·COUNCIL FOR
HIGH BLOOD PRESSURE RFSFANCHI
1955 1956
OFFICERS OF TIIE COUNCIL
President
Vice President
VR MAYNARD H MURCH
MR FRANK E JOSEPH
MR GEORGE E MERRIFIELD
MR I F FREIBERCER
Secretary
Treasurer
OFFICERS OF TUE MEDICAL
ADVISORY BOARD
Chairman
Tice Chairinan
THOVAS FINDLEY MD
MEYER FRIEDVIAN MD
PROGRAM COMMITTEF
MEYER FRIED3/41 VID Chairman
ARTHUR J VERRILL VID
Victor MEYLONITZ VD

·PROCEEDINGS
of the
ANNUAL MEETING
COUNCIL FOR
HIGH BLOOD PRESSURE RESEARCH
AMERICAN HEART ASSOCIATION
Cleveland, Oluo
November 30-December 1, 1956
Volume V

·PUBLISHED JUNE 1957 BY THE
AMERICAN HEART ASSOCIATION
41 EAST 23rd STREET
New York 10 NY
© By the American Heart Association 1957
Requests for permission to reprint any part
should be addressed to the Association
PRINTED IN USA
287

·CONTENTS
Page
Scientific Reports**
STUDIES ON THE HYPERTENSIVE ACTION OF ADRENAL STEROIDS--Abbie
I knowlton MD
Il
STUDIES ON THE PATHOGENESIS OF THE HYPERTENSIVE VASCULAR
DISEASE WHICH OCCURS IN RATS BEARING REGENERATING ADRENAL
CORTICAL TISSUE--Floyd R Skelton MD PhD
31
STUDIES ON THE REVASCULARIZED KIDNEY_Yale J Katz MD PhD
47
THE ELECTRON MICROSCOPY OF THE KIDNEY—Daniel C Pease PhD
57
SOME FACTORS INFLUENCING THE RENAL EXCRETION OF SODIUM AND
WATER-HL White MD
63
Jean Ol er MD, also spoke informally on The Problem of Localization of Function
in the Nephron
In the order of presentation at the meeting

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·Lecturers ANNUAL DIEETING COUNCIL FOR HIGH BLOOD PRESSURE RESEARCH Scientific Reports Y ALE J KATZ VD PhD-Department of Medicine University of Southern California Los Angeles Calf ABBIE I KNOWLTOY VDDepartment of Medicine Columbia University College of Phy icians and Surgeon and the Pre byterian Ho pital lew York NY JEAN OLIVER WD- Renal Res arch Unit Overlook Ho pital Summit J DANIEL C PEASE PhD_Department of Anatomy School of Medicine Uni Sersity of California Los Angeles Calif FLOYD R SKELTOY MD PhD - Urban Vae Research Foundation and Department of Pathology Lour lana State Univerity Medical School New Orlean La HL WHITE MD_Department of Phs 1ology a hing on University School of Medicine St Loui Vlo Reports to the Publie* A C CORCORAM MD-Research Diri ion Cleveland Clinic Cleveland Ohio-(Recent Adiances in Hypertension and Atherosclerosis) GE WAKERLIV VID PhD-Department of Phy jology Unisersity of Illinois College of Medicine Chicago Ill ----Recent 4diances in Ilvper tension) LEVIN L WATERS MD-Department of Pathology Yale Unisersity School of Medicine New Haven Conn -(High Blood Pressure Damage to Arteries Arteriosclerosis An Experimental Study) EDWARD WEISS MD-Department of Medicine Temple University College of Medicine Philadelphia Pa --(The Emotional / roblems of Coronary Occlusion) The foll w geports are not included in the volume

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·STUDIES ON THE HYPERTENSIVE ACTION OF ADRENAL STEROIDS ARBIE I KNOW LTON, VD, Assistant Professor of Medicine, Department of Medicine, Columbia Unirersity College of Physicians and Surgeons, and the Presbyterian Hospital, Meio Iorh, NY For a number of years Dr Emily N Loeb Dr Herbert C Stoerk and mysell have been interested in the relationship between the adrenal teroids and hypertension and we have all hared in the work that I hall report In earlier studies Dr Beatrice C Seegal joined u and along the way we have had considerable a-si tance from medical students who pent the electie period of their third year in our laboratory and who made many valuable contributions to our work I hall not attempt to summarize the literature on the ubject of the adrenals and hypertension for you are perhaps better acquainted with this than I am I shall confine myself to res jewing our own tudies A basic question which remains in con idering this problem is whether hypertension of any type can exist in the ab ence of the adrenal glands or its hormones This question has been answered variously in the literature but in our experience the answer 1 Ye at least in the rat(1) Such a hyper tensive animal is shown in Figure 1 This rat, repre entative of a series de veloped a significant rise in tension after renal damage had been produced by the intravenous injection of an antirat kidney erum in the upper por tion of the chart the weekly blood pressure readings on this animal are plotted In the e and earlier studies the plethy mographic apparatu de scribed by Williams Harrison and Grollmın (2) was u ed in making the determinations After Friedman and Freed(3) de cribed their method in volving the use of the microphonic manometer we hiſted to this technique but did not curarize the animals in the lower part of the chart is plotted the weight of the rat from seek to week The antıkidney erum was in jected 18 days after bilateral adrenalectomy and a high sodium regimen was instituted ie a diet made up of 17 per cent odium chloride and normal saline provided in place of tap water Following the injection of the renal damaging agent, hyperten von developed In order to confirm the complete ness of the adrenalectomy the animal was subsequently at the point indicated by the arros placed upon a sodium restricted reoimen The rapid weight loss dramat fall in blood pres ure and death which en ued afforded con vincing evidence fa lack of re idual adrenal hue ·Rot no 570 160 1405 ADX AKS BLOOD PRESSURE mm Hg 20 - 100 0 - - - 1 2 3 4 5 6 7 8 9 10 NaCl withdrawn 75 50 WEIGHT GAIN gms 25 0 1 1 -25 1 + 2 3 5 6 7 8 9 10 TIME IN WEEKS Ficum 1 Changes in blood pressure and weight in an renulectomized rat given antukidney serum Reprinted from knowlton A. L, Lorb L.hecgal B C Stoerk, IL C and Berg JL Development of hypertension in adrenalectomized nephritse nt maintained on lart Proe hoe Fiper Biol an 1 Ved "1 661 19 0 12 ·It would eem therefore that hyperten ion at lea t of certain types can deselop in the adrenalectomized rat guen no teroid replacement therapy A econd and quite eparate question is whether the individual adrenal steroids may under certain condition be hyperten ive agents The answer to this is again Yes This was first demon trated for the teroid desoxy corti costerone (DCA) by Kuhlmann et al (1) Subsequently Selye (5) pointed out that an experimental animal could be en itized to the hypertensive action of this compound of the renal ma s were reduced of the kidneys were damaged or if a high sodium intake were furni hed The relationship between the odium von and DCA is a particularly interet ing one since the o called DCA hypertension can develop only when sufficient quantities of this son are available In other word this form of hypertension can be wholly prevented by rigid re triction of the intake of this electrolyte even in animals sen itized by renal damage(6) Figure 2 hows graphically ome data which illu trate this point This experiment was de igned so that the odium intake which con tatuted 15 per cent of the diet as odium chloride did not ignificantly alter the blood pre sure either by itself (see the fourth group on the upper line) or in com bination with DCA in a dosage of 25 mg daily (econd group on upper line) or with the renal damaging agent which was a rabbit antirat kidney serum (la t group in lower line) However a combination of the e three factors as anticipated led to a striking ri e in arterial ten ion (econd group on lower line) Of particular interest is the fir t group on the lower line in which the oma sion of sodium entirely prevented the hyperten on which marked the group provided with liberal quantitie of this cation In addition to averting the appearance of hyperten ion the rat on this low odium intake failed to develop other characteristic signs of erce , DCA action ie they showed no renal or cardiac hypertrophy and even the histological evidences of DCA activity were minimized The group shown third from the left in the upper line and also the group in a similar po ifion in the lower line were included in this experiment to determine whether the addition of a potassium chloride upplement would present the appearance of DCA hyperten ion This po ability was considered ince it was known that uch a upplement could prevent the abnormal increa e in keletal mu cle odium noted in DCA dogs It eemed po sible that DCA hyperten ion was in ome way related to the accompanying electrolyte hifts However the data here indicate that the addition of pota ium in no way minimized the re in blood pres ure although the erum electrolytes in the pota ium treated group were le s abnormal than in the DCA groups receiv ing only odium chloride Sub equently Ro enman Freed and Friedman(7) have reported that a liberal intake of pota şium permits the prolonged main ·2005 Low NaCl +DCA NaCI+DCA NaC+DCA KCI Control NaCl 1505 no I 100) DCA STARTED SOLILLLL 1 2 3 4 5 6 7 8 T. OCA STAATED 1 2 3 4 5 6 7 8 DCA STARTED 1 2 3 4 5 6 7 8 Low NaCIDCA + Serum Systolic blood pressure in mm Hg NaCl +DCA + Serum NaCl +DCA KCI Serum NaCl +Serum 100F DCA STARTED لللللللو عطاال 2 3 4 5 6 7 8 DCA DCA STARTED STARTED LLLLLLLL 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 Highest and lowest individual BP reading Average reading of all animals Time in Weeks FIGLRE Effect of DC4 VeC1 KCl and anthidney scrum on rau I lood pressure Reprinted from hnowlion A I. Loel E N Stoerk II C. and Seegal Il C. Diorycorticosterone acetat the potentiation of its act vity by solum chloride J Exp Med 8, 18, 1917 14 ·tenance of DCA hypertension whereas a high sodium diet alone may not due to the development in the latter instance of potassium deficiency Certain other steroids behave similarly to DCA in that their hypertensive properties are accentuated by sen tizing the experimental animal through a reduction of renal mass in the presence of high sodium intake Within the past year Friedman Friedman and Nakashima(8) and al o Selye(9) have reported that 9 a chlorohy drocortisone re embles DCA in this regard As with DCA it is also possible to prevent the development of hypertension with this halogenated hydrocorti one by the restriction of odium chloride provided that a relatnely low dosage of the compound is elected(10) Figure 3 sets forth data on this point All these animals were ensitized at the beginning of the experiment by unilateral nephrectomy half were maintained on a diet re tricted to 002 per cent or le of odium and half were offered a high sodium diet, 06 per cent and given phy iological salıne to drink in place of tap water One mg of DCA was injected subcutaneou ly for ir days weekly this being a known pressor dose of the teroid To provide a comparable degree of sodium retention the dosage of 9 a chlorohydrocorti one acetate was set at 0.2 mg Additional experimental groups were injected with 1 mg DCA and 06 mg of hydrocortisone acetate the latter calculated to upply a degree of activity as measured in liver glycogen a savs equal to the 02 mg of 9 a chlorohydrocorti one acetate From Figure 3 it is evident that evere and equal degrees of hypertension developed in all three experimental groups maintained on a high sodium regimen That this blood pressure effect was virtually dependent upon the liberal odium provided is proven by the absence of hyperten ion in the similarly injected groups in which odium was restricted Although we have had no experience with aldo terone it might be men tioned that this compound also exhibits a DCA like effect upon the blood pressure Intially Grous Loustalot and Meier (11) were unable to evoke hvpertension with the mot potent natural adrenal steroid but Kumar Ander on and Gornall(12) have more recently reported the induction of hyperten ton cardiac and renal hypertrophy with prolonged admını tration of the compound The next question to be an wered is whether those adrenal steroid with a relatively slight capacity to retain odium are alo hypertenne agents and if so under what conditions in our experience and in that of the Fredmans and Nakashima(13) the answer to the first part of this que tion is Yes The conditions under which hypertension occur however are le s limited than is seen with DCA in that it is wholly independent of the odium content of the diet(14)

