a metallic taste in the mouth-with severe palpitations a burning sensation in the face and neck pulsations in virious parts of the body and a sense of alarm One subject (No 6) experienced symptoms suggestive of an SALINE SOLUTION ADRENALINE mg/min 001 002 200 933 F 15 mg BLOOD PRESSURE 180 160 SYSTOLIC 201404 1201 100 80 60 DIASTOLIC 140 120 100 HEART RATE 80H 10 B HAND 65 4 BLOOD FLOW (UW / 14001/1) CALF ROOM TEMPERATURE 20C 05 15 20 3D 4D 50 ED 70 Mnutes Fig 106 Result show ng ſa lume of benz tanr (977F) xk ti hypertensie action of adrenaline (Prunty and Swan 100) ·TALLY I BK 68315 allrart mile Silject ige 18 Dug Banal 3 m I e re 933F 1 m Alle 9331 3 thn After 933 Tomt Altr 133 Itir 15 109/11 BI Pule 1311 0 89 138/ - 12/74 10 160/70 13. 2 Ilr 3 BV 170735 131 40 0 159/72 90 159/40 120 175/64 1.0 3 lir BP 1 1959 50 150/50 89 159 05 112 17, 104 Pulo 104 1 -- 1 170) 0 1 Ir 23 140 20 16 15,69 72 1) 40 212 1714 104 Pulse 1110 5 8 BP Pule 1150) 66 10/06 10 174/10 139 174 ) 11+ JEB 6 104 6 23 BT Pule I. 72 ? 145/106 - 1494 96 hay que Hu 104 GS 60 7 7 Ver 13) 181/104 BP Pulse 007) 140 2011/11) 109 1909) 0. - 3 Tor В Р 1_0 90 150 105 16 1990) 10 105/45 79 Pulse 5 Tor BP Pule 130) 5 1C) 5) 1711100 36 169 69 +5 11) 75 48 ·110 Adrenergic blochade encephalopathy Table Il shows the response of blood pressure and heart rate in nine normal subjects of whom five recented drenaline and four noradrenaline It was thought that apart from subject No 9 no significant fall in blood pressure had been demonstrated In the peripheral circulation an increase in blood flow occurred after the injection of 933F in both hand and calf The results reported above were at variance with those of А B 100 C UUUU wana Hag 107 Record. wlowing that benzodorane (933F) įrobably r 144 cardiac output Intra arterial tracings of the blood pressuto in the brach al artery during the continuous intravenous infusion of a trenaline at the rate of 10 146 min A B before C D after intras enous injection of lu mg benzol xane (933F) 4fter the 933F the pressure falls more rap fly during 1 astule an I the eart rate is in case 1 This impli s a decrease in total peripheral res tan e ani an increare in card ac output Goldenberg et al (1947) and Goldenberg and Arinos (19,0) insofar as Prunty and Swan did not consider the responses they obtained could be regarded as depressor How can this differ ence be explained ' Firstly it must be reniembered that the blood pressure is a balance betucen the cardiac output and the total peripheral resistance Although Prunty and Swan dud not measure the cardiac output they thought that it was increased Pulse contour tracings obtained with a kenetue capacitance manometer (tig 107) supported this The increased cardiac output was considered to overcompensate for ·Adrenergic blockade 111 the undoubted peripheral vasodilatation and so a rise in systemic arterial pressure soon occurred Now posture may play a considerable pırt in determining vascular responses because it will affect the distribution of blood in the veins the right auricular pressure and other variables It is possible that this factor is at least in part responsible for the different results obtained by Prunty and Swan and also by Freis et al (1991) It is difficult however to describe the short hypoten son produced by 933F as evidence of adrenergic blockade Using the intra arterial infusion techniques Swan (1951) Iniestigated the effect of 933F on the blood flow in the hand and also on its effect on adrenaline and noradrenaline vaso constriction Briefly-- 2 mg 933F given intra arterially caused a moderate increase in blood flow of 5-11 minutes duration in bir normal subjects But almost the same vasodilatation was observed in two sympathectomized limbs when 933F was given intra arterially This suggested that 933F in these doses has in part at least a direct dilator effect on blood vessels Further experiments are needed to prove this point If an injection of 1-2 mg 933F was made during an infusion of adrenaline or noradrenaline in intra brachial doses up to 0.pg per minute a transient abolition of the vasoconstriction The constrictor effect of infusions of I ng per minute adrenaline or noradrenaline was reduced by the prior injection of 1-2 mg 933F Small doses of 933F (01 mg to 05 mg ) had little effect on the adrenaline or noradrenaline Vasoconstriction although they did cause some increase in These results at present incomplete indicate that 033F in large doses has a weak adrenergic blocking action in man They do not however explain the action on the arterial blood pressure described by Goldenberg et al (1917) and Goldenberg and Aranow (1930) 3 Priscol This substance is an effective vasodilator in doses which may be given to the human subject The side effects with large doses include tachycardia flushing and conjunctival injection We have had httle experience of its use in this laboratory but our findings agree in general with those of bakım et al (1950) was seen blood flow ·112 Adrenergic blocharle Our observations are reported only to indicite future problems to be dealt with He hrve seen vasodilatation in effectively sympathecto mized limbs thus confirming Grimson et al (1948) In addı tion we have investigated the effects of intravenous infusions of adrenaline and noradrenaline on the peripheral blood flow finding that the constrictor effect in the skin (and in the case of noradrenaline in muscle) is much reduced after 50 mg priscol given intravenously The blood pressure response to the circulating sympathomimetics 18 unchanged 4 Dibennmine This substance is probably the most effective adrenergic blocking agent available (Nickerson and Goodman 1917) It has not been the subject of extensive investigation in man apart from that reported by Hecht and Anderson (1917) These workers reported that dibenamine inhibited the pressor effects of adrenaline and the pressor response to cold One of the difficulties in the study of the effect of dibenamıne in normal subjects is the duration of its action Orthostatic hypotension may last for hours after effectise doses of diben The use of intra arterial technique should overcome this obstacle to experimental investigation Summary Adrenergic blocking agents are those substances which specifically inhibit the response of the effector cell to the sympi thetic transmitter and to circulating by mpathomimetic agents All the groups of substances which produce adrenergic blockado in animals can be shown to do so in man also However the dose required to be effective by the intravenous route is fre quently not tolerated because of unpleasant side effects so that only in the case of dibenamine and perhaps priscol has true ndrenergic blochade been demonstrated on intravenous admin istration The hydrogenated ergotovine alkaloids and 9331 have a blocking action when given in relatiely large doseg intra arterially amine RFFFRF\CI Amott 1 and Vacfie J (1918) Barcroft II honzett 1 an 1 Swan II 112 273 1 PI ? 107 233 (111) J 111 ·113 Adrenergic bloclade Bluntschl H J and (cetz RH (1917) Sfr med J 21 342 Dale HH (196) J Physiol 34 163 Freis P D Stanton J R And Whing RM (1948) imer J met Set 216 163 Freia F D Jackay Candl Oliver HF (1091) Cerrulat: 3 754 Coetz RH (1949) Lancet 1510 Getz R And hatz A (1919) Lancet 1 560) (ldenberg V Sny der CH and Aranow H (1919) Juner med de 135 071 6 Ilenberg anrl Aranov 1 (1950) J Inert med 488 143 1139 rayson J and Swan HJC (1930) Lancet 1494 Crimson Is Reardon J Varzoni FA and Hendrix JI (1948) Inn Surg 127 969 Have D 1 Wakım h G Horton B 1 and Peters (A (1949) Ichin Inzest 28 615 Hecht HH and Anderson R B (1947) dmer J ved 3 3 Kațrert A (1019) Helt med Aeta Sup 22 27 honzett H and Rothlin (1950) Unpublishe! oh criations Morten RS And L1948h h (1938) mer J Pyjarol 123 404 (1919) J Pharm pharm Rer 1 27 Vickerson and Coolman LS (1947) J Plannacol 89 167 Irunty F T O ani bwan HJC (1950) Lancet 1 759 Bullectuer dlad med 1 189 2 249 St127 A ani Hoffman A (1943) Hele clin Acta 26 10 (1943) Hele clin Acta 26 20.0 San ( J c (19,18) Unpublished results (19511) Unpublished results (1951) Dri med 1 1 440 Vleeschhouwer GR de (1947) Pror Sor erp Idol Y 66 il Wakım K Greters G A and Horton ] T' (1930) J Lab rlin Wed 35 50 Sichernon si Rothlin E (1917) ·CHAPIIRI PHALOCHROVE TUMOURS Recent advances in our hnow ledge concerning the nature of the transmitter agents of the sympathoadrenal system has led to better understanding of the effects of these substances in min A condition which gives rise to an excesave liberation is a secreting tumour of the adrenal medullary tissue The majority of such tumours lie in or near the suprarenal glands but also arise in para aortic rests of medullary t19suo The tumours are usually benign adenomata but about 10 per cent tre malignant They are known as phacochromocy tomatı and are commonly unilateral in 12-15 per cent of ciney moro than one tumour is present Until recently phaeochromocy toma way thought to be 1 rare condition but it is now clear that if the possibility of medullary tumour 19 considered in certain hypertensive patients unsus pected cases may be diagnosed In all 270 cases had been reported up to 1919 of which 67 per cent were proven post mortem (Smithwick et al 1950) Early diagnosis and surgical removal frequently results in complete recovery of normal health Therapeutic advances now permit more accurate diagnosis of the condition and have reduced the operatsio mortality thus a more favourable prognose may be given We will therefore consider the clinical aspects of the condition and discues this sole examplo of disordered physiology of adrenal medullary function A reasonable concept of the role of adrenaline and nor adrenaline in the body would be to ascribe the sympathetic transmission to the latter and emergency adrenal medullary function to the former It is probable that the adrenal medulla discharges an effective amount of adrenaline into the circulation during stress Although the natural secretion of the adrenal gland contains up to 70 per cent noradrenaline the mixture all huic the effect of adrenaline (de Largy et al 19,0) Bint in phaeochromocytoma this function is disordered First's large amounts of the medullary hormone are relen el into the 11 ·Phaeochrome tumours 115 Circulation The quantities liberated are far in excess of the need during emergency and cause responses which are harmful Also the predominant hormone liberated from phaeochromo cytoma 19 not always adrenaline for etresa of noradrenaline may be found Noradrenahne does not further the response to emergency--indeed its actions antagonize adrenaline in many respects Finally in a large number of cases there is evidence of a liberation of excesele amounts of medullary hormone over a long period of time which is in contrast to the intermittent response to stress The majority of patients suffering from phaeochromocytoma present symptoms referable to their hypertension but some times metabolic symptome predominate A tentatne classi fication is as follows (1) Hypertensie Group ! Paroxysmal hypertension -ympathico adrenal syndrome 2 Elevated resting blood pressure-paroxysmal hyper tension superimposed 3 Sustained hypertension in niany aspects similar to essen tial or malignant hypertension but certain metabolic signs are present + Sustained hypertension identical with essential hyper tension (B) Jetabolic Group , Glycosuria eles ated metabolic rate and sustained hyper tension 6 Metabolic symptoms episodes of paroxysmal hyperten 810n I Paroxysmal hypertension This syndrome 19 Charac terized by sudden attacks consisting of palpitation nausea and sometimes vomiting headache substernal pain pallor of the face and extremities and tremor (Macheith 1914) At times fear out of proportion to the seventy of the attack occurs The symptoms may be quite mild or of great acventyindeed the patient may die dunng or after an attach The duration of the attack 19 commonly about one hour-but fre quently attacks last only a fex minutes They may recur daily or only at intervals of month, and may alter in sprerity If the patient is seen dunng an attach pallor of the face and ·116 Phaeochrome tumours extremities will be noted while the general condition will vary with the severity of the attack The systolic blood pressure is sometimes 300 mm Hg and there is also a diastolic hyper tension The blood pressure frequently varies during the attack The radial pulse is usually hard the rate varies from patient to patient In several patients extreme