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·AVERAGE OLOOD PRESSURE READINGS RATS ON SODIUM RESTRIGTED INTAKE 5 RAYS ON HIGH SODIUM SNTAKE Do XT che ! 3 200 179 AVERAGE BLOOD PRESSURE AVERAGE BLOOD PRESSURE ANNO $0 100 O } 2 TIME IN WEEKS YHME IN WEEKS cort o GPS BY Ord Cortison oserare O. & xent On conocolata in po yon + ADRX Group X A OCA GORI ay awk Som -510 cor al Goupa II. Ft cket Contpart an al th effect of cort one and BC wron rat 110o) pressure Reprinte 1 from knowlton I Loeb E N. Sra th HIC Inte J P. and Iefer 1841 } F In luction of artenal bypertension in normal anal adrensleriormzed rain enten cortisone seetate J Exper Mel 96 19 19 Fure 4 illustrates the fact la this experiment the effects of cortison were compared to those of DCA in normal als maintained esther or odium restriction or on a high sodium intake Two group of urtreried control animals were also ob ersed on the experimental deels one of the e caling ad lb and the other offered a limited food intake so that the estsuing weight lo s resulted in body weights approximating that of the corn one injected rais In the group guen libesal quantiti af sodrum both the steroid injected froups behaved similarly and developed ankrant ni es in blood pressure in contra l to both vosnjected group The difference Leineen the two steroids became apparent in the groups on odium it friction Here the cortssont treated animals were as hyperter lle as similar rats on a high odus intake althout the DCA sats under the e condition honed no more n e in tension than did the uninjected control A group oi adrenalectomszed a smals wa included and in the in tance it appeared that the effect of corts ont was even mure marked in the absence of the adrenal gland This h35 sot lonerer > in a subsequent tuds in i hich the hypertensie activity of the omp un? ba leen of equal degtee with and thout the adrenals in situ l'esidrs ports unr Friedman Friedman and laka hima(13) have reported that hydrocorts on & hupeta ne orent and the has i een our expectance al o ronet ·TABLE I Incidence of Ilypertension in Sodium Restricted Adrenalectomi ed Rats Injected urth Steroids Intact controls 11ydrocortisone Cortisone 1Jehydro-F 1-dehy Iro--E 9 a-FIF 90-CIF 1-dehydro- 9 --FIF DOC 1/38# 0/5*** Daily steroid 10405c m 0 0008 001 003 01 012 02 0/3 ** 0/8 0/8 0/8 all" 0/8 all* 0/8 10/32 0/4**** 1/7* all" 0 33 12/21 276** all 05 08 10 all* 6/19***** 1/11***** 7/25 13/25**** 5/8 all* 0/1* ***** 0/7' 12 20 5/7* 3/7* 25 28/30 30 6/6 # Numerator denotes number of rats wuh blood pre sure in exce 9 of 165 Each star represents a death or an unobtainable blood pressure reading Unpullished lata 0/8 denominator denotes total number of rats eramın d ·Within the last few years a number of synthetic sterords have been pre pared all pos essing remarkable physiological acizity with respect to lever glycogen a sajs although with us idely varying degrees of actualy nath te pect to odium retaining capacits We have recently explored the effect of a number of these compounds upon the blood pressure in comparı on with hydrocortisone corts one and DCA (15) Adrenalectomized rats were em ployer and a wodium poor diet was selected in order to avoid any facultation of a DCA like hyperten ion such as was demonstrated above with 9. chlorohydrocorl one Table I els forth the meidence of hypertension the numerator gn mg the number of rats with readings in exces of 165 mm Hg and the denominator the number of ammals in which blood pressures were obtained at the tated dosage The data perlaining to cort one and hydrocor Irsone being indistingur hable have been combined so the tables and figures for similar rea ong the data on 1 dehydro hydrocortisone and I dehydrocor is one have been presented jorth 1s had been previously noted the hiperten ne action of hydrocortisone and of cortisone was again evident in the higher dosages and at the 25 and 3 mg dosage levels an overwhelming percentage of the rats were la pertensive At appropriate do age levels each of the several sınthenc compounds tudied resuked in the appearance of elesated readings in a significant percentage of the animals but it is endent from the averages shown in Table II that none led to as cevere a degree of his pertension conse tenths as did hydrocortisone or cortisone in the capacity to induce hypertes son under the e sodium restricted condition all these compounds hehase like hidrocorti one rather than like DCA since this latter steroid even in do pe as high as 3 mg daih on the salt free diet emploved did not result in hyperten son in a single animal Our instsal thought had been that the hoperten ne property of corti sone under these sodium restricted conditions *3» lmked in ome manner to that actitty which is mea ured in let glycogea as ats This would be con istent with the failure of DCA to produce hyperten son with the regimen as the sterord 19 inactre in this particular type of assay At Dr Stoerks uggestion log do e curies of I lood pressure were computed for hydrocorts one DCA and for each of the analogues shown except 1 dehydro hydrocortisone and I dehydrocortisone flere the do age range which permitted suryaal was too narsow to proside the nece san data to compute a line. f 1 ist al ace in these analyses ne a ¢ in delito D John Ferng and 11 EB ou the Slot of Pulte Balth an idm 917ai ne ved cine of the Faculty of Med Columba Up Crus Nex lor 19 ·TABLE II of 4d d Rimod DRI Hyd or rt son MO ad hydo 90-F3F 90-CIF 1-dt 92-F DOC DI Hroid dengan ng 0 OCH 001 TIS+12 7138# 66+21 13) 30 +20) 818) 00$ 1108) 201 +18 (5) 121213 181 120112 118) 117+ 9018) 1531018 165 + 99181 17113 118) 159 + 9218) 01 012 100+ 8181 99+17 (4) 103+113177 02 03 0.35 11181 MB) 157514 118) 16+116(8) 161 +10 218) 160+12 916) OS 0.8 1181 118) 131 8711) 1 3+13 (8) I 19+17019) 10 1 2 76(4) ## 156+233(8) 16:16 (5) 1378318) 130+ 28(3) 151 108(8) 16615615) 16+ 2 847) 13 +15816) 166+12 7471 169 9618) DI 10=11817) 138(1) 20 2.5 11821 9/11 177+18 118) 15921 0(7) 18515218) 192="8(6) 181 + &B(8) 181 +15 718) 189+10616) he wood primurerede (1 30 SA ESF prex 150+ 7 118) 33 d da es bases d d der ht11 © det m d Eldar IT na hend um ·Log Dose Response 60 34 Due ton drone งา BO* Dace mg FICURE 5 Effel of analogues of hlucort on on iloa ! prasure of ad enalec tom ze ) rat From hnonlinAlloel Land to KHI C Ene I of synthel an logu of lyd ocort son on the bloo] pr 11r falenalectontzed rt sodiunt trtim To be pull she in Endocrin logy 03 Figure 5 pre ents the e log do e curses and the lope of 738 for the hydro corti one and corleone line is significantls dillerent tatistically from the slope of 31 9 for DOC Were it true that the lood pre ure elevating activity of the several analo,u s varied directly with Iner glycogen activity then the Ime of ea h hooli paralle} the hydroconui one hine white u the blood pres ure elevating activity tarudith the capacits to relain odium cach hould parallel the DOC line Rether hypothesis fits the ob ered findings that the lopes of the lines for 9 a fluorohydrocorti one and I dehydro 9 a fluoro hydrocorti one do not differ ignificantly from that of the hydrocorti one line while the slope of 9.a chlorohydrocortisone reembles that of DOC It will be recalled that the ti o Nuorinated compounds dulder Irom the chlorinated compound in that the ratio of the actually a measured by the inser glycogen as ay to the activity with regard to odium retention is relaties higher (po Table all in hi h data relating the actual of the peçal tetoid as com 21 ·TABLE IDI Relate Ictity of Synthetic Steroids Compared to Cortisone and DOC 101 ECITISOSTE DF SCTYCC 7TI CIT DOC FELTROCO?Los 10 PTD LOT 1100 CON 4 "slicht IR 1 go ? LO Cmo TISO O FP 10 t 1 1t 5 1 c OCS w oc TI * sto 5 99- CO Sv-CI 3 to! 2 to 0 Unpublih I lata ·pared to hydrocorl one and de orycortico terone has been gathered from the literature) This gave ri e to the hypothe is that the blood pressure el rating the effect of the e teroid was dependent on neither of the e two adrenal activitie alone but in tead was dependent on the ratio of the two present in the compound This po sibility was pursued with an attemit to reproduce the lope of 9 a chlorohydrocorti one by a combination of 1 dehydro hydrocorti one and DOC in which the relative proportions of Iner glycogen to odium retaining activities duplicated tho e exiting in the chloro compound Examination of Figure 6 rrjeals that the attempt wa highly succe ful the lope of the two lines being indi tingui hable although each hoxed a ugge tion of a lack of linearity The e ob ervation till leave unknown the mechanisms by which the adrenal steroids evoke a nie in blood pre sure although one may conclude that different mechanı ms operate in the ca e of DCA and of corti one In an 200 TTTT 180 160 0. 90-CIF 21 BSE 25 140 BLOOD PRESSURE mmHg 120 1-DEHYDRO-F+DOC 176 SE 2 3 100 80 ILLEU 00 DU 1o DAILY DOSE IN MG FIL NE 6 Lot loser pone 9-2 CIF $ 1.delloF + DOC Irman wllon A1 Loe! EN and Stoerk II C Effect of synthet e analoguet of lyd ocort sone on th bl od sue of Ir alert nu I rats on olum r t ctin To le plus I sled in Indocrinology 23 ·21 TABLE IV Rod, Weight Blood Pressure and Carcass Composition of Rals After Tro Weeks of Restricted Sodium Intake Carcass analysis Bater Final i ody weight (m 160 113* 166 Final blood pre sare mm Hg 112 81" Fat 9 DTI CI FFDT2 N % HFWs cm Group Normals ADRI ADRI + DCA ADRI + E Mormals on limited intake 667 700 Na mEq/100 Gm 153 25 0 133 25 5 119 236 15 I 21 1* 201 110 111 119 10 2 108 C" FFDT Gm 108 113 99 102 3 03 3 17 125 103* ION* 686 65 2 106 2.66 3 25 1/1 112 69 5* 15 1 170 219 117 110 309 1 Drei tresue 2 Fat free fried fis ile » Fat free wet tis. ue Sgn ficantly lufferent from normal values P=007 Unpulli hed data ·as well altempt to characterize further the difference between DCA and cortisone hypertension we has undertaken të sue analys s of electrolyte content on pooled ti ue of groups of ra Currently thi tudy has been repeated ana lyzing each rat indesidually (16) Many tudies are avaçlable indicating that DCA re ult> in marked alterations in the composition of keletal mu cle an increa e in the intracellular content of sodium and a decrease in pota ium heing characteri tically found(17) Other ti sues have shown changes le s consistently A feu tudies are available for corti one the changes in dogs being les consi tent but in the ame direction as tho e seen with DCA (18) Rather than analyze individual tis ues we el cted to determine the electrolyte content of the total carca - althougı ve recognized that this approach might not detect ubtle changes limited to a Ingle to sue such as increases in the arterial ti suc a reported by Tobran(19) and that even significant changes in one ti sue might be ma ked by oppo ing changes in another However if a major difference in the effect of the two steroids ext ted it seemed con ceivable that it might be reflected in the total body composition The carcasses analyzed were tho e of adrenalectomized rals which had been injected with 25 mg of DCA or cort one daily for a two to three week period The effects of the e compounds on odtum re tricted regimen as under conditions of high odium intake were explored and appropriate control group included At acrifice the animal were er anguinated and the gastrointestinal tract was removed along with the heart kidneys right femur and gastrocnemius and a 12 cm of kin On the remaining carcass water content was calculated from the weight loss of 20 Gm aliquots of ground 11 ue after a two wcek period of de iccation in an electric oven at 90 to 105 C The dried tue from ti o to four individual animals was pooled and the fat content determined by ether extraction in a Soxhlet s apparatus The defatted to sue was then finely ground by hand in a mortar and triplicate determinations of odium potas rum and chloride sere carried ou 05 Gm amples and of nitrogen on 10 cm samples Table IV pre ents the data obtained in the rals maintained on a odium restricted intake under which circumstances the cortisone but not the DCA injected rats became hypertensne in the fir t two columns terminal body weights and blood preures are gren Intial weight and blood pres ure in all groups had een comparable averaging 129 131 cm Adrenalectomy without steroid replacement therapy led to rapid weight lo s and fall in blood pre sure and nece sitated the acrifice of this group after four to six days because of their moril und condition The Hody weight of this group has been market with an asterik and throughout thi and the sucreeding two table determinations varying ignificantly from the normal have been o indicated * Fosta: tical a luce in the e anal, he arei delt d to D Agn TB rger ad Miss E Berguo of the Sho I of r blc Ile Ith a d Adm istralne lis e of th Faculty of Ved cine Col mba U ty Tew loki on 25 ·26 TABLE V Body Tercht Blood Pressure and Carcass Composition of Rats After Three Feels of High Sodium Intake Carcass analysis Final hody weight Gin Final blood pressure mm Hg N % FFDT2 % FFWT Gm Gin Hat Water yo Na h mEq/100 Gm CI FFDT? Group 9 DTI 207 155 126 77 Sormals 165 ADRI 163 IDRI + DCA 163 IDR + DCI + LCI 167 108* 172 175 167 673 71 5* 688 70 2* 658 189 191 175 176 166 21 2* 191 175 25 5 217 22 3 237 23 1 119 136 135 149* 12 5 114 110 112 111 105 3 19 295 300 297 3 13 T seu true. rewet ormal values. P=003 ·The two adrenalectomized groups injected with teroid surned the experi mental period of two weeks tho e on DCA growing as well as the normals The terminal weights of the corti one treated rats empha ize the impre ile osowth uppre ion which this compound exerts in the rat at the do age level of 2.5 mg daily The final group were included to examine the effects of a imilar degree of weight lo s per se of interet in the carcass analyses were the findings in the hyperten ne corti one injected rats The water content of this group was significantly less than that of normal animals taned to a imilar weight and the pota lum content was trikingly reduced The remaining determinations in this group did not differ from normal The DCA injected rat which on the odium re tricted regimen remained normolensive honed no vanation from normal in the compo ition of carca es Turning to the groups maintained on a high odium regimen (Table 1) it is evident that on this regimen the adrenalectomized rat is able to grow normally without steroid supplements However the weight loss of the corta one injected animals remained as striking as on the low odium regimen Both DCA injected groups as well as the cort one group exhibited blood presures ignificantly hiher than those of the adrenalectomized control although not higher ihan those of the normals which in this series were slightly elevated Also of interet in the carcass analyscs were the findings in the two groups of DCA injected hypertensive rats Here the impressive changes from normal were the increases in body water in the rats given a potasium supplement and in carcass sodium in the other DCA group Since equally impre ive increa es in body water occurred in the normoten ne adrenalectomized con trols and since the addition of a pota sium supplement presented the accumu lation of erce s amounts of sodium without dımını hing the blood pressure it is difficult to be certain of the relation hip of the e changes to the DCA hypertension In contrast to the DCA injected group the rats receiving corta sone did not how any increase in body water or in sodium The reduction in potas jum noled in the low sodium groups was not impre se in these animals on a high odium regimen The e ti ue analysis studies demon trate differences between the effects of DCA and corli one in the rat DCA when accompued by liberal sodium lead to an al normal increa e in the total body content of this son With corti one neither of the expenmental regimens Id to an increa e in total body od: im De pite this lowering of the pata sium did occur and most markedly in the sodium restricted animals which in this particular tudy were relatively more hypertensie than the group on lugh sodium One might hypothe ure that with DCA the primary action of the compound 13 to increa e odium retention while with corti one it is the pota tum decrease which is the primary one ·20 TABLE VI Body IP'eight Blood Pressure and Carcass Composition of Rals tuith Renal Damage Carla s analysis Final body weight Gm Final blood pressure mm lig Water Fat % DT: % Na mEq/100 cm N % FFDT2 Gm CI FFDT % FFWT Gm 135 I 16 658 210 166 268 107 111 321 Regimen High a controls High Na + renal infarct I ow Ma controls Low Aa + renal infarct 176 183 46 231 1 16 7009 65 7 19 7* 16 1 210* 261 129* 105 100 11 1 2 91 3 28 185 207 67 8* 155 160 25 5 98 106 301" 1 Dried to uc Fat free dne line Fal free wet tatsue gnificantly different from normal" values. P=003 Unipobl hed data ·What relation the e electrolyte changes bear to hypertension of any is not known In order to determine whether the e changes were an essential accompaniment of hypertension in general or were seen only in the hyper tension induced by steroid å similar eties of anals es was undertaken in fats made hypertensne by means of renal damage Dr bernt Hokfelt of the Karolinska In titutet in Stockholm as good enough to prepare for us a eries of animals unilaterally nephrectomized and with an arterial infarct in the remaining kidney a technique first described by Dr Dorothy Loomis of the Long Island College of Medicine To make the data more comparable to these described above the rats were placed on similar high and low odrum regimens Table VI shows the data obtained in these animals along with control rats observed at the same time Body weights were comparable in all four groups Blood pressure in the group, with renal damage was markedly elevated in all of the 11 animals in the high odium grous and less consistently so in the sodium re tricted rats in which only four out of 10 became persistently hyper tensne The animals listed in Table VI in the low codium group were the four mot hypertensile members of their group As compared to the normals on high salt the rats with renal damage showed significant increa es in carcass water and odium similar to the DCA injected animals In addition these renalls damaged rats exlubited an elevation in chlonde and a reduction in potassium Although sodium restriction did not alter the increa ed water content it did prevent the electrolyse change It would seem that this renal hypertension was similar 10 DCA hypertension in that it was accentuated by a high odium regimen and imilar al o in the character of the electrolyte changes which des eloped on this diet It difered from DCA in that sodium restriction although it decreased the hyperten ise action of the renal damage did not prevent it entirely This however may le a quantitative rather than a qualitative difference and the over all similarity between the two is striking On the contrary cortione hyperten ron is di tingurshed from the above by 1te independence of sodium intake and hy the fact that it may occur without overt evidence of renal damage ·REFERENCES 1 Knowlton AI Loeb E N Seegal B C Stoerk HC. and Berg J L Develop ment of hypertension in adrenalectomized nephritic rat maintained on NaCl Proc Soc Exper Biol and Med 74 661 1950 2 Williams JR Jr Harrison TR and Grollman A A imple method for deter mining the systolic blood pressure of the unane thelized rat j'Clin Invest 18 373 1939 3 Friedman M and Freed SC Vicrophone manometer for indirect determination of systolic blood pre ure in the rat Proc Soc Exper Biol and Ved 70 60 1919 4 Kuhlmann D Ragan C Ferrebee J Atchley D and Loeb RF Tortc effects of desoxycorticosterone esters in dogs Science 90 496 1939 5 Selye II Hall C F and Rowley EM Malignant hypertension produced by treatment at de oxycortico terone acetate and so frum chloride Canad Med In J 49 88 1913 6 knowlton AI Loeb E N Stoerk II C. and Seegal BC Desoxycortico terone acetate potentiation of its actinty ly sodium chloride J Fåper Med 85 187 1911 7 Rosenman RI Freed SC and Friedman M Fflect of variation of pota stum intake on pres or acti ity of de oxycorticosterone Proc Soc Exper Blol and Med 78 77 1951 8 Friedman SM Friedman CL and Naha hıma M The hyperten ne effect of compound F acetate (17 OH-corticosterone 21 acetate) in the rat Endocrinology 51 401 1952 9 Selye H On the tori ity of 9a fluorohydrocortionc nnd 9a chlorohydrocortisone J Clin Endocrinol and Meta! 15 381 1955 10 Anowlton A I Loel F N and Stoerk II C Unput I. hed data 1) Cros F Loustalot P and Meier R Vergleichen le Untersuchungen uler de hypertensive Wirkung von Aldosteron und Desorycortico teron Experienta 11 67 1955 12 Kumar D Anderson and Cornal! A G l'o tmorten study of rats made hyper tensive by aldosterone J Clin Fndocrinol and Metab 16 918 1956 13 Friedman S MI., Friedman CL and Naka hima M Observations on the cardio *a-colar renal effects of 9a-chlorol ydroco tisone a cale in the rat Fndo rinology 57 10 1955 14 Anowlton AI lol E. Stork 1 C White J P and Jeffernan JF Induction of arterial hyp rten ion in normal and adrenalectomized rats guen cortisone acetatc J Fuper Med 96 187 193 15 Knowlton A1 Loe! EM and Stoerk HC Fffect of synthetic analogues of Iydrocorti one in the I lood presure of adrenalectomiz irals on simre tri tin To be publi hed in Inlocrinology 16 knowlton AI Loe! E and Stork II C. Depletion of carcas p la 1C1 ani c r one injecte rats To be pull hed in icin Invest 17 Ferrebee J Parker D Carnes II Gerity M Atchley D and Loeb RF Certain effects of dotycottico lerone in ) I hy jol 135 930 1911 1& Day An, Ba A Canl crman 1 R Comparative effects of corto one and DCA on jonic I alone and flad solumes of normal and ad enalectomiz u dogs. Am J Physiol 1/6 193 19,1 19 Tobtan LJr., and Binton Artery wall electrolytes in renal and DCA byper ten ion J Clin Invest 33 1107 1991 מר מעוז ·STUDIES ON TIIC PATHOGENESIS OF THE HYPERTENSIVE VASCULAR DISEASE WHICH OCCURS IN RATS BEARING REGENERATING ADRENAL CORTICAL TISSUE* FLOYD K SKEITON, MD, PhD Director of Research, the Urban Vaes Research Foundation, and Associate Professor of Pathology Louisiana State University Medical School, New Orleans, Lot Whether or not some functional abnormality of the adrenal cortex plays a role in the pathogenesis of hypertension and lypertensive cardiosa cular renal di case still remains one of the major problems confronting investigators in this fi ld The lack of unanimity of opinion on this que lion is well allus trated by statements from two well known investigators one of whom(1) has aid that the e glands probably play an important part in the pathogenesis of hyperten son while the other (2) has stated that it is equally unju ti fiable to conclude that the adrenal cortex plays an importint role in the pathogene is of the di order Much of the esidence upporting adrenal cortical participation in the gene sis of hypertensive vascular di ea e has been derned from observations on the hyperten ise and angioloxic properties of various steroid (3 15) ante Tior pituitary substances (4 6) and chronic expo ure to cold ( 1 7) On the hasis of the e tudie it was postulated(8) that under suitable conditions both hypertension and certain ti pes of cardiovascular di ea e might be the result of an inten e response of the anterior pituitary adrenal cortical system to non pecific tres The original con ept that the changes were imply the result of increased anterior pituitary ecretion of adrenocorticotrophic hor mone (ACTII) is tenalle no loner since non pecific tres with the ingle fxception of cold(7) ind the admini ttalion of large do es of adrenorortico trophıc hormone have been notably unsucces ful in producing either hyper ten on or vascular lesions (1) Neverthele a recent ob errations have gener ally upheld the hypothe is that this gland does play an important yet poorly understood part in their pathogene i For example it has been hown that * T) 19 in est gation was sup! tted by a resta ch grant (II 00") from the National Hart I ttute and a research grant (A 796) from the National In Itutes of Arthriti and Metabol c d eases of 11 