bradycardia has been noticed during the attack The extremities are cold and blanched but usually moist Sweating 19 common during the attacks at times streams of sweat course down the patient 8 face and trunk while the hands and feet are relatively dry The mouth temperature 19 usually elevated during a paroxysmal attack Urinary examination frequently reveals glycosuria The piroxysm may terminate fatally by reason of acute pulmonary oedema or cerebral haemorrhage Other wise the patient suddenly becomes aware that his unpleusant symptoms are diminishing Sweating may persist and indeed increase while flushing of the face and extremities is common The flushing may be associated with a sensation of warmth spreading over the neck and face The blood pressure falls rapidly to normal or subnormal values In some cases the fall may be extreme and ultimately fatal For a more complete account see Macheith (1914) 2 A number of patients have been seen in whom the resting blood pressure level is high and who suffer from further paroxysms of hypertension superimposed upon a symptomless hypertensive state They may represent an intermediato group between 1 and 3 and are separated here from the other groups because they represent a different diagnostic problem 3 Patients with sustained hypertension closely resembling essential hypertension and without cudent paroxysms of hypertengon This group probably contains the greatest number of patients suffering from phacochromocy toma Green (1946) reviewed 51 adequately reported cases which he selected from the literature and obser ed that 70 per cent had suffered from sustained hypertension during life The patients may have mild sei ere hypertensito symptoma or may at times exhibit Aigns constent with malignant hypertension The differentiation of the rare phaeochromocytoma from the common essential hypertension is therefore a problem to test the diagnostic shill of the ог ·Phaeochrome tumours 117 physician in the majority of these cases however symptoms ard elgtis are present which may suggest the correct ciagnosis The most important of these 19 excessive sweating Smith wich et al (1990) reported that this symptom occurred in only 2 per cent of patients with essential hypertension but in 9 out of 10 patients with phaeochromocytoma Symptoms referable to a sagospastic condition of the hands and a raised mouth temperature nere also reported by many patients with phaeo chromocvtoma--but were uncommon in essential hypertension A raised basal metabolic rate glycosura and an elevated fasting blood sugar also occur more frequently than in essential hypertension 4 Patients with Bustained hypertension without any symp tome suggestie of adrenal medullary dysfunction Thus Variety is uncommon and usually 19 drawn from post mortem material Although the symptoms during life may have been ma lequately noted in some cases it seems clear that some patients with a medullary tumour die in cardiac failure without any symptomg referable to the tumour 5 Glycosuria elevated metabolic rate and sustained hyper tension In some patients the metabolic symptoms may pre dominate and when weight loss is extreme an endocrino dis When a high fasting blood sugar 19 discovered diabetes mellitus may be considered A good example of this variety is the case reported by Raab and 6 In a small minority of patients metabolic symptoms and Bigns predominate while the blood pressure remains normal Paroxysmal hypertension only occurs These patients are usually considered to have other endocrine disorders ADRENALINE NORADRENALINE AND PHAEOCHROMOCYTOVA It is certain that both adrenaline and noradrenaline are present in excess in the blood of patients suffering from phaeo chromocytoma Holton (1948) and Goldenberg et al (1949) have reported large quantities of both aminag in tumourg following surgical removal while Engel and Euler (1950) have demonstrated large quantities of adrenaline and noradrenaline in the urine of such patients lle discussed in earlier chap ters information obtained from infusions of adrenaline and turbance is suggested Smithwick (1949) ·so 118 Phaeochrome tumours nordren line in norm ul subjects Are the symptoms and signs in patients similar to the laboratory findings on infusion of the amines in normals' In certain important respects this is not The probable explanation of the discrepancy lies in the differing rates in which the hormones enter the circulation In phaeochromocytoma enormous quantities are liberated and effects are therefore seen which could not be deliberately induced in normal subjects nor indeed tolerated by them We will therefore discuss the signs and symptoms of phaeo chromocytoma in regud to the known action of adrenaline and noradrenaline in man and consider the discrepincies which exist Both adrenaline and noradrenaline cause the normal subject mental disturbance adrenalino to a greater extent than nor adrenaline This varies from subject to subject—but on two occasions subjects who had previously had adrenaline reported their sense of alarm to be much greater with noradrenaline Palpitation and tachycardia as caused by adrenaline or bradycardia (Barnett et al 1950 case 3) as with noradrenaline have been reported in prtients The tremor weakness and fatigue common in patients are all seen on infusion of adrenaline in normal subjects A symptom of interest is the excessivo sweating which is a feature of phaeochromocy toma We have nei er seen su cating in some 300 infusions in normal subjects The sweating in phaeochromocytoma has been attributed to a retention of heat owing to the cutaneous vasoconstriction But there are reasons for believing that this may not always be so Many cases have been reported in which profuse sweat ing occurred within a few seconds of the appearance of pillor and frequently in association with headache Also it is strange that we have never seen@sweating in normals in spite of long infusions which caused sustained pallor and presumably con siderable heat retention It seems likely that hypothalamic stimulation may be responsible for this symptom Sivan (1912) observed that sweating persisted for a week after removal of a tumour Flushing and vasomotor collapse have been reported follow ing hormonal drscharge The flushing is probably similar to that seen follow ing the end of an adrenaline infusion Smith wick et al (1930) also thought that a heat retention mechanism ·adrenaline adrenaline increast Phaeochrome thinOnTS might underlig this response But adrenaline Cusy a central inhibition of soconstrictor tone (Ssan 191b) Thin 14 not thought to be due to heat retention for althouglı tasodilatation in the hand was found to follow 20 ng adrenaline for 3 min it occurred only infrequently after 10 Mg for 10 min A more extreme response probably of the same nature is the hypotension obsers ed after doses of 100 18 per minute (Green et al 1918) Collapse 19 not infrequently keen both during the course of the diverse or after removal of the tumour at operation This collapse may be transient due to inhibition of vasomotor tone and will respond well to intravenous nor But at times an irreversible effect 19 produced Hypotension anuria and death may result in spite of heroic efforts at medication This latter state corresponds to the adrenaline shock seen in animals after masive doses of adrenaline ( gran and sger 1949) The changes in blood pressure and overall haemodynamics are of considerable interest Briefly both adrenaline and nor the systolic blood pressure in normal subjects but whereas noradrenaline also elevates the diastolic pressure adrenaline usually cau es no change or a slight fall in the diastolic pressure We hase peen a rise in dinatolie pressure only occasionally with moderate doses of adrenaline in normals Coldenberg et al (148) observed that while noradrenaline increased the total peripheral resistance moder ate doses of adrenaline caused an overall vasodilatation Now patients with phacochromocytoma have always a high diastolic pressure if they are in a hypertensive state and the superficial evidence pointed to a raised total peripheral resistance This Bulgested to Prunty and Swan (1990) that it was likely that noradrenaline and not adrenaline caused the hypertension But it 19 now clear that this is not the case for tumours con taining predominantly adrenaline have been removed from patients who had considerable elevation of the diastolic pres Whereas small doses of adrenaline cause an overall vaso dilatation larger amounts such as occur in phaeochromocytoma must cause an overall increase in peripheral resistance (Golden berg et al 1930) a concept of adrenaline action in keeping with observations made in the dog and cat direct evidence for this action in man Whereas small doses Виге There is some ·120 Phaeochrome tumours of adrenalino given intra arterially cruse little change in the calf blood flow doses greater than 6 ng per minute cause a definite reduction in blood flow (Swan 1951) Therefore it is clear that both amines can cause a rise in diastolic blood pressure and an overall vasoconstriction Increased oxygen consumption and an elevation of the blood sugar have been reported to follow adrenaline infusion With noradrenaline the metabolic effects are much less Reale et al (1950) found no alteration in the oxygen consumption during infusions of noradrenaline in normals This might lead one to suppose that patients who exhibited metabolic symptoms might have tumours containing predominantly adrenaline But this is not the case for high fasting blood sugar levels and raised metabolic rate hase been observed in patients with 88 per cent and 97 per cent noradrenaline tumour contents (Goldenberg et al 1930 cases 13 and 12) He must therefore conclude that at high dose les els noradrenaline influences metabolism by either a direct or indirect action This discussion has so far centred around the production of the main symptoms and signs in phaeochromocytoma by the action of adrenaline and noradrenaline We will now concern ourselves with the clinical classification of the condition as suggested in the beginning of this chapter lle divided the condition into those presenting with predominantly hyper tensive symptoms and signs and those with hyperinetabolic minifestations The former group shows the development of a definito pattern of hypertension Thus some patients exhibit paroxysmal hypertension (Group I) others have an elevated basic pressuro on which an additional paroxysmal hypertension is clearly superimposed (Group II) The majority of patients have clear evidence of sustained hypertension with indefinite evidence of further paroxysms of hypertension (Group III) and finally a minority of patients die from a hypertension in no way different from essential hypertension (Group II) Let us suppose that in the natural fustory of an adrenal medullary tumour the discharge of hormone 18 at first par otysmal but after some time a small continuous brsal libera tion is established with superimposed paroxysmal dischargo occurring from time to time Gradually tho basıl secretion ·121 Phaeochrome (umours mi ht nen nse within progressile diminution of the effects of paroxysmal hormonal discharge This Is A Ter onable sex to tabe as the level to which the blood pressure cin ni o with surviral of the patient is reduced with the progressive eleration of the basal blood pressure and paroxysms of great intensity are not likely to be frequent Finally it is possible that a stite may be reached in which further production of medullary VASCULAR NIY HUMORAL (SUSTAINED HUMORAL (PAROXSYSMAL HISTAMINE + 933F + +OR+ + BLOOD PRESSURE GROUPL GROUPIT GROUP II GROUP FS 111 Cla ficat on of phaeo hrume tumours according to tho relatie amounts of humoral paroxysmal humoral sustained and es ential (vascula slista ned) hypertense element Tho relative mportance of tho paro rysrnal element may bo judged by the extent of the blood pressure r e caused by histamine The relatio import ance of the sustained hypertens eleru nt may be judged ly the extent to which the blood pressure a lowered by 933F hormone is no longer necessary to maintain hypertension and another mechanism has developed in response to the continued relerse of the amines Or perhaps this group represents the normal occurrence of essential hypertension in a group of individuals Fig 1 1 diagrammatically represents the present concept The dise ise may be present in any stage and remain there or progress to another sanety It 19 clear that many