Ntonal In titutes of flealth Pullc il alth Serike † Th 3 work was done wl Jeth a tho #3 A st tat Profesor of Path logy id al College of Ge rgia Augusta Ga ·growth hormone administration to uninephrectomized salt treated rats re ults in elevated blood pressure and widespread va cular changes when the ad renal, are intact(9) but not when these gland are ah ent(10) Furthermore It has been demon trated that the most potent naturally occurring mineralo corticoid aldosterone is excreted in increased amounts by patients with essential hypertension(11 12) and produces moderate hypertension when admin tered to intact rats(13 11) Additional evidence implicating the adrenal cortex in the pathogenesis of hypertensie va cular dı erse is the observation that hypertension and necrotizing va cular le tons occur during regeneration of the adrenal cortex in uninephrectomized immature rats given 1 per cent sodium chloride to drink (15) Since the only difference between the rats which become hyperten ile and the control animal which do not 19 the presence of the regenerating adrenal gland this new form of experimental hypertension has been termed adrenal regeneration hypertension (16) This new technique for the production of experimental hypertensne va cular dı ease has afforded an excellent opportunity to study the interplay between the endocrine electrolyte and metabolic factors which contribute to the pathogenesis of both the hypertension and the vascular lesions For example recent investigations (17) have hown that regenerating adrenal cortical tu sue is e ential for the desclopment of the e change hibition of regeneration by either hypophy ectomy or the pre ence of the contralateral adrenal gland completely prevents them from taking place I urthermore reduction in renal mass by unilateral nephrectomy and provi sion of 1 per cent odium chloride to drink are al o necesary for the hyper tension and va cular changes to occur(17) The development of thus form of <sperimental hypertensive sa cular de ea e is al o influenced by age for it has been hown to occur in immature rather than in mature rats (18) Studies now in progres have demonstrated that it is inhibited by thyroidectomy (19) The results of the pre ent experiment contribute additional information on the role of regenerating adrenal cortical tis ue not only in the genesis of this form of experimental hyperten le va cular di ea e hut in its maintenance ince in as well EXPERIVIFITAL PROCEDURE Sixty female Sprague Dawley rats weighing 12 56 cm were uninephrecto mized and maintained on Purina I al oratory Chou and 1 per cent odium Chloride drinking olution ad libitum Ten rats recented no further treatment and erved as controls (Group I) The remaining 50 rats had the right adrenal completely removed and the left adrenal enucleated according to the method de cribed by Ingle and Higgins(20) In this procedure the adrenal cap ule 15 inci ed and the medulla and as much as po abile o ilue cortex ·extruded by the gentle application of pre sure with cursed forceps thus leasing only a fex cells of the zona glomerulosa attached to the capsule which remains in situ Ten of the adrenal enucleated rats recensed no further treatment (Group III) At the end of six weeks an additional 10 rats were subjected to re enu cleation of the regenerated adrenal by the same procedure as that originally employed (Group IV) and the remaining 30 had the regenerated gland com pletely removed Fue of the re enucleated rats and five of the adrenalec tomized animals died within 18 hours as a result of hemorrhage from either the re incised adrenal capsule or severed adrenal arteries Since these animals had severe hypertension and many had shown signs of cerebral lesions they have been considered together (Group II) with a view to obtaining informa tion as to why some rats rapidly develop hypertension and vascular changes following adrenal enucleation while others do not Twenty two rats survived excision of the regenerated adrenal until the end of the experiment and of the e animals 19 exhibited con ustent changes in blood pressure and saline consumption that differed considerably from the three other rats Thus the 19 rats have been considered together as Group V and the remaining three animals make up Group VI Body weight and systolic blood pressure the latter by the microphonic manometer method of Friedman and Freed (21) were determined initially and weekly thereafter throughout the experiment The consumption of 1 per cent sodium chloride drinking fluid was measured daily and the average 21 hour intake per rat was calculated weekly for each group The organs from the animals which died after six weeks were removed weighed fresh on a Cramatic balance and fixed in Bouins olution At the end of 12 weeks all rats were killed by decapitation and their organs handled similarly Paraffin ections were prepared from the ti sues to be studied and stained with he matoxylın and eosin RESULTS The average weekly body weight salıne consumption and systolic blood pressure of Groups I II III and IV are shown in Figure 1 and of Groups I III V and VI in Figure 2 The organ weights are pre ented in Table 1 Before considering this data however it should be noted that one control rat dud and that only five rats in Group III and four rats on Group IV urvived the 12 weeks of the experiment The animals which died in Group III all had hypertension and sa cular lesions and their death was the result of cerebral infarction econdary to the e changes. The deaths in Group IV were due to po toperative hemorrhage at ix weeks hence these rats became part of Group II 33 ·TABLE I Influence of Adrenal he enucleation and Adrenalectomy on the Organ leighis oj Rals uith Idrenal Regeneration llypertension Group No of rats Duration in veels lleart Brain Spleen 9 12 Control 10 908 +26* 1033 +38 1118 +68 Average organ weights in mg Lirer Adrenal (8) 1735 7525 656 +5 +320 +26 1835 9369 462 +17 + 480 25 1773 10820 52 7 +30 +1400 +31 6 Kidney 1588 +63 2007 +93 2311 #210 583 +27 831 #61 736 +31 Thymus 256 +13 214 +10 260 +26 5 12 Adrenal enucleation III Adrenal enucleation IV Adrenal enucleation + Adrenal re enucleation Six weeks V Adrenal enucleation 1 12 1250 +12 2132 +160 1804 +28 11010 +215 19 6 +56 710 176 +26 +19 19 12 950 +18 1732 +50 1830 +16 8276 +210 719 +13 199 +26 Adrenalectomy - 1x weeks Decline ol hypertension VI Adrenal enucleation Adrenalectomy-six kechs Per 1 tent hyperten ion 3 12 1303 +118 2302 +290 1911 #:60 9611 *400 805 +48 169 +44 Standard error of the meat This group cons sts of rats which died within 48 hours following adrenalectomy o ad enal reenucleation at ex weeks.

·The rats which died po toperatively at the sixth week of the experiment (Group II) showed significant growth retardation wlule the rats rf the other groups grew at es entially the same rate (Figure 1) The animals of Crou II also developed the highet blood pre ure and drank significantly more ljer cent sodium chloride solution than did the control Although the rats of Group III slonly became hyperten me their blood pre sure was ignificantly lower than the sy tolic blood pre sure of the rats in (roup II at ir needs and neser reached the les el attained by the latter animal It is al o noteworthy that the salıne con umplion of the rats in Croup III wa significantly lower than in Croup II at six weeks and indeed did not differ ignificantly from the intake of control rats (Croup I) throughout the experiment The salıne intake and blood pressure values of the re enucleated rats (Group IV ) were between those of Groups II and III at the sixth week and did not differ significantly from them After adrenal re enucleation the salıne intake and systolic blood pressure of these anima! decreased slighils Iut not significantly for two Weeks followed by a ne to lesels above thot which had evi ted before the regenerated adrenal was re ( nucleated and higher than tho e which were attained by the rats of Group III There were no significant differences between the growth curves of any of the groups hown in Figure 2 The blood pressure and alıne consumption Were virtually identical in Groups III and V for the first six wecks of the ex periment but following removal of the regenerated adrenal gland in the rat of Group V the blood pre sure de crea ed to a level approximately that of the controls (Croup I) while the salıne intake dropped below that of either Groups 1 or III The changes oh erved in the identically treated animals of Group VI were con iderably different Botha blood pre sure and aline con sumption of these rats decrea ed for two weeks after exci ion of the regen erated adrenal but increa ed thereafter to approximately the same levels which had exi ted Fefore the operation and similar to tho e an Group III In Table 1 it can be een that the hearts of all hyperten ne animals (Croups II III IV and VI) were significantly hypertrophied as compared to controls (Group I) The ab ence of cardiac lypertrophy in rats in which the regenerated adrenal had been removed after it weeks and the blood pressure had returned to normal lesels (Group ) contra ts markedly with the cardiac hypertrophy in similarly treated rats (Group VI) in hich the hyperten son persisted The changes in renal weight es inually paralleled the changes in cardiac weicht hypertrophy being pre ent on all groups ex hibiting lis pertension and an ent in rats with normal lood pre ures The Weight of the brain as slichtly increa ed in all groups as compared to con trol values but the increa e a ignificant only in Group II IV I and VI The Iner was ignificantly enlared in the ral of Croup II M it and VI while no enlargement wa present in the nonhypertensne rats of Group V 35 ·200 260 2404 2204 200- 180 160 120- 100- 00 5 BROUI CONTROL Broum MCLEATON 1 OROU 46 NUCE STON SHOW ME LA NUCLE 80 ON 40 7 9 10 12 120 110 100 90 0011 IL NCI INTAKE ml/2011 TO 60- 301 40 30-4 10 210 200 100 100 170 130+ SYSTOLIC BLOOD PRESSURE MAMA 130 120 E110 100 10- 10 . . 10 11 WEEKS Fictis 1 Influence of taline consumption and adrenal reenucleation on the develop ment of "adrenal regeneration hypertension ·210 2001 2401 2204 2004 110 140 600T WEIGHT 140 110 100 10H TO MU AMaLATION NOUS ORAI TORTY MAU 3 TRUCLEATION ADA AL CTON . ** POS ADRENALE TO MERCATO GO 401 0 10 12 120 110 100 yo 80 IX WCH TAXE /24 hrs not 70 90 40 30! O 0 O 12 210 200 10! 1160 TO 160 30 SYSTOLIC BLOCO. ESSUAE MR Mug 0 30 20 10 00 90 . . wet s 12 n the mnie ance o! Irenales FILLE 2 Infu nce of d n le to y hyperten n ni ·TABLE II Summary of Morphological Obseriations Group hidney Heart Brair A Irenal (s) Pancreas and mr entery Mo lesions no lesions Mo lesions No lesions IL Arteriolar sclerosis and fibrinoid necro 14 perivascular tloka tac Froliferation Severity of Je tons 21 Sclerosis and fibrinoid necrosis of cap ular arterioles with focal necrosis Periartering nodosa and sclerosis and fibrigord necrosis of arteriales Severity of Jesions 21 of cortex Severity of le long 25 Shigh degeneration f gl merular capillaries focal tubular la ochilia an Wilatation Tova cular le one Sclerosis and hil rinoid neurosis of glomeruli and arteriol tullar la ochila 1 latation an! luyaline ca ts Severity of IN 24 Iske Group II Severity of Je on 18 Lihe Group II Severity of Io son Ilyperpla.tic arteriolar clero 1 present in 12 out of 19 tals Like Group II Seventy of long 2.5 Elema focal hemorrha, asteriolar sclerosis ant fibrinoid degeneration and Cvetic infarcts Severity of lions 27 Like Croup II Severity of le ions 06 Like Group II Severity of lesions 10 No lesions INC IY Like Group II Se enty of le tons 09 Like Croup II Severity of less 10 No lesions Iike Group II Sescrity of le long 10 Lake Group 11 Seventy of Jesions 20 Hyperplastic sclerosis of Like Group II Serenity of les ons 01 Like Group II Severity of lessons 17 No lesions V caj ular Like Group II Severity of lessons 08 Like Group II Sererity of lesions 10 arterioles in + out of 19 rat. Lake Group 11 Lesions in 2 out of 3 rats Severity 10* Like Group II Seventy of le long 05 Adre als temored at sx weeks.

·The weiht of the regenerated adrenal gland in Groups 11 III and IV was Slonificantly less than the weight of botli adrenals in Group I Furthermore no ignificant difference existed between the weight of the regenerated adrena! at ir and 12 weeks (compare Groups II and III) and no greater adrenal regeneration was produced by rc enuck alion (compare Groups III and IV) The plcen was enlarged in all experimental groups The weight of the thy mus in the rats of Groups II and III was not significantly different from the thymus weight in control rats (Group 1) but in the re enucleated animals Croup IV) this gland was significantly maller On the other hand the thymus was significantly enlarged in both groups in which the regenerated adrenal had been removed (Groups V and V) despite the difference in blood pre surt in the e rits Morphological Studies Since a detailed presentation of the morphological changes which deselop in rat with this type of experimental hypertension has teen publi hed el culiere(16) they will not be described here other than in the brief outline contained in Table I In general the le ions are virtu ally the same as those wluch accompany experimental hypertension produced FICURE 3 dn y of rat wth prst nt hyp rt nin xwek trampl to remov I oft regenerat d drenal gland (op 1) Cloner ! h w fbrinj n cro$an! ffer nt artel lowe Wyperplasti fi rolo cl 19 wth ma ke ! nrrowing of it fann Il nato ylna deo i X 100 39 ·in this species by a wide variety of procedures and except for periarteritis nodo a they closely resemble the changes of malignant hypertension in the human being The eserity of the lesions has been evaluated grossly and microscopically on a scale of 0 to +++ and the figures for each group shown in Table II represent the p oportion of the possible maximum The most severe and widespread lesions occurred in the rats which died after six weeks (Group II) The hemorrhage causing the death of the e animals probably was the re ult of the severe sa cular clerosis and fibrinoid necrosis of the adrenal arterioles which presented the e vessels from con tracting after being evered the lessons in the rats which underwent adrenal re enucleation (Group IV) were more severe than in the adrenal enucleated rats of Group III but less severe than in the rats of Group II Except for light renal arteriolar hyperplasia no lesions were ob ensed in the animals of Group V On the other hand the similarly treated animals of Group VI howed changes identical with those observed in the other hypertensive rate I epresenta ive lesions from one of the animals in this group are illustrated in Figures 36 4 FICLA 4 Pertartentie nodo e of panereatie intery from rat with permittent hyper lension dix weeks after complete removal of the regenerated a frenal gland (Croup VI) Mote aneuryumal dilatation largely fille 1 with organizing thromt us Hema 1orylin an I cos n X 68 ·5 FIGURE > Coron ry ve el of rat with perse tent hyperten ton weeks fter en plete emoval of the rep n rated adren 1 gland (Group !) nor early fib nor! d& nerat on of the tred a and the Irge I amy 11 in the tima of tl Ves ? Hen atoxylın anleo in X 30 t 6 F1CL RE 6 Sect on of b ta from it with PSD hyperica on weeks o plet ren oval of the ten rat ! Iren Il nd (Group VI) sh wing hypert at lo cler sis and unde lyi & old cysti infarct. Im toxin in i en in ·DISCUSSION The present observations substantiate the important role of regenerating adrenal cortical tis ue in the pathogenesis of the hyperten ion and va cular lesions which develop in rats following adrenal enucleation Thus re enuclea tion of the regenerated gland in rats already hyperten ne from adrenal enu cication six weeks before produced only a slight and tran ient decline in blood pressure which subsequently ro e above the pre existing level as the corter again regenerated Furthermore complete removal of the regenerated adrenal at six weeks in similarly hypertensive rata produced a fall in blood pressure to normoten ne levels un 19 out of 22 animal On the other hand three such adrenalectomized rats remained hypertensise While the e result hould be considered preliminary becau e of the small number of rats wluch remained hypertensile they nevertheless suggest that adrenal regeneration hyperten ion is initially dependent upon the presence of regenerating adrenal cortical tis ue but that it can become independent of adrenal cortical func tion The persistence of hypertension after removal of the regenerated adrenal cortex in some rats is remini cent of the hypertension ( meta corticoid hyper tension) which remains in rats after cessation of prolonged de oxycortico terone acetate admını tration (22 23 21) The mechanı m re ponible for the maintenance of meta corticoid hypertension or that hyperten ion which persi ted after removal of the regenerated adrenal in three rats in the present experiment is not known However renal arteriolo clero is is e pecially prominent (24) in animal with meta corticoid hypertension and bilateral nephrectomy in uch animals is followed by a reduction in blood pres ure toward or to normal limits (21 25) Hence the pre ence of evere renal le ions in the three rats with persistent hypertension and their virtual absence in similarly treated animals who e blood pre ure returned to normal following removal of the regenerated adrenalvage is that ome renal mechani m may be involved in the maintenance of the po t adrenalectomy hypertension in the former rats The 10 rats that died within 48 hours after the econd operation (Group II) point up the etiological significance of odium chloride in the genesis of adrenal regeneration hypertension and vascular di ea e The c rats devel oped the highest blood pres ure and mot evere sa cular lesion and alo drank the mot alıne olution On the other hand the rate of Croup Jil he came hyperten ave more lowly and generally shoned k s trere la cular changes than the rats of Group II they never drank significantly more tline than control animals in hort it has now been de mon trated that with onh adrı nal regineration hyperten ion does not develop (17) with a alıne con umption no greater than uninephrectomized controls it dx water to drink 12 ·develop while with a consumption of saline greater than the controls the great est hypertension and mo t sesere sa cular lesions have occurred A further correlation between blood pressure and alıne intake was ob ered in their trikingly parallel changes following re enucleation and ex cision of the regenerated adrenal Whether the changes ob erved in the sodium chloride consumption under the e conditions reflect altered adrenal or renal function is not known Hontser the fact that after removal of the regener ated adrenal the hyperten ne rats with renal lesions drank more alıne than the normoten ile rats without renal lesionsuggests that under these condi tions at leat the polydip ia was on a renal rather than an adrenal basis As tated previou ly (16) the mechanism by which regenerating adrenal cortical tissue participates in the genesis of adrenal regeneration hyperten sion remains unknown Nevertheless it has been con idered of significance that hypertension and cardiovascular renal le ions result from conditions in which altered adrenocortical function presumably exits and in which non specific tress appears to play no part(15) It was originally suggested that the regenerating adrenal cortex might ecreting increased quantities of gluco corticoid mineralo corticoid or both in respon e to the increased an terior pituitary secretion of ACTH induced by the sudden fall in circulating blood corticoids econdary to the adrenal enucleation of the e suggestions perhaps the most rea onable i that an imbalance exz is between the produc tion of gluco corticoid and mineralo corticoid as a result of the enucleation procedure This would be quite compatible with the fact that enucleation re moves those zones of the cortex which are felt to be associated with gluco corticoid secretion but leaves at least part of the zona glomerulosa which is considered the site of mineralo corticoid secretion and from which the adrenal cortex largely regenerates The sugge ted imbalance might be ex pected therefore to be in favor of mineralo corticoid secretion This possa bilty remains to be tested under in rito conditions similar to those of the pre ent experiment although in titro studies (26) have hown that the principal teroid ecreted by the zona glomerulosa of enucleated rat adrenal glands is aldo terone SUMMARY Severe hypertension and vascular lesions are produced in rats as the cortex regenerates following adrenal enucleation Previous experiments are referred to and discus ed The e demon trate that thi new type of experimental hyper tensive vascular disea e develops in young growing female rats that have the renal mas reduced by uninephrectomy and are given 1 per cent sodium chloride solution to drink Although it is not necessary for rats bearing regen erating adrenal cortical ti sve to drink greater quantities of ahine than con trol rats in order to des elop hypertension and sascular lesions it has been ·shown that excess sodium chloride must be available since replacement of the salıne drinking olution with tap wa er presents the hypertension and vascular changes The present expriment further implicates sodium chloride in the pathogenesis of adrenal regeneration hypertension and vascular dis ease since rats which de seloped the most fulminant hypertension and vascular lesions also consumed the greatest quantities of salıne The pre ent group of related cxjeriments al o shows the effects of (a) a second enucleation and (b) remosal of the regenerated adrenal six weeks after the fir I enucleation when hypertension was pre ent Re enucleation of t'le regenerated adrenal in four rats produced a transient decrea e in blood | ressure and salıne consumption followed by a rise to above the pre exist ing hypertensie levels Complete removal of the regenerated adrenal cau ed a fall in blood pre sure from hypertensie to normotensne levels accompanied by a drop in saline con umption to below normal limits in 19 rats while three similarly treated hyperten ne animals showed only a transitory fall in blood pre sure and saline intake which returned to preoperative levels The presence of moderate to ciere arteriolar lesions e pecially of the kidney in the three rats which remained hypertensive and the finding of only light thickening of the renal arterioles in 12 of the 19 rats which became normotenente sug that the hyperten ion in the former an mals had become independent of tra regenerated adrenal and was maintained by ome renal mechanism Acknouledgements The author wr hes to thank Viss Anne Dye for technical assistance in the conduct of this experiment and VIt Petty Talson for the histological prepa rations The charts and photomicrographs were prepared by the Department of Vedical Illu tration REFERENCES I Coldblatt II Inatomical Considerations of Hypertension Hypertension a Sym pouum Vinneapoli Uni ersity of Minnesota i re Edited l, Bell F T 1951 D 5 ? Crollman 1 Experimental Studies on Hypertension llypertension & Symposium Minneapoli Uni erity of Minnesota I se Edited by Bell ET 1951 p 2 3 Selse 11 fla!! E and Rowl y F1 Valignant hyperten ion produced by treatm nt with devory corti o les ne acelate and sodium chloride Canad Med As n J 49 88 1913 + Selye H1 l'hy rolngy and Pathology of Fxposure to Stre & Treatise Ba ed on the Conc pts of the General Adaptation Syndrome and the Disease of Adaptation Montreal Acta Inc 1937 5 Selse 11 Produt n of hyperten son and hyalino w ly deeorocorti one Brit Med J 1'03 1930 6 Selye 11 Role of the hypoplysis in the pathogenesis of the di ses of adaptatan Canad Ved In J 50 195 19H 41 ·7 Selyet On the production of malignant hyperten only chroni epo ure to various damaging agent Rev Canad de Biol 2 501 1913 8. Selye | Gen ral adaptation syndrome and di ea es of alaptation J Clin En docrinol and Metab 6 117 1916 9 Selye, 1 Rol of somatotrophıc hormone in production of malignant nephro clerosis, pertarteritis nodo a and hyperten Ive diseas Brit Med J 1-63 1951 10 Selye I and Bois ? Indispensability of the ad enals for the nephrosclerotic action of hypophyscol preparations. En locrinology 58 739 1956 11 Genest J Lemieux G Da ignon A Low E Mowa zynski tani Steyermark P Human artenal hype tension a state of mild chronic hyperaldo Ieron m' Science 123 503 1956 12 Gornall AG Gwilliam Cand Hall AED All tero etc etion in various clinical states J Clin Endo rinol and Metab 16 950 1956 13 Kumar D Hall A ED Maka hima R and Gomall AC Cumulative effect of ald terone adm ne tr t on in rats i roc Canad Pl, ols 1955 p 37 14 Kumar D Anderson and Cornal AG Postmortem study of rats made hyperten ise by aldo teron J Clin Endocrinol and Wet b1 13 1 353 15 Skelton F R Development of hyperten on and card o a cular renal lesions during adrenal regeneration in the rat Proc Soc Expe Biol and Ved 90 349 1955 16 Skelton FR E perimental hype ten 1 e a cula de a accompanyink adr reg merata n n the rat Am J Path 32 1037 1956 17 Skelton FR Adrenal teg eration hyperten n and factors influe cing its de el pment AM4 A ch Int Med 98 419 1956 18 Skelton FR and Gullebeau J Influe ce of age on the development of adrenal reg e ation hype ten on Endoc i ology 59 01 1956 19 Gu llebea J and Skelto FR Inhabitio of adren 1 reg n atron hypertension by thyroid ctomy Unpull hed ob ervati 20 Ingle DJ and Higg GM Regene tion of the adrenal gland following enucleatin Am J Med Sc 196.39 1938 91 Friedma and Freed SC M crophcm omet findet determi ation of systol c blood pressure in Prc So E per I and Med 70 670 1919 2 Prado J 1 Estudos Tre Hipe te sao Horm n 1 Fxpmntal Tese para o oncurso a Cadeira d Quimica Fı 1ologica-Fscola Paul la de Meica S.Paulo 1950 93 Fredman SM Friedman CL and Naka h ma Sustained hyperten on lico ! following adoiini tration of dor) ne acetate ( d enoco tier prep rs son) I Exper Med 93 361 1951 4 Creen D M Saunder Fehlgren N and Cra RL Self sustaining po DCA hyp rtens e card o ascular disease Am J Phys of 170 91 195 a d Sturt ant FV Jr Me ha ma 95 Green DM Calg RL Saunders FJ of n phre tomy Im Ihysiol 190 477 of de ycort costerone act on efft 1952 Sec to of aldosterone by the 26 Giroud CS Stachenko J and Inning E. HI I or Sor Frrer B 1 and zona glomeruloe of rat adren l glands 1 cuhati Med 92 154 1956 t Ar