tumours are present for a considerable time for calcification 8 CTB E ·122 Phaeochrome tumours in diegener ited art is in the tumour have been reported It would therefore seem reisonable to take the view that the patients symptoms might change as the secretory activity of the tumour altered It would also seem reisonable to associate a sustained hypertension to a continuous release of adrenaline and noradrenaline although it is possible that other activities stimulated by transient discharge of medullary hormone for example pituitary ACTH might cause the sustained hyper tension This possibility is supported by the occasional finding of a slow fall in blood pressure listing several days after removal of the tumour In the metabolic group less information of day to day changes is available but it seems clear that a mechanism exists in which transient hormone liberation results in sustained endocrinc changes Further speculation on this aspect 19 not warrinted in our present state of hnow ledge THE DIAONOSIS OF PRAEOCHROVOCI TOMA The ultimate diagnosis of the condition depends either upon the anatomical localization of its presence or on the demon stration of circulating adrenaline and noradrenaline The dig cussion of the anatomical localization is not our purpose here suffice to say that in the case of small tumours it is difficult if not impossible and that a number of unsuspected tumours have been discovered at operation or post mortem The demonstration of excess medullary hormone may be achieve either directly in blood or urine or by producing effects which only occur in association with a biologically actrvo tumour The demonstration of an excess of adrenaline or noradrenaline in blood 19 not always feasible but the amounts excreted in the urine can be estimated (Engel and Euler 19.0) Theo worhers demonstrated a great increase in the urine content of adrenaline and noradrenaline in two patients with phuco chiromocytomi and also found a good correlation between the relative preponderance of either amine in the unne with the concentration in the tumour The pharmacological tests which reek to demonstrato specific effects due to circulating medulları hormones are more complex The first group are those which produce a pirorysmal discharge of medullary hormone of which the best ·123 Plereochrome Inmour: known as the histamune test of Roth and halt (1943) intravenous injection of Or ng kustamine is given to the patsent If a phaeochromon tomu 13 present there is a brisk rise im blood pressure often to extreme limits with associate symptoms similar to those experienced during the prrorismul attacks It is clear that this test will be of greatest use in the patients in Group I and the accuracy suli decrease in Group III Indeed a moderate rise of blood pressure sometimes follows an intras enous histamine in essential hy pertension and there fore the interpretation of this test may be cfficult A postste response to the histamine test us & rise un blood pressure greater than the response to the cold pressor test Histamine probably acts by a direct stimulation of the cells of the adrenal medulla and not by a refer In normals only small amounts of hormone are liberated insufficient to cause much effect but with phaeochromocytoma large amounts enter the circuhtion A number of other substances also cause transient liberation of pressor hormones from the adrenals These are adequately considered in the clinical literature The second group of pharmacological substances are those which modify the action of adrenaline or moradrenaline OF these the most important 18 933(piperidyl methylbenzodi orane) In 1947 Goldenberg Snyder and Aranow demon strated a fill in blood preasure in patients with phuochromo cytoma following injection of 0 25 mg 933F per kilogram body Weight In patients with essential hypertenson this amount of adrenergic blocking agent caused either no change or a rise in blood pressure Goldenberg and Aranow (1930) were able to report 59 positive (taso depressor) no false positare and 3 false negative responses to this test Clearly on clinical grounds the 933F test is of value in the diagnosis of phaeo chromocytama But a negative response will be obsen ed if the test is carried out in patients who are non hypertensite or if the hypertension is due to permanent vascular change Although of grent clinical salue the physiological basis of this test is complex and requires further elucidation In an earher chapter se discussed the obsery ations of Prunty and Swan (1930) who were unable to obtun a fall in blood pressure on injection of 933F un normal subjects rendered hypertensse by means of a continuous infusion of adrenaline We wonder ·Phaeochrome tuinours whether the dose of 0331 gn on to him ins by the intravenous route is sufficient to produce true adrenergic blochade In general the duration of the adrenergic bloching action of 9337 13 much less than the reported period of hypotension following its administration to patients suffering from phaeochromocitomi 14 70 SWE 90 20 NG 300 CE SWETG co scOUS RESTLESS ON WOOD NEST ASS ARTERIAL BLOOD PRESSURE (8) 50: NORADRENALINE 0 é Haves Fig 11 14 Days The arterial blood pres ure lur ng an l after tho Burg at removal of a phacochromneytoma The hatche 1 squares indicate the rate of administration of L noradrenalino intravenou ly in re per minute Alter v noties the infu fon of nor edernalian mag rey lac d by one of Anline but a th Byxtol c pressure f il below 100 mnm lig the nora trenaling was rentartel 1nra farti pro of nora Irenalino fr 3) minuter the pressuro rema ned at a nati fu tory! vel (Suan 10,la ) The treatment of this condition is the sugu removal of the tumour In most cases this is techınıcılly casi-out care must be taken to avoid or combat a post operatne hypotensile state which frequently dcs elops II JI 2 shows the changes in blood pressure in a 12 year old man during and after surgical ·blood pressure Phaeochrome tumours 123 removal of a phaeochromocy toma (Sw in 19la) In this patient an infusion of noradrenaline was used to maintain the In this case there had been sustained hyper tension of 10 years standing and the tumour contained more than 90 per cent noradrenaline It 19 considered that the noradrenaline acted as a temporary replacement of the tumour secretion which had been so acutely removed Mot all patients in hypotension respond to medication as firourably as the case just mentioned Indeed several cases huve been reported in which the hypotension is unaffected by heroic efforts at medication This is probably due to a condition analogous to the adrenaline shoch described by Tigran and Essex (1919) In an attempt to avoid this fatal complication Cahill and Monteith (1951) used dibenımıne in two cases before operation with a fivourable result RIFERICES Harnett AJ Blachett RB Dep norter A E Sanderson I II and Wilon ( 1 (1930) CI Sci 9 151 Cahill ( F and Monteith JC (191) en Engl J Ved 244 657 le Largy c Greenfield ADM McC lry R L and Welin RF (190) Clin Sci 9 71 Engel A Anl ruler US on (19,0) Lancet 2 387 (oldenberg Snyder CN and Aranow H (1947) med R$ 135 971 Goldenbery, M Pine K L Baldwin E de F Greene D G and Roh C F (1948) mer J Ved 5 79 Goldenberg V Faber V Al ton1 Jandl (hargaff EC (1949) Science 109 34 Goldenbery Arenw H Smith A A and Faber V (1950) drch intern Mert 86 873 oldenbert V and Aranow I (1990) J A mer med des 143 1139 (1946) J Amer med 488 131 1260 Creen DM Johnson A D LobbA an Cu ich G (1948) J Lab clın ved 33 332 (1949) J I hysiol 108 25 Vackeith R (1944) Brt Heart J 6 1 Prunty FTG and Swan HJ (19 0) Lancet 1 759 and Smithwick RH (1019) J Clin Endocrinol 9 782 Reale A kappert A Shogh n C Hand Sutton GC (1920) Acti physiol Scanı 20 153 Roth Gvand hvale F (1945) mer J med Sci 210 653 Smithwich PH Creer V E R Robertson 1 and Walking R 1 (19,0) Tew Engl J Ved 242 259 Swan но с (1951a) Brat med J 1 440 (19511 ) J Ph sao 12 428 (1031c) Unpublished obs nations gran I M and 1 B. ex H (1949) Amer J 11 48161 162 230 Green DM Holt on P C Raab ·CHAPTER 12 THE VASO VAGAL SYNDROME suro It will be remembered that Barcroft Edholm McMichael and Sharpe, Schafer showed that the vasomotor centre could excrte active vasodilatation in skeletal muscle during fainting (Chapter 2) Other circulatory changes taking place in this curious and common circulatory mishap will be described in this chapter Michael Foster (1888) believed that funting was a form of cirdinc syncope due to vagal inhibition of the heart The out put uterual blood pressure and cerebral blood flow dwindled and consciousness was lost In World War I Lewis (Cotton und Lewis 1918 Lewis 1932) questioned this In the dog Starling had shown that vngal inhibition comparable with that in funting did not materially diminish the arterial blood pres increase in strohe volume compensated for decreased rate Neither was there hypotension in heartblock though the heart rate was halved Lewis concluded that tho fall in blood pressure must be due to peripheral vasodilatation To confirm this he atropinized subjects who had just fainted the brady cardır was abolished but the blood pressure fall persisted Ho introduced the term vaso vagal syndrome to emphasize that both vagal inhibition and peripheral vasodilatation were among the physiological changes taking place in the faint Soma Weiss Wilkins and Haynes (1937) and Wilkins Haynes and Weiss (1937) induced funts for the purpose of investigation This they did by oral administration of sodium nitrite followed by tilting upright They confirmed that the fall in blood pressure persisted after atropinization and con cluded likewise that it was due to peripheral unsodilatation Their concept of the nature of the dilatation differed from Lewiss Lew is seems to have considered it as being arteriolar chusing decrease in resistance and so fall in pressure They thought it u 19 venous causing decrease in the effective blood and so decrease in output During collapse in the upright position they sometimes recorded negatite senoug volume 126 ·The caso tagal synilrome 127 pressures at heart level They thought that the arterioles were constricted since the blood flow in the hand decreased to zero But they observed that the circulation in the lege #19 not much changed since the oxygen saturation of the femoral renous blood remained normal (their table shows an increase) 30 20 10 TOTAL PERIPHERAL RESISTANCE CHANGE, TPR OH -10 80 -20 HR HEART RATE (min) _30 60 120 GBP 40 100 RAP VENES ECTION 1020 cc 14 FAINT 80 (mm Hg) CARDIAC OUTPUT SYSTOLIC BP (litres per min) 12 R AURICULAR PRESSURE (cm SALINE) CO 1 11 11 3 0 4 8 12 16 Minutes Fg 191 Result obtained by JcV chael and Starpey Schafe 19 an expriment on a Fri n le Ambulance Unit Solunteer showing that faint ng 18 not a form of card ac yncope During th faint in this subject the ca dar output actually mncreased (Barcr fi Edholm Vhael and Sharpey Schafer 1944 ) VcVichael and Sharpey Schafer (Barcroft Edholm VcVichael and Sharpes Schafer 1914) were the first actually to mensure the right auncular pressure and cardiac output by cardiac catheterization during the faint Neither changed appreciably as shown in Fig 12 1 Their findings have since been confirmed by Warren Brannon Stead and Verrill (1945) ·128 The taso eagal syndrome and by Food and Burchell (1030) Funting was not a form of cardiac syricope The abrupt fall in blood pressure was due to decrease in peripheral resistance In the same investigation at the British Postgraduate Medical School peripheral vasodilatation was found in the skeletal muscles and later shown to be of nervous origin (Chapter 2) In connection with this Sharper Schafer found an apt observation of John Hunters (1793) I bled a lady but she fainted and while she continued in the fit the colour of the blood that came from the vein was a fine scarlet Commenting on this before the publication of our results McDowall (1938) thought it signified muscle vasodilatation Increased muscle blood flow during fainting probably also explains the rise in brachial 1 enous pressure previously observed by Erahler hossman ind White (1943) The question arises as to whether this vasodilatation in muscle also occurs in funting due to catises other than hemor rhage Is it really part of the vaso vagal syndrome mo tional fainting is the commonest mamfestation of the syndrome, but here one is up against the difficulty of inducing a subject to faint from emotion while his forearm is in a plethysmograph However during an experiment one of Sharpey