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·SI UDIES ON THE REVASCULARIZED KIDNEY* HALEJ KATZ, VID, PhD, Associate Professor of Verlıcıne Department of Medicine, Unirersity of Southern California Los Angeles, Calif The idea of increasing the kidney s blood supply in order to improve its function or lower I lood pres ure is not a new one According to Siter(1) the fir t attempt at renal reta cularization was made by Tumlier of Parig in 1890 In 1901 F debohls (2) of len Jork decap ulated the kidneys of a number of palients with chronic nephritis He beliesed that the beneficial effects of this procedure re ulted from the growth of new blood vessels into the kidney from the urrounding tructures A few others(1) shared this enthusiasm for renal reva cularization but in general little attention was paid to the ubject until Paunz(3 4) in (ermany and Mar Video and Don nelly (5) in the United States grafted omentum into the incred cortex of the kidney Paunz occluded the renal artery of several does after the procedure Following Goldblatt (6) of ersation that some of his hypertensive dogs became normoten ive if they developed spontaneou ly an accessory renal blood upply interest in the deliberate revascularization of the kidney was renpwed In addition to omentum (78) mu cle(8 9 10) and sleen(11 12) came into ue as blood ve el donor tiles There were a few observa trons(11 12) of amelioration of hypertension in dogs following ome of these procedures but re ults in human hyperten ion and renal insufficiency were disappointing(9 13) It appears to be not generally appreciated that for the satisfactory revas cularization of any organ the blood ves el donor mu tte endowed with a rich blood supply and in the ca e of renal reiascularization the blood reach ing the kidney mu t be at a suficient head of pre ure to upport glomerular function Baronofsky Sprafka and Mobler 14) u ed loop of intestine for the re va cularization of the heart Becau e of its rich blood supply and the rela tively small drop in arterial blood pre sure between the aorta and the intes tine a egment of intestine seemed ideal as a donor of blood ses el for the kidney These studies for the mot part have been described el ewhere(15 16) They show that va cular communication between the intestine and the kidney can be developed and that kidney function can be supported by such a blood upply * Th s study was supported by grants from the Un ted States Publc Halth Service the Los A les County Heart Associat on and the life In urance 11 die I Re a ch Fund 47

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·FICLAE 3 Radiogr pl slowing barium sulfate injected into bran h of mesenteric tery of segment of stall i te t ne attached to kidney 51 ·se TABLE JI Acute Renol Artery Occlusion and Indigo Carmine Freretion Dog Type of renal teva cularization I Nephrocolonopery-2 months R Nephroduode nopexy-2 weeks Nenal artery occlusion 5 56 pm Indigo carmine injection 20 ml Dye appearance an urine 6 10 pm 603 pm 6 03 pm 10 ml R Nephrojejunope1)-3 months I Nephro iteomy-6 wechs 6 10 pm to six wechs) Table III li ts the animals o fudied and the effect of renal mo e instances after total occlusion of the renal arteries (approximately three after occlusion of the renal arteries had their renal arteries tran ccted in 6 05 pm WE Bilateral nephrojejunopexy-1 month 1 52 pm 5 Otp m liv 10 ml 453 pm 10 ml R Nephro ileopess-1 months I Nephrozujunopeu 10 weeks 1 31 pm 1 59 pm I 50 pm L Nephrocolonopers 3 11 pm Vone by 3 15 pm 20 ml 3 12 pm 2 O ml 3 25 pm Released renal artery clamps 3 50 pm ·TABLE III Animal Suriital and Plasma Nitrogen After Renal Artery Transection Dog Survival Pla ma urea nitrogen Before After tran ect on tran action (Average) (Maximum)] (Average) 13 29 22 19 27 17 II III 18 32 11 Sacrificed after 212 months 17 months still living 22 months still living 18 months still living 171 months still living 6 months dead IV 21 25 12 V 14 20 12 VI 12 27 23 Av 167 28 9 162 artery transection on blood urea nitrogen and animal survival and includes follow up studies on dog> previously reported (10) Table I lits the renal function in dogs who e renal arteries have been tran ected or occluded TABLE IV Effect of Interruption of Renal Artery on Renal Function in Revascuları ed Kidneys B! et an echon After trn ct on Renal blood flow (ml/mn) GC merul 61t la rate (ml/mn) Rnal blo d F Itration f to (per cent) Gl me ular filtrat on rate (ml/mi) FItrat on fction Dog (ml/min) (per cent) I 200 15 11 174 43 39 V 200 56 8 57 37 299 171 VI 227 51 41 12 #VII 213 49 33 122 25 32 Penal a ter s Lot lly occluded but not tran ted 53 ·DISCUSSION It appears from the e studies that the kidney of the dog can do well sth a blood upply which is entirely peripheral Cook and Pear on17) report a ca e of a 28 vear old man with bilaterally thrombo ed renal arterie The ource of the kidney s blood supply way from dilated capsular se els Prior to death the urt a clearance was 75 per cent of normal One might que tion the sidom of introducing additional blood in the kidnes of patients uffering from renal arteriosclero is or chronic glomeru lonephriti when such kidneys do not lark for blood at their portal let once the blood enters the kidney it is up again t an increa cd re istanct to its flow out to the corter becau e of carring and contraction Therefore it is pos sible that bringing additional blood to the nephrons by a peripheral type of ory blood upply would improve the kidney , function One po ble method of achieving this purpo e has been de cribed There is nothing to suggel that the procedure hasm the kidney and studies to be reported later uger i that under ome circum tances renal blood flow in dogs is increa «d Acce Ichnorledgement This tuds repre ents the combined efforts of a number of individuals The author is grateful to Di lian D baronof hy in sholahoratory at the Ancker Ho putal St Paul Vinne ota the e me ligations were initiated and to Dr Donald Hannon John Alden Charle Turback and Jo eph Spralka of the Univerity of Vinne ota who gau generou ls of their time and urical Gratitude is al o expre ed to Dr Paul Starr Profe or of Vedicine Uni veraly of Southern Lalifornia for his inter i and enroura ment and 10 Dr Frank (arbak for hi able as tance REFERENCES 1 Siter E. U Results of expriments on kidn ys will pe sal reference to decap ulation and tabl, hent of collat ral circulation org Gynec an i OL 15 70 191? 2 Edelsohi с } The cure I chronic Bright s diaset (peral n Ved Rec 60 961 1901 3 Paunz, L Dauenerguch uler die Fr etzung der Arteria renalit durch lun tlh h norgerufene letzana tom n Zucht fre riper Vet 71 3 1 4 Paunz L Die ertraglomerul se lasrulati ani ndilir annd dur I hul be Netzansstomosro Zisch grs exper Med 93 396 393: 51 ·5 Nachder del nd Donnelly GL Vale of omentop sy in establishing an ad entitious circulation in the n mal k dney Pro Soc Exper Blol and Ned 10 271 1939 6 Coldblatt I Stude on exp rimental hypertension VII E perimental produ tion and pathogene is of hyperten von due to renal ischemia Am Clin Path 10 40 1940 Ahad 7 Dav: H4 and Tullis I FJr Effect of the exprimental produ tion of an acces o y hlod supply upon normal kidney Po Soc Exper Biol and Med 40 161 1939 8 Goldberg S Roltard Sant Katz L M In rea d collate al blood supply to the kid ey in re I hype ten on Surgery 7 869 1940 9 Brucer Mand C ter RF Nephro o ne topevy a d nephromyopery in the treatment of arterial hyperten on Ann Surg 113 3ui 1941 10 J zbas DM Das Prollem der Ke kuları atio der Nie e und ein Bd utu fur de B handled neph n bed gt n Hochdrucks bull chi e med W1 sens h 2 399 1917 11 Ce qua S and Samaan 4 Cure of e periment 1 renal hyp ten ion Clin Sc 4 113 1939 12 Mansfield J S Weeks DM Stein A and Vi to Redu tion of e peri mental enal hype ten zon pest of spleen o omentum to th kid cy Proc Soc Exper Biol and Med 40 708 1939 13 Weeks D M Steiner A and V ctor J Spleno enopexy Brential hypertension report of 3 ca es su gery 19 515 1916 14 Ba onof ky ID Spraha J L and Nobl JF Ue of intestinal loops for re as ularization of th heart Crculat on Re 2 506 1951 15 Katz I J Hannon D T Aldi J F and Baronof ky I D Re ascularization of the kidney Surgery 39 693 1156 16 Katz Y J Hannon D W and Baronof ky ID Stud es on hid ey reva cularıza on renal fun to following r a ularizati n d Lulate enal at ry trn Srgery 40 140 1956 17 Cook CT and Pe son RSB Hype] is wth ath omatous (bt uction of rnal a ter e J Path and Bact 58 561 1910 J tio 55

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·THE ELECTRON MICROSCOPY OR THE KIDNEY* Summary of a Review Presented to the High Blood Pressure Research Council Meeting, 1956 DANIEL C PEASE, Pu D, Professor of Anatomy, Department of Anatomy School of Medicine Untersity of California, Los Angeles, Calif INTRODUCTION AD VETHOD Our present understanding of the complex structure of the kidney has been developed during three hi torical periods When ectioning techniques suit able for clectron microscopy were first being devised the kidney was studied in Bethesda in Paris and in my laboratory in Lo Angele By current standard the work was crude As methods improved Dr B Vincent Hall at the Univerity of Illinois (1) devoted his efforts to a study of the glomerulus and added greatly to our knowledge of the important part of the kidney In the third hi torical pha e currently acceptable methods were employed to obtain high re olution electron micrographs of adequately preserved material The Karolınska Institutet laboratory in Sweden (23) and my laboratory (15) have licen particularly concerned with this work O mic acid carefully buffered as the firalive of choice for almo 1 all elec tron microscopy that deals with tissue ections in our laboratory the most atisfactory results were obtained when an ice cold olution of fixative way dripped on the expo ed surfaces of kidneys of living animal after removal of the capsule The fixative penetrates e tablishing a concentration gradient Just below the urlace is a zone particularly well pre erved Obviou ly this technique is limited to the corlex when the medulla is to be tudied excision techniques are required The pre ervation in that ca ei not as good lluman material of course cannot be handled in this manner and this impo es a definite limitation on the work that may sub e quently be done Glomerular Capıllanes Flection micro copy has demon trated that glomer ular capillartes have a surpri inely complex and unexpected trucluri Epithelial cells are su I ended in th urinary pace and make contact with the capillary all only by myriads of tiny terminal prore es or leet The terminal proce es from different cells or from different arm of the ame cell form sy tems which interdigitate with one another everywhere over the urface of S prorted by er from the Uited States Pull II alth Srce 57 ·the capillaries There are slots between adjacent feet so that this layer does not constitute a barrier to diffusion processes On the endothelial ide of the capillary perikarya abruptly transform into excessively thin sheets of cyto pla m that extend long dutances constituting the great proportion of the capıllary lining The attenuated endothelium is perforated by large numbers of pores These usually measure a little over one tenth of a micron in diameter and are closely spaced one beside another They are een particu larly well in tangential sections of the capillary wall Obuously such a fenes traled endothelium cannot be regarded as an important diffusion barrier The only continuous barrier between the blood stream and the urinary spaces is the basement membrane Three extracellular layers constitute this structure in the center is a layer of dense material that is probably the principal structural component On esther side of this den e lamına are zones of low density On the outer surface the epithelial fet penetrale slightly into one of these zones and on the other side the endothelial heet rests upon a similar zone One might wish to call such layers cement layers and they apparently serve to bind the cellular components to the structural part of the ba ement membrane In tangential section the e layers of the basement membrane can be viewed in the horizontal plane In the author s experience they are homogeneous in character esen when viewed with great resolution although other inveligators have claimed that they observed auggestions of fibrous components It seems necessary to regard this basement membrane as the only important filtration barner between blood and urinary space but it does not «rem po zble that it could provide any regulation of the urine output Po sibly regulation might be prouded by changes in the aize of the endothelial pores or by swelling of the epithelial feat so that the caps between them would be more or less obliterated We have howeser no physiolog ca eudence to upport uch hypothe rug Peruubular I ascular Bed The peritubular capillaries also hase a notably thin endothelium in uitable preparations it can be een that the attenuated sheet is o perforated by a system of pores The pores are markedly smaller than in the ca e of the glomerular capillaries being approximately 6/100 * in diameter Alo they are paced (urther apart in the medulla the system is not as *ell de eloped as in the corter and there one find only patches of fene trated endothelum Once again we are forced to conclude that the fenestrated endothelial heet represents a pecialization facilitating defu son proces es rather than con tituting a diffu ion barrier The endothelium of the peritubular capillaries tests upon a ba ement mem brane The den e tructural portion of this membrane is extremely thin and 19 in etishing contra t to the thick truclural membrane of adjacent tubule A thin cement layer lies between the den e portion of the bi cment mem bran and the endothelium 58 ·The Tubules Basal Infolding Probably the mot important contribution of electron microscopy to tubular morphology is the discovery of the extra ordinary infolding or intu u ception of the pla ma membrane demon trable in the basal regions of tubular cell B: this mean the basal surface area presumably is va tly increa ed The infolding is most elaborately developed in the distal tubule where the osmiophilic line representing the plasma mem brane folds deeply into the cytopla m and then reflects back to reach the surface once more This repeats over and over again to form deep scallops These folds anastomo e freely with one another laterally so that in horizontal section one ees a veritable honeycomb of membranes The Swedih in vestigators (3) who first saw this well pre erred emphasized that this system of double membranes divided the ba al cytoplasm into open ended compart ments which tended to contain mitochondria corre pondingly oriented We have physiological evidence that these membranes are in fact the effective physiological urface of the cells and thu truly the plasma membrane of the basal end The proximal tubule shows a considerable development of this system of in folded basal membranes which are al o a ociated with the mitochondrial zone The collecting tubule hows this system as well although the folds do not penetrate deeply onto the cell Nonethele they ramify greatly in a lateral direction in the collecting tubule the mitochondria are in a totally separate zone o that relation between the e two systems may be entirely for tuitous In our laboratory we wondered whether this specialization would be found in other 11 ues noted for their water transport mechanı m We have examined the chorord plexus of the brain ventricles and the epithelia of the ciliary body of the eye and of salivary gland In all of the e ca es we have found analogous infoldings of the ba al urface of the cells Folding of this sort is not known to occur in other epithelia which are not involied in ater transport There would eem to be legitimate reason for po tulating that there is cau e and eflect relationship between the infolded ba al urface and water tran port It is particularly interesting that the collecting duct of the kidney shows something of this ) tem and therefore presumably would have some phy iological activity Furthermore it is tempting to think of the infolded membranes as being dynamically active and a degree of regu lation might be accompli hed by alteration in the total surface area again we must emphasize that this is a hypothesi unsupported by jhysiolo, Ical evi dence Prormal Tubule Apicol Region The brush border of the proximal tubule may be demon trated very beautifully by electron micro copy There is no doubt but that it repre ents a simple extension of the apical cytoplasm 59 ·Here and there between bru h proct e tiny ducts may be ein penetrat ing into the apical cytopla m These ometimes open into acules of con siderable size This sy tem can be identified as a specialization of the o called endopla mic reticulum This may be defined as a s tem of mem branes delımiling cisterne The membrants are peculiar in that they have an affinity for RVA granules Inie figators at the Rockefeller Institute have lieen tudying this item in many different cull types in certain in tance the sy tem communicates with call surface and is ometimes insolved in pick ing up material in other in tance it is known to be in olied in the climina tion of material Thuc in relation to the proximal tubule we cannot be cer tain whether we are ob enving an accesory excretory s tem or whether it is a means for picking up material from the tubular lumens and thus in corporating them within the al Both Rhodın (2) and Pea c 151 have reported un uccessful efforts to cor relate changes in the proximal tubule with different physiological load upon the hidney Sniall differences in the way kidney amples are prepared produce large variations in the observed morphology of the proximal cell These terminal change as fixalıse is applied probably overwhelm any original patterns The terminal changes are such as to indicate that the apical end of these cell is very labile and can quickly pick up or lo e water Thin Segment Flectron micrographs of the thin egment portion of the nephron reveal one interesting pecialization The cell hase folded edges so that neighboring cells interdigitate with one another in a remarkably com plex manner It would seem that there interdigitations greatly increa e the available cro ection area of intercellular pace that might be a route for ionic erchange as Chambers sugge led many years ago in regard to capillary endothelium litochondria Rhodin (2) has followed by electron micro copy the milo chondrial changes een during the resorption of albumin He reports an appar ent lu ton of mitochondrra a an early respon e to protein resorption followed by a lo s of their characteri tic internal tructure as they combine with the re sorbed protein This re ults in the production of very large granules without internal structure other than a fine granulation Eventually the large granules cem to reconvert back into typical mitochondria Both the proximal and di tal tubules are unu ually rich in mitochondria El ew here mitochondria are of only moderate size and abundance RYA Granules It is now po able to characterize RNA granules with the electron micro cope It may be noted that the cytoplasm of the proximal tubule cell is notably rich in the e organelles This gives it the pronounced basophilia well known to the light micro copi! Although some of these 60 ·granules are found in other portions of the nephron they are not notably concentrated elsewhere CONCLUDING REMARKS An effort has been made to discuss the newly discovered cytological pecial izations of the kidney In general these morphological details could not have been revealed by conventional micro copy they demanded the resolution made possible by electron microscopy It is surprising how complex this organ now appears to be yet no doubt we will find in this complexity new ways in which the kidney can perform its precise regulatory function Un doubtedly the future will see this new morphology coupled with physiological and pathological knowledge This will constitute the fourth and most impor tant epoch in our tudy of the kidney by electron microscopy REFERENCES 1 Hall BV Studies of Mo mal Clomerular Structure by El ct on M croscopy in Pro Fifth Ann Conf on Nephrot Syndrome Spnsored by th Nat o al Nephrosis Foundat n Inc New York 1953 p 1 Rhod a J Correlation of Ultrastructu al 0 g n2 t on an Function n Normal a d E perimentally Changed Proximal Convoluted Tubule Cells of the Mouse kid ex an Electron M1 croscopic Study Sto Lholm Aktiebol et God 1 1951 P 74 3 Systrand FS and Phodin Ultra t ucture of the provimal convoluted tubul s of the mouse kidney as revealed hy high resolution electron mcro opy Exp r Cell Res 4 4 6 1953 4 Pease DC Electron microscopy of the va cular bed of the kidney cortex Anat Rec 121 01 1955 5 Elect on moscopy of the tubular c Ils of the kidney co A at Rec 121 7 3 1955

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·SOME FACTORS INFLUENCING THE RCNAL LXCRETION OF SODIUM AND WATER III WHITE, MID, Professor of Physiology, Department of Physiology, I ashington Unnersity School of Medicine St Louis, Mo The rate of excretion of sodsum and water represent the differences be tween the rates at which they are filtered and at which they are reabsorbed by the tubules Our present tak is to con ider the factors : hich can effect in normal or abnormal state alterations in these difference If increase in reab orption equals increa o in filtered load there is no change in eture tion Retention means merely that output has fallen below intake and this is because tubular realusorption is excessne for the current filtered load We do not know why this occurs in for example congestive failure but we may ronsider briefly some of the po sibilities FILTRATION RATE It 19 sell estable hed that in the case of normal kidney an acurely pro duced malt percentage fall in glomerular filtration rate (GFR) as for in stance by mechanical compre son of the renal artery by a fall in sy temic arterial pressure or by postural changes brings about large percentage acule falls in rate of sodium and ater excretion that reabsorption as temporar sly excesse for the reduced filtered load If however the fall in GFR is main tained output res to normal ze rerbsorption fails until output again equals intake As examples the chronır Coldblatt dog does not show edema nor does the hypophy sectomized dog with chronically reduced CFR We may postulate that the transitory retention produced by the temporary per si tence of reab orption which is high relative to the reduced filtered load eventually stenals the tubul directly or indirecik that a susplus exs and reab orption falls until output again equals intake We can only specu late as to whether this adaptation in tubular behavior is brought about al by a light and not ea ily detectable increa e in plasma odium concentraison which signals the tubules either directly or va a reduction in output of salt retaining adrersal teroids 1b) by volume receptor which bring about alteration in tubular activity in some unknown way (as by refer suppression of ADH or aldo teront ecretion) or ir) by one other undennified process or combination of proce es 63 ·We do have experimental evidence that if such temporary retention is pre sented the cine e tubular activity relatise to the reduced filtered load per st and the sodium and water outputs of the affected kidney remain lon & long as its CFR 1 low This is shown as follows (1) Bith trained un ane lhetin dogs presou ly operated upon to permit spara e urine collec trons from the two kidney the outpuls of odium and water on the two des arue entially equal geare ( FR and renal pla ma flow (RPE) with chronic con friction of one renal artery aufficient to produce permanent small per centage falls in GER and RIF in that kidney the outputs of odium and waler lug that kidnes slow pusmanent large percentage falls per istıng as long ar the con triction is maintained This is presumabls becaut retention has Tecn limited by the undt turbed companion kidney in wluch output of odium and water ri es until the combined outputs of the two kidneys equal the nor mal for the ino kidney ie until output equals intake If hypertonic salıne is gnen intravenou l both hadness hos a great and equal percentage rise in odium output the output of the kidnes with the constricted artery remains the same mall frachon that of its companion If the con tricting liga ture is removed the output of the previou ly con tricted kidney ni es and that of its companion falls until they are again equal their um continuing to equal the intake This cycle mas be repeated A numerical example with no preten e of quantitatae accuracy may al lu trate this viewpoint A ume a steady tale with GFR of 100 ml/min sodium concentration in filtrate of 11 mEq/100 ml and odium excretion of 011 mEq/min With each kidney excreting 007 the tubules of each kidney are set to reab orb 6 93 mEq/min which they will continue to do unul omething happens to change their behavior Con Iriction of one renal artery drops the CFR on that sade to 45 ml/min with no immediate change on the other ide With 63 mEq/min now filtered on the con tricted side and the tubules (since there has been no change in pla ma compo ition) still set to reab orb 693 none would be excreted if reabsorption continued at its former rate Since removal of the last traces of odium is difficult reab orp tion fall a little liort of being complete with 6 293 reab orbed and 0 007 excreted With GFR 90 per cent of its precon triction value sodium excre tion on that side is only 10 per cent Becau e of diminished total excretion sodium retention des elops provided intake is maintained The surplus of odium ignals the tubules to cut down on reabsorption As this signal de velops the output from the unconstricted side rises until balance is re estab 1. hed This ignal al o operates on the con tricted side but produces only a small absolute rise in excretion from that side since the reabsorptre set can be reduced considerably and still exceed the amount filtered ·With moderate constriction the sodium and water outpuls from the con tricted ide may be only 10 per cent of tho e of the companion while GFR and RPF are 80 to 90 per cent If now the companion kidney is removed the remaining kidney s arler) till being con tricted its odium and water out puts quickly ri e from ay 10 per cent of the intake to equal the intake At the same time its CFR and RPF rise to a lesel omewhat higher than that of one normal kıdney but considerably lower than that of the two normal kid neys Here again we ee normal output of sodium and water