Schafer s sub jects did faint spontaneously and increase in forearm blood flow 194 recorded (Brigden Howarth and Sharpey Schafer 19-0) This was confirmed by Greenfield (1951) A preclinical student who fainted at the sight of blood offered to act as subject But in the experiment when shown syringe of blood he did not do so As he and Greenfield were an rious for a faint Greenfield put the blood in a beaker and asked him to drink it This was successful and the fall in blood pressure bradycardir ind increise in foreirm blood flow seen in Fig 12 2 wero recorded Besides emotional fainting there are other causes as for erimple anoria Schneider (1918) found that subjects ren dered unconscious by orygen lack fell into one of two groupe and fainter's In World llar II Ander son Allen Barcroft Edholm and Manning (1946) insestigited the effect upon the foreirm blood flow of breathing origen nutrogen mistures calculated to provide origen tensions At equn alent to heights of betneen 18 000 and 24 000 feet non fainters ·The 1980 tagal syndrome 129 the time consciou nest 17 lost thic circulation of four fiftlis of the subjects 174 in the hypurdy name state their cirutics were pulsatin, Lorously and thero » 14 tachycardiz ind Increased arterial blood pressure they corresponded to non funters However about one fifth the hnd typical vaso ingal syndromes including Schneider fainters ARTERIAL PRESSURE (mm Hg) 2130 120 110 100 90 80 70 60 50 90 80 70 60 5D 40 B HEART RATE Am mu mani FOREARM BLOOD FLOW {ml /100 ml/mn) NWA o 10 20 30 40 50 60 70 M nutes Fig 1 Experim nt hring tht sod 1 tatin fa nting duced by emot 14 in Circulat ry changes luring em tonal faint 1 wat lap ep Irati watcle i nopuncture ( nee lle int arm D Inks ml of 1 locul That ppl ng repre ente tou of nation In ep te of th ext ne fall, thei! I prr N r t trs the full the rear llon flow rema nel Atal gnis & miel AN I latt D 1 (Genf ld 19 ) increase in foreirm blood flow (l'ug 12 3) Brigden Howarth and Sharpey Schafer (190) recorded increases in foreirm blood flow in faints induced by tilting spinal anflesthesiz and other meing They concluded that muscle vasodilatation was in essential part of the vaso Vagal aj ndrome Inother important question is whether the fall in blood pressure is entirely due to vasodilatation in muscle or whether SCHB F*

·130
The caso lagal syndrome
I 190dilatation elew here is partly responsible Fortunately
we now know what happens in the circulation through the laser
kidneys and brun The effect on the Iner blood flow was
studied by Bearn Billing Ldholm and Sherlock (1951) in eight
Hypoxia fainter
98% O2
150
---Cy wed
HEART RATE
Beats per min
100
ARTERIAL BLOOD PRESSURE
(Tom Hg)
FOREARM BLOOD FLOW
(ml/100 ml/min)
30
Mimites
Fig 123 Results showing that vaeo lilatation in muscle occurri in fuint
in luced by breathing 9 & per cent o, (And rson Vlen Barcroft Fdh Im
and Manning 1946 )
subjects The liver flow was measured by the bromsulphalein
(BSP) method (Bradley et al 1945) The principle of the 14
as described in Chapter 9 Bearn et al results show that
during funting hepatic blood flow decreased on the average
to about half its normal rate As the decrease in the blood
pressure was relatisely more there is probably some 1190

·The m80 tagal syndrome 131 dilatation in the splinchne ure? (my on in Suin (1930) showed by a qualitative method dlecrease in blood flow in fainting in the colonic mucosa de llurdener and McSwicy (19.1) studied the renal blood flow by ob eri ntions on the clearance of para aminohippuric acid (PAH) During the faint kidney blood flow decreased on the average to about three quarters of its normal rate As in the case of the liver there was a relatively greater decrease of arterial blood pressure and probably some rennl vasodilatation Lennox Gibbs and Gibbs (193») studied the cerebral circui lation by two methods "The first wis by means of a heated thermojunction placed in the internal jugular vein the temperature of the junction being an inverse function of the rate of the blood flow The sccond by measurement of the oxygen saturation of the internal jugular venous blood The results of both methods Icare no doubt that the cerebral flow decreases during the faint To return to the question of the extent to which the blood pressure fall in vaso vagal attrchs is attributable to vasodilata tion in muscle The circulation through the liver kidneys skeletal muscles and brain accounts for about four fifths of the total cardiac output During the faint the flow through the muscles is doubled but that through the other princ pal organg 19 decreased The vasodilatation in muscles 19 far greater than that elsewhere In as much as vasodilatation does take place in the splanchnic area and hidneys it must be in part accountable for the blood pressure fall It is worth considering whether dilatation in tho coronaripg could contribute significantly to the fall in peripheral resistance The resting flow amounts only to about 200 ml a minute (from Bing et al 1949) but in exercise it may be 2 litres (Hill 1926) It has not been measured in the faint It seems unhkely that there would be much vasodilatation Probably the most Important factor controlling the coronary flow 19 the metabol ism of the heart Sinco in the faint heart rate and arterial blood pressure are decreased so very likely are cardiac metabolism and coronary flow Flectrocardiographs tnhen during the syndrome show no sign of anoxia of the heart muscle (Weiss et al 1937) Vasodilatation in another small part of the peripheral ·132 The taso lagal syndrome I ascular systein the finger tips 118 recorded plethysmo graphically by Rushmer (1914) As the skin in the funt is pale and the blood flou in the hand diminished (Chapter ) this may signify some release of constrictor tone in the abundant arteriot enous anastomoses in the finger tips Some further points are of interest As the sympathetic nervous system mediates the vasodilatation in skeletal muscle (Chapter 2) it probably does so in the splanchnic area and kidneys The corollary of this is that there should be no vasodilatation or tall in blood pressure in faints in totally sympathectomized subjects In fact totally sympathecto mized subjects are very apt to faint when they stand upright The ciuse of these faints' needs further investig? tion may be the hypotension is due to pooling of blood in the lower part of the body and consequent decrease of right auricular pressure and cırdınc output which cannot be com pensated for by splanclinic s asoconstriction Recent work suggests that hormones may play a part in the changes occurring in funting Brun Knudsen and Raaschou (1945) noticed that the vaso vagal attacks induced has tilting were followed by pronounced oliguria They sug gested that the cue was ccretion of antidiuretic hormone by the pituitus This was upheld by certain experiments Druresis m 1 waterlouded normal subject was inhibited by blood transfusion from one in the postsyncopal state The changes in the chloride in the urine resembled tho e found after injection of pituitary extract and postsyncopıl oliguria mas much less in two patients suffering from diabetes in lpedu Taylor and Voble (1950) recovered from postsyncopal urine posterior pituntury lihe antidiuretic substance Stead hunkel and ll etss (1939) anrl Su hara Duncınson and Fdholm (1919) found that injection of posterior putuitary extract in normal subjects caused niusez abdominal chiscomfort asken pillor and headache Pitressin secretion in the fint probably et plains the persistence of pallor and splanchnic rasoconstriction for so long after the return of the blood pressure to normal (Beim et al 1971) The possibility of suprirenal secretzon must be considered too since it might explain the output of hver glucose ind niuscle lactic acid (Beam et al) Aow thet a taethor of urine analysis is available for detectin, inertave 112 ·The 19750 lagal syndroine 133 blood catechol derut atures it would be interesting to applı 10 to postsyncopal urine (Euler and Hellner 1900) Hon 12 fainting caused Lewis (1932) noted the resem blance of the raso rigul changes to those of erotid sinus stimulation in anumals (Heymans and Bouckaert 1928) and in sensitae human beings (Danielopolu 1929 see also less and Baker 1933) He thought that they were caused by the same centres in the brain excited by the higher centres or by unknown afferent paths Weiss Biking and Haynes (1937) thought that vaso vagal attacks clused by nitrite and tilting Were due to cerebral anoria but this cannot be ao Breathing nitrogen (Lennox Gibbs and Gibbs 1935) or air diluted with nitrogen (Anderson et al 1946) so as deliberately to produce anoxia of the brain beyond the point of unconsciousness does not as a rule cause fainting How does nitrite and tulting induce fainting' Brigden Howarth and Sharpey Schafer (1990) have shown that tilting lovers the right auricular pressure Lowering of the right anricular pressure is caused by other procedures which induce fainting For example by haemorrhage (Brigden et al) spinal anaesthesia (Brigden et al) the post exertional state (Mateeff 1932 Eichna Horvath and Bean 1047) and by forcible compression of the chest during full inspiration followed by sudden release (Lennor et al 1939} In these cases fainting is probably induced as Sharply Schafer once suggested by stimulation of unknown sensory receptors in the cardho pulmonary system or great eins Recent work by Pearce and Whitteridge (1951) and by Dawes and Vott (1990) empha izes the possibility of a refler from these areas It is not yet known whether pituitary secretion precedes the on et of fainting If so it may help to precipitate the funt Stead hunkel and Iless (1939) found that intramuscular Injection of pitregsın induced fainting in two out of sur subjects m the upright position They thought that it caused pooling of blood in the lower part of the boly Rutherford Godfrey and Griffiths (1911) have since found that pitressin decreases the curculating blood volume These remarks on the cou e of famting shot that it is still far from being understood Lennox Gibbs and Gibbs (1935) were interested in the ques tion of why funters loso con ciousness They noticed as did ·1341 The taso tagal syndrome Iless and Biker (1933) thit pressure on the carotid sinus sometimes caused loss of consciousness but no fall in blood pressure The loss of consciousness was caused by neural mechanism They wondered whether in fainting loss of con sciousness was due to fall in blood pressure and cerebral anoxia They found that during the faint the origen saturation of the arterial blood was almost normu02 per cent but that of the internal jugular venous blood was only 20 per cent (normally 56 per cent) This was explained by the decreased cerebral blood flou As reduction of the internal jugular venous oxygen saturation to below 30 per cent by breathing nitrogen invari abht caused unconsciousness they thought thrt unconscious ness during the 1950 i agal syndrome was usually caused by anoxia However they could not say whether it was due to the direct effect of anoxn on the cells responsible for the conscious state or to stimulation of a neurri mechanism It remains to draw attention to some other vascular con ditions remarhably lhe funting The first of these is the action of apomorphine reported from Innsbruch in a stries of papers by Jarisch and his col lergues (Cowin 1943 Gsell 1943 Hothe 1943 Schneider 1943 Ehlch and Wallisch 1943 Bertolini and Jarisch 1947 Seidel Jarisch 1948) Subcutaneous injections of 10 mg cruse lassitude viwning sweating simnation extreme pallor naixei vomiting and often unconsciousness Defaeer tion occurs occasionally Breithing is not affected Tachy cırdın is soon followed by marked bradycardia and precipitate fall in blood pressure as shown in Fig 12 4 Jarisch and his colleagues thought that the blood pressure fall 11 29 due to peripheral s asodilatation as it persisted after restoration of the heart rate by atropine There were signs of vasodilatation Though the s2 in sas deadly pale the hands were warm and digital temperature often rose conspicuously olling the thought to dilatation of the A 1 anaston099 The origen aturation of the brachial venous blood was increased and it sometimes became bright reil They recaller John Hunter x uberi ition on the ins who funted during blood lettm, Onin, to the te semiblince of the changer to those of carotid sinus ini de pre-sor nerve stimulation they thought that the dirtition 114 munk in the hentic are!

·1 he tviso zagul syndrome 13) splenic bloul reservoirs (hoch 1931) and in the skeletal muscles (Jarisch 1920) Frimination of the electrocardiogr im of these subjects showed no impairment of the heart They thought that the apomorphine acted directly by stimu lation first of the sympathetic and then of the parasympathetic centre As unconsciousness sometimes supervened when the blood pressure was normal they believed it excited Hess & 90-1 BLOOD HEART RATE 1 2 4 5 6 FINGER TEMP с 34 120- 32 110- 30 100-ARTERIAL 28 PRESSURE 26 80- 24 70+140 22 60+120 20 50+100 18 40+B0 - 60 -40 UL Min 0 5 10 15 20 25 30 35 40 45 FS 16 Fxperiment showing the likene e of the eff ts of apomorphine to those of the Vaso vaga! ynd om Th bra ly ar la pre ip tate fall in blo pre re ani va otlatation in mus le as shown by a th vyg na taration of the venous blood from th arm en I Oxyg n atu at on pe ent 10 mg apomorphin 3 Tawning feeling of fatigue 4 and 5* Oxvg n maturati n 49 an 1 50 per cent respot rely orn ting 18 lenote 1 by th sol 1 rect ngle (Eht and all sch 1943) (1929) sleeping centre As yet there have been no meusure ments of cardiac output forearm blood flox or urinary antı diuretic substance after apomorphine Vaso ngal attacks very like faints occur in the anaesthetized cat Jarisch (1941) noticed that esery now and again at the beginning of an experiment the blood pressure fell spontane ously and abruptly to about half its initial value and at the $ame time the heart slowed Recovery usunlly occurred in a few minutes Altogether he recorded 41 attacks wluch occurred in 10 per cent of his experiments They took place ·136 The caso lagal syndrome during chlorulose pernocton but not during ether or urethane anaesthesia or in decerebrate animals They invariably happened in the first ten minutes of an experiment and never except in one cat more than once They seemed to be related to the entry into the circulation of sodium citrate during the prepiration for recording the blood pressure with the mercury minometer The fall in blood pressure was not abolished by atropine The pulmonary arterial pressure fell superior venr caval and right ventricular pressures remained constant the volume of the Spleen increased The phenomenon or rose -220 LIN BLOOD PRESSURE Hg! W 1 Min. Fig 1.5 Prec pitate fall in arterial blood pressure recordel by Jarisch during & vaso vagal syndrome in the chloralo ed cat Sin the va40 vagal phenomena were abolished by cooling the vage they were believed to have ben triggered by afferent en ory impulsos fim the heart krag cooled 11 warme 1 (Jarı h 1981) reminded Jarisch of the Rezold effect (Jarisch 1910) Ho thought that the blood pressure fall and brads cardıı might bo due to excitation by the sodium citrate in susceptible cuts of sensory receptors in the heart In the Bezold effect cooling the sagi abolishes the fall in pressure and bradycardır due to stimulation of these receptors by veratrine Cooling the sagi in these vaso vagal attacks also usually terminated the attack This 19 shown in Fig 12 5 In one case the attack persisted due to continued spontaneous activity of the centres konzett and Rothlin (1951) lase confirmed Jarsch 8 observations and recorded decreises in the volumes of the gut and hidney They added the very interesting ob ersation that intris enoug injections of adrenaline sometimes induce vaso vagal attacks by stimulation of the Bezold receptors ·The edo lagal syndrome 137 RIFI RPCES anderson DP Allen W Barcroft H Fdholm OG ant Vanning (1916) J Physiol 104 496 Barcroft H dholm 0 (Velehael J and Sharses Schafer EP (1914) Lancet 1499 Beam A Billing B Idl olm O G and Sherlock s (1951) J Plynol 115 42 Bertolini 11 and Janiach 1 (1944) Arch erp Path Pharmal 203 93 Big RJ Hammond VV Handel-manff JC Por era SR Spencer F C Fckenhoff JL Goodale 11 T Hafhenschiel JH and hetty SS (1949) Amer Heart J 38 1 Bradley SF Ingellinger Fj Bradley 6 P and Curry JJ (1945) clin Inrest 24 800 Brigden Howarth and Sharpey Schafer EP (1950) Clin Sc: 979 Brun Chunudsen FO Land Raaschou F (1915) Icta med Scand 122 486 Cotton TF and Lewi4 T (1918) Heart 7 23 Danieloprolu D Aslan A Maxim Proca ( 6 and Varcu I (1929) Wien Arch ſinn ved 17 391 Dawes GS and Vott IC (1900) Brut J Pharmar l 5 lu Ihlich 1 anil Wallisch R (1943) Z KreislForeci 35 625 Fichna L11 Horvath SV and Bean B (191) mer J merl Sct 213 641 Irshler I housman CL and White VS (1913) Imer J Physiol 138 593 Euler US von and H llner S (1950) Acta plygiol Scand Foster M (1889) Textbook f Physi logy I Gowin HJ (1943) 2 Kresl Forech 35 225 Grayson J and Swan JC (1951) J Physiol 112 441 Greenfield ADV (1951) Lancet 1 1302 Geell M (1943) Z hrere Forsch 35 239 Hegy WR (1923) Arc) Psychiat 88 813 Heymans C and Bouckaert JJ (1928) CR Soc Brol Paris 99 1871 Hill A (1926) 11148cular Actruy Haltunore WJlname and Wilkins 109 Hunter J (1793) II orle of John Hunter edited by J I Palmer London 1836 III Jarisch A (1925) J Physiol 60 410 (1940) drch hre sl Forsch 7 260 (1971) Zhrerel Fors! 33 267 (1948) Alin Ved 15 zen 3 056 hoch E (1931) Die reffektoriscle Self st sieuerung des Kreidlat fes Dresden honzett Hand Roth lın T. (1951) Z hrenalForech 40 193 Lennox 11 G Gibb Aan 1 GibbA IL (1935) Irch eurot Psychrat Chicago 34 1001 Lewis T 11932) Bnted J 1 873 McDowall RJS (1038) Ti Control of the Carcı lafton of thr BI London Longnans

·138
T'he caso zugal synulronu
Yatecfr D (193») drbeitsphysiologie 8 5))
I earce J and Il butteridge D (1951) Quirt Jep 1 h/zol
36 127
Rushner RF (1941) mer ) Ihysiol 141 722
Rutherford RB Godfrey T 11 and Griffiths J (1941)
j I hysol 134 508
Schneider ( (1918) J Imer med des 71 1381
Schneider G (1943) 2 AreislForsch 35 636
Serdel HH (1943) Disch Z Venrenheilk 157 149
Stead I A hunkel 1 and llere (1939) J Clin Intel 18 673
Sunahara F Duncanson D and Edholm (
(1919) fed Proc
8 152
Taylor B6 and loble R L (1920) Proc Soc erp Biol)
73 207
Hardener HL de and Vic #ney RR (1001) Clin Scx 10 101
Warren Jy Brannon L S Stead Land Verrill AJ (1911)
J Clin Incest 24 337
Weiss S and Baker JP (1933) Medicine 12 297
Weiss silkins R and Haynes F# (1937) J clan incest
16 73
Walkins RU Haynon + Wand Herys S (193) į da Intest
16 82
Tood EH and Burchell H B (1950) Personal communication
Mothe (1913) Z KreislForsch 35 23.

·IPPENDI I'I ETHISTOGRAPHY Thts appendix is intended for those who are unfamiliar with the plethysmograpluc method and is divided into two parts A few historical notes form the first part the second contains a short general description of the experimental procedure HISTORICAL NOTES Apparatus for determining a change in the volume of an organ was in use in the seventeenth century Borelli held the view that during contraction a muscle becime inflated I rancis Glisson (1677) confronted this with a single experiment In his book de Ventriculo he sai! But incecd this explosion and inflation of spirits has now for some time past been silenced convated by the following experi ment Take an oblong glass tube of sutable capacity and shape Fit into the top of its side near its mouth another small tube liko & fann! Let a strong muscular man insert mto the mouth of the larger tube the whole of his bared arm and secure the mouth of the tube all round to the humerus with bandages so that no water can escape from the tube Then pour water through the funnel until the whole of the larger tube is completely filled and some water rises up into the funnel Thiy being done now tell the man alternately to contract powerfully and to relax the muscles of his It will be seen that when the muscles are contracted the water in the tube of the funnel sinks rising again when relaxation From which it is clear that muscles are not inflated or swollen at the time that they are contracting but on the contrary are lessened shrunk and subsided For if they were inflated the water in the tubule so far from sinking would rise From this therefore we may infer that the fibres are shortened by an intrinsic vtal movement and have no need of any abundant afflux of spirt either animal or vital by which they are mflated and being so hortened carry out the movements ordered by the brain Some ingenious experiments leatlın. Jan Swammerdam to the same conclusion are shown in 116 Ap 1 (Johnston 1910) In 1824 Por culle applies the principle to the study of the circu lition He was interested in the change in diameter of an artery caused by the heart beat Thus he was able to measures ob ervin 139 arm takes place ·T T < C Hi 17 Hug Ap! A reproduction from Boertaases Biblia aturar showing alts trations of the plethy mnographe used by Jan Swammerdam The test is a literal translation from part of the orig nal text to thu figum I Muscle movement n the frog as the mus le tend ns graspel by the fingers 6 when the hanging nerse is touched the mu cle contraction d*** the hands together II Diethod showing thick ning of muscle during con traction a glass tube through which mu le 18 drawn seedk tran piercing tendons c the nerve touched e contracting muscle fills up centre of glass tube" III Vethed showing these the heart occupies le a space in contraction upon pi ton of glastube lb gla s tube contracting fieart is plent tube of siphon descends with heart contraction e water droplet introduct into d place in tube sh r 78 distance masel by droplet during time of descent 'l\ Vettinad ehostus that contracted muscle takes up less space o tube b musc! threal through lonp of which the nerve is pa loop at top through which silver thrend is drawn ant trop de depeni a little Another metho l of showing the above ture drilled in the siphon c nerve drawn through the sporture (Johnston 1910 ) calier dcpper thral th water froplet sa siphe a glass siphon baper ·Plethysmography 111 the movements of a colunin of water in a graduatel vertical klass tube communicating with 2 watertr,ht chamber which contained a segment of a large artery The same principle was employed by Picgu in 1846 and inde Pendentif by Chelius in 1890 to study circulatory and respirators volume changes in the human limbs The first instrument to record volume changes graphically which could therefore be truls said to have been a plethysmograph (77702 dud a filling and youfeer 1 record) was described by Burson in 1862 Details of the well known Jlosso plethysmograph in use in 1870 are shown in Fig Ap 2 (Luciani 1911) In 190. Brodie and Pussell discovered that the plethysmograph could be used to determine the rate of the blood flow through an Organ This discovery had such far reaching results that it 19 best described in the authors own words Brodie and Russell say Most valuable information is to be gained by the plethysmograph as ordinanly applied but it gives only qualitatıre results which Moreorer in many cases are difficult to interpret During the past three years we have applied a simple modification to the plethysmo graphic method which enables us to determine the rate of flow quantitatively with considerable accuracy In principle this con 9ts of blocking the vein of an organ enclo ed within the plethysmo graph for a short interval of time The whole of the venous blood is thus retained in the plethysmograph and leads to a rise of the lever of the recorder If the recorder be calibrated the rate at which the lever mises enables us to determine the rate of blood flow into the vein In applying such a method as this it 19 obviously essential that the blochage of the sein must not be maintained so long as to impede the flow through the capillaries Under all ordinary conditions the veins are never completely filled so that It possible to store up in them a small extra quantity of blood without checkin, the inflow into them from the capillaries [omission) The danger that the artificial Fenous obstruction may be check in the capillary inflow 19 easily guarded against by noting whether the lever of the recorder continues to rise at a unform rate during the whole period of observation Should this not be the case but the tracın become concare to the zero abacresa line the clamping is being maintained too long a time and the ob ervation must be discarded We have controlled the method by comparing it with obser vations upon the rate of renou outflow as conducted in the esperiments of Barcroft and Brodie upon the kidney the only modificatione se huse introduced being to record the fate of flow ·G E Fug Ap Mos os plethygmograph for recorling sk variat »9 in olure of vessels of forearm (dtagram) glass cylinder to receive the forearm close i bs rubber lapu thin rputs on the board E wluch 13 suspended from the ceiling by art C opening closed with a cork through which the cylindr can be filled with lukewarm water opening through wh ch a thermometer i prani show ing temperature of water O tube through which the cylind r containing the forearm ommunicates with the small cylind e bich float ahti the leser of the fuld ad contained in large sessel P lea i weiglt carrying the pen to write on moving Ozlender of ky mograph wh ch counter, with which it is ronnected by two silk threads pas ing user the od puble pules L1 burette that can be raised or loweret in siling or changing the water in the float The rstrument works as follows when the cheel of the forear contract an amount of water corresponding with the dir tion in volume 19 aspirated from the hoat W to the cylu di Rht raison the font an i depresses the counterporse which recorts tre lun stitilor volume on the rools ing cylinder'17en on the cor trary the role of the forearm iilate A quantity of water in the cylinder BIs det en gut ist Vo that it sinks and 14 rai el recording tla inen A4e of olume To Alou positne or negat so pressure abose the forearm immen in the eyfin Water contarni in the recen er p Where 11 sating (11 unt 1913 A B cara must be taken that its upper I bel is at the eam level o beat the ·Plethysmography from the vein in tead of time, it is a stop witch lekure mine that the two methoxh live nearls uletul result llic method is also able tus ill 1974 which can k* in ertel into an uncometer provided that the sein (an be clamjxd within the oncometer It is also applicable to a limb for the venous outflow can be blocked there by a circular ligature applsed with so much Fug Ap 3 Th mna Cregor Bode FPS The orignal was k ndly loer i by the Royal Suxe ety force as to compress the reins without interfering with the arterial inflow In 1905 Brochte held no fewer than three posts in London Professor Superintendent at the Brown Institution Professor of Physiology at the Royal Veterinars College and Lecturer in Physiology at the London School of Vedicine for Women HI portrait iskoun in Fig Ap 3 It ze not clear where ho and Rusell ·Plethysmography performed the experiments referred to in their paper Nor is it known whether they actually recorded the rate of the blood flow in a human limb though their words oul-gest that they did so Brodie and hussells remark that the plethysmograph could be used to determine the blood flow in a human limb was followed up by Hewlett and van Zwaluwenburg in 1909 The hand forearm and elbow were enclosed in their instrument Compression of the veins without interference with the arterial inflow was achieved by the use of a narrow pneumatic cuff placed on the upper arm Their observations were made with the plethysmograph filled with air and the noted that the rate of the circulation was profoundly affected by fluctuations in the temperature To avoid errors due to temperature fluctuations and those due to movements of the limb in and out of the Wosso type of plethysmo graph used by Hewlett and van Zwaluwenburg Lewis and Grant in 1925 devised the type of plethysmograph shown in Fig Ap 4 It enclosed a segment of the forearm and contained water to main tain the temperature constant The first plethysmograph to be used for the determination of the rate of the blood flow in the hand was described by Freeman (1939) A simple form of hand plethysmograph is shown in kg Ap 5 Zhree years later Granit and Pearson (1938) showed that what was measured by the hand plethysmograph was for the most part the circulation through the skin and what was measured by the forcarın plethysmograph was mainly the blood flow through the sheletal muscles The value of the plethysmograph for the deter mination of muscle blood flow was improved by placing it on the upper fleshy part of the forearm and by arresting the circulation at the wrist to prevent the entry of venoug blood returning from the liand EXPERIMENTAL PROCEDURE This ma conveniently be described by consulering an experiment in which the effect of some procedure is to be tested on the rate of the circulation in the right hand and in the left forearm Room temperature is kept constant at 20 C Fi and entry of persons during the esperiment is discouraged Fig Ap 6 show8 & general view of the subject and plethysmographs on a comfortable rubber mattress on a narrow table luis head sup ported and his body covered with a single blanket is cosered with a rubber surgical glove (herslabe 1949) erseral sizes too large which is stuck round the wrist to the edge of a hole in a f in thick soft rubber diaphragm The diaphragm fits this ystiet snugls-but not tightly for Venous congestion must be The subject 1 The left hanc

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·146 Plethysmography avoided By means of wing nuts and two semicircular metal plates the periphery of the diaphragm is bolted firmly to a 2 in wide flange on the end of the plethysmo,raph The plethysmograph contains water up to the lower part of the vertical glass tube The weight of the water presses the glove every w here agunst the hand From time to time the water is agitated by squeezing a bulb communicat ing with the interior of the plethysmograph and its exterior is heated with a small flame to keep the temperature at 32 C The plethysmograph is mounted on a retort stand placed on a small table beside the subject its height is such as to ensure that the veins of ile Fig. Ap 6 Photograph showing plothysmographs on the right hand an ) the left forearm tho hand are collapsed (Cooper Cross Greenfield Hamiton and Scarborough 1949) The elbon is slightly bent to prevent the communication of respiratory movements to the hand and rets on a comfortablo pillow A narrow pneumatic cuff surrounds the wrist and is held lightly but firmly in position by a crepe buruze The same principles apply to the plethysmograph on the other The upper part of the forearm is covered with a loose sleeve (hrogh Landis and Turner 1932 Grant and Pearson 1938) of thin later rubber fired at each end round a grutably shaped central hole in a soft rubber diaphragm The temperature of the water for the forearm is kept at 34-3, r (Barcroft and Edholm 1913, arm ·Plethysmography 117 1916) The collecting cuff is placed just above the elbow and the arresting cuff on the wrist Both are held in position by crepe bandages (This 19 a convenient point to note that a more even constant temperature 19 maintained in electrically heated thermo E F D C с H A к N M M Fig Ap 7 Dagram of apparatus fo reco ding the rate of arter al nflow nto the ght hand and I ft forearm 14 plethysmographs (thpridom ters n t shown) BB vertical glas tubs ८८ three way glass tapa DD Alde tuba mmunu ating with oom air EE o dera PF trap GC yringes HHO pneumat uffy JJ threr way gl ay tape kẢ de tubeg commun at ng wth room ar LL regeryr fo compresse l ar + / fa rcury màn m ter AN float fyot pump statically controlled plethysmographs which on the other hand are more bulky and must be very carefully made to avoid danger of electrocution (Abramson 1944) The recording apparatus and arrangements for inflating the cuffs are shown diagrammatically in Fig Ap 7 Each plethysmograph ·148 Plethysmography A A is connected through a vertical glass tube B B to a wide bore three way alass tap CC by means of which it can be put in communication with the room through a side tube D D or with a float recorder E E Reflux of water from the recorder into the tubing is prevented by a small trap I The level of the writing point can be adjusted by means of a syringe G G The two collecting cuffs H H are connected to a wide bore three way tap J by mtans of which they can be put in communication with the room through the side tube K or with a reservoir of compressed air L The pressure of the air is shown by a mercury manometer M and maintained at 60-70 mm Hg by a foot pump N The arresting cuff O is connected to a second similar set of apparatus JKLMN with the differenee that the air in the reservoir L is maintained at a pressure of 200 mm Hg All four taps C C J J and both syrines C G are mounted on a borrd on the ky mo,raph table with the foot pump readily neces bible below Before beginnin, recording the writing points are adjusted one above the other on the smoked ky mograph paper and horizontal bise lines are drawn round the paper To obtain simultaneous tracings of the rates of the arterial inflow into the hand and into the forearm the procedure is as follow, Tho air pressure in the reservoirs is checked The tape are turned to put the plethysmographs in communication with the recordere As the recorders aro apt to stick when empty some air is introduced by means of the syringes so that the writing points are raised a httlo above the base lines Taph is then turned to arrest the circulation distal to the foreirm plethysmograph Three quarters of a minute later the kymograph 18 started the switch also turns on a fight illuminating a notice in front of the subject with the words hetp quite still and look at this light One minute after arresting the circulation in the hand (herslahe 1918 Roddie 19.1) tap F 19 turned to inflate both collecting cuffs simultaneously The water level in the vertical glass tubes begins to rise air is displaced into the recorders and the arterial inflow curves are inscribed After 10 sec of venous compression the hj mograph is stopped and the taps turned to put the plethysmographs and cuffs in commumeation with the room air At the beginning of the experiment tracings of the arterial indow are generally recorded at 5 min intervals for or I an hour to con firm that the circulation has reached a steady stite some procedure 19 then tested If a rapid alteration in the rate of the circulation is anticipated inflow curres may be recotiled at more frequent inter als For this purpose the collecting pressure Is applied for about 5 sec at the beginning of ench k or 1 min Thr cfft ct of ·Plethysmography 119 interval the circulation in the hand remunin, arrested anıl the drum continuing in motion At the end of the experintent each recorder 14 calibrated by intro ducing a known volume of air into the stem with the syringe The ditance travelled by the recording paper in 1 min 19 marked fetament imm M 5 D 5 > trac ng Fug Ap 8 Poceduro for calculating tho rate of the blool flow from the To Inflow curve with sloping lue drawn en continue 1 through ho zontal ba o lino B ttom UND of graph pape uled n cont metroy and mill metres to read off tho rate of the blo 1 flow directly in ml/100 ml limb/inn Lower edge of pape on base i ne wth mark D at point of intersection of sloping lin Cent metre scal upight hand de Sloping in ntersects at 2 cm wh ch is al oth ate of the I lood flwn ml (100 ml te uo/main upon it and the volumes of the portions of the hand and forearni cnclosed in the plethysmographs measured by water displacement The rates of the blood flow are then calculated from the curyce traced on the hymograph paper Sloping lines are drawn through the inflow curves to cut the base line as shown in Fig Ap & The cxperiment constant D 19 obtained from formula DE XV ·150 Plethysmography Where is the vertical distinco travelled by the recorder writin point for 1 ml increment of content I is the volume of the hand in hundreds of milliltres V is the distance in centimetres travelled by the hymograph paper in I min A piece of graph paper ruled in centimetres and millimetres 19 trimmed square and a mark made at the bottom edge D cm from the right hand corner as shown in Fig Ap 8 A centimetre scale 18 marked along the edge of the right hand side with the zero at the right hand bottom corner The rates of the blood flow are now read off the ky mograph paper The graph paper is placed with the bottom edge touching the horizontal base line the marh D coinciding with the point where the base line is intersected by & sloping line The distance from the right hand bottom corner of Cthe graph paper up the right hand side to the point of intersection of this sloping line is yad off on the centimetre scale The figure obtained is that for the rate of the blood flow expressed in millilitres per 100 ml hand per minute The rates of blood flow in the hand are read off from the other inflow curves in a similar way To obtain thore for the forearm the values of 1 and 1 being different a new value of D must first be found from the formula The method has the advantage that once the value of D hes been obtained the rates of the blood flow for all the inflow curve for a part can be quickly read off without any further arithmetic The basis for this graphic method is as follows Let X M and I be lefined as above D be any given stance in centimetree travelled by the / be the upward movement of the writing point in centi metres while the paper foes Demn I be the rate of the blood flow in ml 100 ml tissue/nun Then LV IDI In any eren experiment and I are constant can therefore he chosen so that drum paper A distance D os Substitutin, tlus in equation 1 LJ Х V or ·Plethysmography 151 Iluat in the rate of the blocxl flow in ml/100 ml truc/min equal to the upward movement of tlie yriting point in centimetres Similar principles apply to the method of measuring the rates of the blood flow in the calf of the leg and in the foot REFFRE\CFS Abramcon DI (1911) I ascular Responses in ti e Frtremities of Van in Ilealth and Disease Clucago Luiersity «f Chicago Presa Larcroft Hand Exholm 0 G (1943) J 17 y a 1 102 5 (1946) J Physr 1 104 366 Brodie TG and Russell (1995) J Physt ( 32 xlvur Cooper h E Cross hit Greenfi ld A D I Hamilton D Nch and Scarborough A (1919) Clin Sci 8 217 Freeman F (1935) Amer J Physiol 113 394 (li son Francis (167) Tractatus de tentriculo el intestinis Quotel from Michael Fnster (1901] Lectures on the History of Pl jainlogy page 290 Cambridge University Press Crant RT and Pearson RSB (1939) Clin Set 3 119 Hewlett A and Zwaluwenburg Jovan (1909) Heart 1 87 Johnston CA (1940) Surg Gynec Obstet 70 31 herslahe D Mek (1948) J Physal 107 43P -- (1919) PhD Thesis Lon lon Lniversity krogh A Land andTurner AH (193) J Clin Intest 11 63 Lewis T and Crant RT (19) Heart 12 73 Luciani L (1911) Human Phynoli Translate<l by F A Welby London Macmillan Rocktie IC (1951) Il/ye1 112 904 ·Author Inder 66 Ingelfinger FJ 92 Friedlander HD Frost J 29 34 Furcolo CL 75 Jari chA 135 136 رأي Gubbe G6 G181 ell l II 36 43 (eohegan HA 76 Gibbon J H 70 (bbe L 13) 132 133 Gibbs FA 131 132 133 Gilding HP 12 Gli son f 139 Goetz RH 61 97 112 Goldenberg 11 88 90 106 110 Il117 113 1201 Goltz F 58 Goodman LS 119 Gowin H1 134 Grant J1 (rant RT 1 lllu 38 52 uh 67 Grayson) 58 106 131 Green DM 84 116 119 Greene D G 88 90 119 120 Greenfield AD 30 33 79 114 128 Grimson h S 112 Gross F 34 Gruber CMI 29 Gsell VE 134 (utran JB 69 unning RI I 29 happert 1 102 hatz A 102 hatzenstein III 53 hennes RA hetis hing DH 93 hirs HD 75 hnud en O E 132 LochT 13 ) Lonzott H 30 31 93 91 101 102 103 136 ho man ( 129 koster 1 37 Kramer 43 48 hrogh hunhel P 52 132 huntz A 5 hiale ! 123 Landis CM ud 70 Lancia A 95 Largu Cle 30 33 114 Larreboe MG 87 LeCompte PV 67 Lee Tc -6 I ehmann ( 36 I enner la 131 133 134 Telvi T 9 5. 59 9 126 Linchard J 36 Lisah 1 106 Loncland (J 1 Luduena + 1 Lynan (P 60 9 Lynn RB 59 Hamilton GTI 0 Hampel (1 Fig Chap 7 66 Hartmana 20 Haxton HA 0 73 Hajes D1 9 Haynes F11 126 133 Hecht HH 112 Hellner s 133 Henderson a 36 +2 Hermann H 69 Hermann L 3 Hess HR 13 Ifeng C 133 Hoffmann Holling HF 11 15 Ilolton P Foling RC 29 95 Hos arths 128 129 133 June Wt 83 Hunter J 19% Human A 85 Vacfie J 11 8,00 Vacheith R Ilu 110 Varning G1 124 133 Vartazzi 19 Varru J1 Var ca 1 +2 Vic(latches H I 11 Clure ( 9 Vir Lorry RL 31) 33 33 WcD) wat R19 $19 Viel irr Vc Vrchnel 1 12" Ve Swiney RR 131 Velur R Vencler 1 N 81 ·Author Inder 155 דין Vermill AJ Verteris o 43 Dillen JLC 37 Vongar JL 26 Monteith JC 123 Morrison PS 106 Morton ML 56 Yunro PAC 7 TIyers T T Smirk FH Smithwick RH 67 114 117 113 Snyder CH 106 Sokoloff L 93 Spalteholtz 11 5 Stanton JR 97 Start I 88 90 Staub H 2€ Stead I A Ieg 11 213 Stewart T 30 93 132 Stoll A 97 Sunal Arg 132 Swan DA 56 Swan H J C 21 20 23 30 56 81 90 96 101 102 104 106 107 111 119 120 123 12 131 Vickerson M Noble RL 9b 119 13. Obal F 13 Okelberry AM 6 1 Pear on 6B 11 18 59 Periman I 66 Phillips R Pins E L 89 90 119 120 Pollack AA Prinzmetal Prunty FTG 107 119 123 Tanner JM 52 Tavlor BL 44 13_ Trotter 11 6 1 U nas B 29 34 Quensel 43 1898 CCN Vigran IV 119 125 Veeschhouwer G R de 107 Raab 11 117 Raaschou F 132 Rapaport 1 56 Ray BS 75 Reale 1 120 Pein H 43 Reys JHO 37 Richards AN 20 Richter CP /? Pob C 88 90 119 10 Rosenbleuth A 6 Pogg J 70 Roth GM 123 Rothlin C 101 136 Ru 1 mer RF 13. Wahir IG 111 Wallace J 9 11 allzech R 134 Wardener HE de 131 Warren J1 127 Heber E 37 Weiss S 53 126 133 Hest B 90 Whelan RF 93 26 27 30 White JC 67 White 198 Whitelaw GP 61 hins RW 53 59 D0 97 111 126 133 Talson ( 1 Wood E 198 Ho lazd HH 1 1 otte 134 amaan 4 1 Sanderson PH 30 90 99 93 94 95 118 Saul A 56 Schneider M 13 124 134 Sharpey Schafer L 1 9 12 128 129 133 Sheehan D 0 Sherl ch Serringt na 43 Vinmong HT 0 Skr 75 Joung IV 30 Young J2 6 28zeela 11 1 Zweifach B 1 99 5

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·SUBJECT INDEX ADRENALINE action of differences from noradrenaline on arterial blood pressure in animale 94 un man Don on cardiac output 90 on circulatio in brain 03 in tsand 80 m kidneye 02 10 laver 9. in muscle 31 on tu hing of the face 81 on heart rate 88 89 on peripheral resistance on symptoru, 88 after dilatation 3 hand 81 in ay pathectomized muscle 25 central Asociat r action f 31 effect tortorial blood pressure in animal 94 m man SK Os ble d leht after everes 58 on cardiac Sulut 90 ut curculus in brass 93 in calf cer Blot flu calf in capillaries a za czte muscle 2 in forearm de Bi d flow forearra in hand see hand in ks Iner 92 en liter 0. in antzscłe 1 After sympathectomy !! after tal lenerystinn 27 turung ecere se $5 n getreral circulation 88 on heart free best 88 a heart rate 1999 1 oxygen c neurngton 196 or respirat) n 89 elettrophoregs of flust mng After 84 hyperienhlation due to 89 antit iton of 189 ntne tone by 96 Telp tati ne RS ·158 Subject Index ADRENALINE peripheral vasodilator action of 90 role of in fainting 132 136 in phaeochromocytoma 114 in reactne hyperaemia 81 in regain of tone after sympathectomy 67 in transmission at sympathetic nerve endings in muscle 33 in vasovagol attacks in cat 136 in man 132 choch 87 site of peripheral vasodilator action of 92 in stress 155 supersensitivity after sympathectomy 6. in urine in phaeochromocy toma 122 vasoconstriction in hand 80 in muscle with large doses 24 vasodilatation in cats muscle 27 in human muscle sustained 22 transient 17 in peripheral circulation 90 92 ADRENERGIC agents definition of 96 ADAEVERCIC blochade 96 ADRENERGIC bloching agents definition of 96 AFTER dilatation see Actrenaline ANOXIA faunting induced by 128 APOMORPHINE action of 134 BEZODIOLAVES 106 BENZODIOXANE test for phaeochromocy toma 106 123 BEZOLD effect 136 Blood debt after exercise effect of actrenaline on 55 of relense of sympathetic tono in muscle on 51 BLOOD flow calf after rhythmic exercise 54 and intravenous adrenaline w and relen o of constrictor t net during rhythmic exerc; 4 su toined contraction 3" 48 effect of adrenaline on intra arterial infusi ns 10 21 of stepwise increase in strength 21 intraj enous infu ton 2 after sympathertory 23 ·Subject Inder 159 BEDOD flow call effect of benzcilsorane nn during intravenoug in furons of artsengine or pra frenaline 10 of the clasy dlm als lors of the ergat sa group on intravenous infusions 9 during action (f Adrenaline an i norrdrenaline 10- of mixtures feisenaline an l rora Irenalne guent intrueniously on 33 of nordrenaline on intra arterial infume 31 32 Intrar en un infusun2 311 cerebra! amom per minute 03 (talla 1111) effect of a Irenaline n 93 of fainting m 134 of noradrenaline on 93 foot effece of dahydro alkatuds of the ergotoxine group on 97 104 of sympithectomi on JS forearm after nem e blick 2 23 and blanchung in kympathectomuext retro 7 rhythmic exercise 3 and relense of constrietor tone 3 ustainel contrartion 36 1 of sympathectomizel fyrearm 3 during sustainer contractin 36 effect of adrenaline as intra arterial infusi ne 93 (tał le 113) in Aympathectomized fireann 23 (talle III) 2 travenous infusions 15 after nere block ? after sympathet my acute 27 chrys 19 2 of fainting on 9 after nen e block 11 after sympath ectomy f nora trenaline on piraten un infans 30 f ky mothertomy 1764 of warming the barely en 3 After blanching i after my achat my 1 hand effect factrenaline on intre arterial infissi 8 HT) efter synpathurt my intravenous nua no 81 after pathectomy 8 ·160 Subject Index Blood flow band cfft et of benzoritovane on intra arterial infusions 111 after sympathectomy 111 during Infusion of alienaline or noradrenaline ill of dihydro alhalords of the ergotovine ge up intra arterial infufions 99 during action of adrenalme or noradrenalina 104 intravenous infusions 97 after sympathet torty 101 during action of adrenaline or noradrenaline 10. of nerte block on after sympathectomy 101 of noradrenaline on intra arterially RM of ympathectomy op 58 of warming the body on " after 4 mpathectomy 71 hepatic amount per minute 9) (table VIII) bromsulphalein method for estimation of 92 effect of adrenaline on 32 of fainting ort 130 of noradrenaline on 92 muscle amount por minute 93 (table VIII) effect of adrenaline on 93 ( ee also Adrenaline) of exercise or rhythmic contraction , sustained contraction 36 of fainting on 196 129 131 (f noracirenaline on 93 ( eo al , loradrenalin) plethysmographic recording during rhythmic exerci e di thermoelectric method 37 renal amount per minute 93 (table VIII) effect af alreruline on 32 of fainting on 131 of noradrenaline on 9 para amino hippuric Ack thethod of e tmmation of 132 CAPILLARY perimeshihty after sympathectomy of tono after inpathectomy of CARDIAC output effect of adrenaline on 89 90 of fainting on 13- of noradrenaline on 88 90 CEREBRAL blood flog sne Blood flow cerebral COLD constrictor test 104 COVSTRICTOR fub tanco superrengtas ity to after kympathectam in the rabbit 61 CONSTRICTOR tone are l asoconstrictor Tone CONTRACTION sep I xercise ·161 Suljert Index Dp ERU ATT 7 spesi! Tympathetemi Ide of defigit 62 m relation to regain af tone e nature of change in cells after fu ampsthetic hlmxHow in forearm before and after 04 in hand and foot berre and after 6? Celat el 10 in ford flow after 61 early changes after 59 finger temperature after 9 Increase songsvity in chemical stimulation after 6 preganghonic and pnathangloonse effects compare ! 63 recovery of arterinlar tme after of capillary tone after 58 tres temperature change alter 61 erous capacity increase after 64 Wall-ru regenerati un rate of after 6 DIASTOLIC pressure effect of adrenalırsa on my of noradrenaline on 9t) in phaeochromocytoma 11 DIBENARINE 112 DIHYDRD athalosd of the erg t rie grnur 90 Ecton » le circulation 1 I rn of actif DIRYDROERCOCERNIVE 97 }} actrati of 97 17 after adrenaline 103 more action t } Dix DPOFRECRISTIVF 97 Prvi PROFKK OCRAZINE 97 1- NOTOVAL fantir 1.3 FRCOTOXING 16 1 Trrrr99 mlm percin 43 rhythmic bl ddelt efter 2 bloul fon changes during 4, mechans al ut friction luring fu muscle 1) ud fra during 15 role of metabolites in I 53 of sympathetic Med in 18sodilatati n during 4 su teinert blod Aw change during strong entra ti n 49 during weak contrarten 37 Tr echanical t truet nn luring 4 www ·202 Subject Index ERENCISE role of metabolites during : 51 of sympathetic nere during 51 temperature changes in muscle during 37 thermoelectric method 37 FUNTING cardine aynrnpe not the cause of fainting 127 ret ed by anoxia 128 by emotion 128 by haemorrhage 9 127 by httrites 126 by tilting 126 129 decrease in peripheral resistance during 128 effect on blood flow 1 brach 131 in colonic mucosa 131 in coronaries 131 in finger tips 131 in forearm 9 after svmpathectomy it after here bloch 1 in hand i1 in Iver 130 in kidneys 131 on blood pressure 9 $26 on brachiai senous pressure 128 ont cardiac output 126 127 on colour of venous blood 228 on electrocardiogram 131 on heart rate 126 on right auricular pressure 127 233 mechanım underlying 133 role of paturn in 13" of sasadulator fibres to mu clo 13 Similar changes After spomorphine 131 in Anesthetired cat 135 Lulconscioupas during cause of 133 FATICOE caused by adirenutne 88 ILAEMORRHAGE fainting due to 9 137 FIFAPT rate effect of actrenaline on 19 89 33 of fainting on 126 of noradrenaline in B9 80 HEATING Ratio 10 HISTANINF test for phaeochromnej tona 193 HORSOVAL changes in fauntung 132 HIDERTIF ele Dhystm alalls of the engotothe group ·Subject Index HYDROC FNATED alkalonts of the ergotovine pour alkalds HAPFRE EVTILATION lue to adrenaline BB Ils roTFASION FAINTIVE 1126 sce Dihyam ISOPROPYL nora trenaline transient vagodilatation in $34sclo bs 32 hion blond fon see Blod flow Tena! LEER HIX AX see Blood for hepatic VICSCLE Akele tal artero venous anastomoses is 225 blood flow see Blood flow muscle dual cuculatan in us YLACE smooth effect of sympathectomy on 68 VERtr block effect on blood flow in foreren 2 after blanching 7 after byty athectoray 7 on blood Box in hand after ej mpathectomy 72 TORADAT LINE action differences from adrenaline see Adrenalne bradycardia 89 90 effect on arterial blood pressure 90 on cardiac output 10 on circulation LT) animals 33 in cui Bec Bio xl flar calf in forearm see Blood for forearm in hand see Bled flow hand in kidneye 92 22 luter 02 in muscles 03 on general curculation 88 on leart rate 89 90 on peripheral resistance 3 on respuration 89 on skin colour 801 89 11ypertenst n by 90 perspheral asoconstrictor action of 90 in phaeochromocytorna 114 reflex inhibition of the heart by go role ih trongmission at nerte en snigs 33 in urine in plibrorisromocy totie 117 Va oconstrictor schon in hand 87 in muscle 31 in şeriplieral circulation 90 vasod lator acting transient in rauscle 30 ·16% Subject Inder JAFOCIIROVF turnours 114 adrenaline in 114 11" BVP increase in 117 diagnosis of 122 sly cosura in 117 hypertension in 115 120 incidence of 114 noradrenaline in 174 117 treatment of 12 PITUITARY role of in fainting 132 PLETHYSVOGRAPHIC method calculation of results 148 experimental procedure 144 historical notes 139 PRISCOL 111 RELEVERATION of sympathetic fibres 76 RESPIRATION effect of adrenaline on 89 of noradrenaline on 89 REVAC blood flow see Blood now renal RAYTAC contraction see Exercise rhythmic STRESS arenaline in Il SUDOMOTOR test 72 results of after sympathectomy 73 SUSTAINED contraction rce xercise ustuned! SWEATING in phaeochromocy toma 178 SAVPATHECTOMY see also Denervation recorery of inneri ntion after "3 cause of 70 Southwick s pre,,angle mir operation for 70) Tasospastic attacks after 70 SYMPATHETIC Inner ation cold constrictor test for 104 indirect heating test for 170 sudornotor test for 72 vasomotor test for 1 70 TREVOR by artrenaline 89 URINE actrenaline and nord Irenaline ycretion 11 4SOCONSTRICTION in muscle by large do es of adrenaline 24 hy noradrenaline 31 in shin by adrenaline 80 81 by noradrenaline si 81 TASOCO\TRICTOR derse bris to muscle } to skin 59 8 ·166 Subject Index ASOCONSTRICTOR tone central inhibitor action of acirenaline on 81 of dihy riro alkalords of the erg ut wine groups on 4, 102 decrease of in faint 9 regain of after gympathiec toms in fot ,9 in hani u in mu cle 64 release of in muscle by nerve blacks 2 95 by sympathectomy 64 by warming the body I 53 in hand by nerve blacks 2 by sy mpithectomy 6! by warming the body VASODILATATION in fainting 9 129 in muscle sustained by adrenaline 22 transient by adrenaline 17 by is proprl noradrenaline 39 by ne ra Irenaline 30 VASOSTOTOR entre effect of on muscle vessels during exercise 51 54 VASOVOTOR e llapse in phaeochrom scy toms 118 VASOVOTOn test for sympathectomy 0 VASOVAOAL attacks in the cat 13 VASON IGAL syndr ine 126 tee Fainting