with chroni cally reduced total CFR e thus ee that bilateral reduction in the GFR produces only temporary reduction in the output of odium and water and unilateral reduction in the CFR produces persi tent reduction in the output on that side o long as the companion kidney is pre ent But after removal of the companion the output of the remaining con tricted kidney ni es to normal even though its (FR (in pite of a n e above that seen while the compinion was present); till below the normal for the animal We can go further and apply a constriction so evere that the kidney be comes completely anuric although blood flow persists as shown by x ray ex amination (nephrogram) after intravenous Urokon injection (2) If now the companion kidney is removed urine flow from the everely con tricted kidney is ree tahl, hed and the animal suruises without odium or water retention With the ( FR at zero or very low in the anuric or near anuric constructed kidney Lefore removal of its companion the GFR r es to about that nor mal for one kidney but fails to rise as high as it does after unilateral neph rectomy with the remaining kidney not con Iricted The e dogs howed ar terial hyperten ion in the postcon triction prenephrectomy stage (ra e from control mean of 112 to mean of 150 mm H) with no further r e after removal of the uncon tricted kidney Thus the resumption of filtration and urine flow is not explained by a further rise in perfusing pressure but mut be due to a fall in preglomerular renal va cular re istance Striking elevation of plasma urea after remo, al of the companion kidney was only temporary Me thus eu that when one renal artery i con tricted so everely that urine flow from that kidney completely or almo ! completely cea es urine flow from that kidney adequate to maintain odium and water balance and an almost normal pla ma urea level is re e tabli hed after remos al of the com panion kidney without further increa e in arterial pre ure The peak again t the view that hyperlen son is a compensatory proces to ensure ade quate kidnex perfusion The mechanı m by which va cular resi tance in a remaining con tricted kidney fall after remos al of its unconstricted com 1 anion presumably the ame as after unilateral nephrectomy where the re maining kidney is not contracted the repon ble factors are unknown ·These experiments peak against the view that sodium and water reten fion in congestie failure can be referred to a lonered GER 1Lith bilateral chronic reduction in GIR normal tubules re pond bis diminishing their re oli orption of odmm and water until output agamo equal intake The ability of the tubulem to alter their reab orptise achats toward odium and water o that output equal intake lon a day to day or week to week although not nece arily on a minute 10 minute or hour lo hour buss) may indeed be taken as the definition of normal tubular beliauor so far as odium and water are concerned The retention of odium and water in conge true failure is then bus definition there ult of an abnormal lehavior of the tubule reab orption from the filtered load of uch an mount that the quantity is capin, rib orption « le than the intake They do not mean that we mu i con ider const100 failure to be due to primary diva e of the tubules The tubules mas be quite normal but re ponding with unde irably fugh reab orptist artrit to exaggerated factor timulating reab orption before it can di cu this matter with any dlegre of ati faction me mu know more about the factors than is now known Four of the e mas be mentioned lere change in pla ma odrum kiel in CFR and in extracellular flund volume and finalls hormonal influences An important recent ob ervation de mon trating increa ed Tubular reab orp lion of odium in congestist failure is reported by Barger et al (3) In a dog with tno bladder pouches permitting urine collection from the eparate led ney mall catheter is chronicalls implanted in a renal artery Infu non of small amount of a hyperlome alıne olution into one artery of a normal dog produces a five fold to lenfold increa o in odium excretion by the injected kidncy without a detectable change in the GFR or the RPF and with no significant change in excretion on the other ade This means diminished tubular reab orption not dependent on (Fl changes or sy te mic hormonal influence Pre umably the tubular cells here change their beliauor in direct respon e to the locally increa ed altıne s of the pla ma and filtrate It may be that this normal acute te pon e is imply an unchanged rate of reab orp tion in mll per unit time in the pre ence of an increased filtered load of sodium in any event the end re ult, the rejection and excretion of more o dium per unit time in re pone to the local increa e in concentration The ame experiment in a dog in conge the failure however hons no increa e in sodium excretion on the injected side re the tubules reab orb all the er ce s salt presented to them in the filtrate The e failure dogs honed a normal GEL but a low RPF This convincing proof of increa ed tubular reabsorp the activity for sodium in failure till leaves the mechanı m unexplained Le s expected is the authors finding that injection of cardiac glyco ides into one renal artery in amounts insufficient to produce sistemic effects also in crea es sodium excretion from that side in dogs in failure & 66 ·FACTORS INFLUENCING TUBULAR REABSORPTIOV OF SODIUTI AND WATER Plasma Na Letel If the pla ma sodium level is raised within physiologi cal limits by oral inge tion or intravenous injection of hypertonic aline tubular reabsorption of sodium may dımını hie excretion is increa ed even though the GFR may be unchanged Even though the GFR and the ab olute amount of sodium reab orhed per unit time may be increased when plasma level is ratsed one can at least ay that a smaller percentage of the filtered sodium is reabsorhed This tubular re-ponse i more prompt in the do. than in man It may be due to a direct sensing by the tubults of the increased saltıne s of the pla ma or indirectly to a dımını hed output of salt retaining steroid or to both Evidence for the second mechanı mis spen in the hi tochemical and cytological changes in the zona glomerulosa of the adrenal cortex following incrca ed salt intake Conver ely if the plasma odium level 1 lowered even lightly a by salt depriation or by dilution with water drinking tubular reab orption of sodium becomes more nearly complete output falls even without a di cernille fall in filtered load There is no evidence however that the increa ed audity of the tubules for sodium in congestie failure is due to a lowered plasma odium lesel The above cited observations of Barger et al indeed show that uch increased avidity persi is even when the plasma sodium level is locally increased This is in keeping with the previous finding that the failure patient fails to excrete a salt load in the normal fashion Changes in GFR Some a pects of the effects of changes in GFR on tubular reabsorption of odium and water have been discussed above but it may be appropriate to consider here the question of Tm" The uggestion (4) that distal reabsorption of sodium is limited by a maximal rate is recognized to be an oversimplification If during abundant sodium excretion (di tal odium reab orptive mechanism presumably aturated) GFR is reduced it is true that odium excretion will how a large fall perhaps almo t to zero If Tm were con tant odium excretion hould remain low until the distally pre ented load of odium ries (through a ri e in pla ma level with continued intake) to the control value But sodium excretion will ri e long before the pla ma les el shows such a nie indicating that I does not operate at a con tant and maximal rate Smith accepts the po sibility that Tm® is subject to in rea e or decrea e in re pon e to one or everal physiological factors (5) Another po ability as considered in the next paragraph is that with a de crea e in CER an increa ed percentage of the filtered load is reabmorbed proximally lower the di tally pre ented load below Tm" If this low ered percentage of proximal reab orjhion begins to return toward normal before pla ma odium kvel hous a certainly demon trable rice (we do not ·know whether or not this occurs) the distal load may again ri e ahore Tm". with increase in output Dr Surt lun and 1(6) recently inse tigated postural effects on tubular reabsorptive activity in normal human subjects in maximal water drure is The ac umplions are made that (a) proximal reab orplion is 140 more and (b) distal water reab orption has ceased Creatinine clearance was slightly lower on alanding Since the percentage fall in water etcrelion on chang ing from lying to standing was considerably greater than the percentage fall in GFh it follows that the percentage of filtered water reabsorbed proximally was increased on standing Since proximal real corption is con idered as 10 motice the percentage of filtered sodium reabsorbed proximally was also increa ed on tanding Since free water clearance honed a greater per centage fall on standing than did the GFR di tal reab orption of olutes largely odium alt showed a greater percentage fall than the GFR Thu me conclude that on changing from lying to standing in maximum water diuresis the percentage of filtered water and odium reabsorbed proximally is increased hile the percentage (and ab olute amount per unit time) of odium reabsorbed (listally is decrea cd The same conclusions hould fol low from ans combination of cireum tances leading in maximum water diuresis to a greater percentage fall in urine Ron and free water clearance than in GFR While maximum water diuresis is u ed here as a tool to de termine proximal water and sodium realisorption and dr tal codrum reab orption ие ee no rea on why the ame considerations should not apply at other rates of urine flow If these interpretations are alıd it is seen that considerable variations in the proporhons of odium reab orbed proximally and distally can occur physiologically Changes in ECF ) olume lo esidence is known for any type of tretch or baroreceptor in the inter bitial spaces but they are known to exit in blood vessel walls in various regions If one is to postulate extracellular fluidol ume effects regulating excretion of water and sodium it therefore seems most reasonable to postulate such stretch receptors in vessel walls Evidence that such stretch receptors operate in vesels of the head has been reported (7 8) while others have failed to obtain these results (9 10) Eudence for intra thoracic receptors presumably on the senous side of the pulmonary circuit affecting renal excretion of water without effect on sodium excretion or the GFR is reported by Gauer et al (11 12) We spre unable to find any difference between the normal and the denervated kidneys respon es to such stimulation (13) Since the increa ed urine flow occurs without a change in the GFR or the rate of sodium excretion and is unaffected by renal deneria tion a reflex inhibition of ADH formation eems the mot likely mechanism We are inclined to discount the importance of such stretch receptors in regu 68 ·lating blood and inter titial ffurd volume ince the increa ed water output is not accompanied by odium Humoral Influences te will mention here only the well known effect of ADH in increasing di tal reab orption of water uithout olute and the in crea ed reab orption of odium under the influence of variou adrenal ter oid particularly aldosterone The important but unan wered question of how the output of aldo terone s regulated can only be touched on here it may well prove of importance in the edemas of conge tive failure and of the nephrotic syndrome Dog, with demon trated complete ab ence of neurohypophysis and median eminence can still form a hypertonic urine on water deprivation but the que tion must remain open as to whether the tubules in everely dehydrated subjects can hill reabsorbome water in excess of olutes without ADH or whether the effect is due to residual formation of ADH in the hypothalamus Peflex stimulation of ADH formation in re pon e to painful stimuli or to Inght has been demon trated beyond a reasonable doubt(14) Various work ers have reported hypnotically induced water diures in man presumably resulting from erebral inhibition of ADH formation There are al o reports that in dogs pure is will occur without water admin tration even when the kidney is denervated if a conditioned stimulus has been e tablı hed by re perted applications with water The e finding are consi tent with the view of reflex inhibition of ADH formation but Bykow , finding(15) that condi tioned initiation or inhibition of water druresis persists after hypophy sectomy but not after renal denervation plus hypophy ectomy is interpreted as indi cating cortical control of water excretion at the renal level independently of variations in ADH formation Whether this direct renal effect is a cular or tubular remains unan wered even if one grants that it exit It may well be that Bykow s removal of ADH forming tis ues was incomplete although this would not explain the lack of effect after renal denervation since the influence of ADH is still seen in the denervated kidney The entire matter of central nervou effects on water and sodium excretion remains in an un atis factory state although my per onal view is that the eudence for direct nerv ou influences on tubular activity is quite inconclu ise (15 16) We may briefly con ider ome clinical evidence for central nervous sys tem regulation of odium and ater excretion Salt wating I adıng to severe hyponatremia and dehydration in the pre ence of apparently normal an terior pituitary and adrenal cortical function has been de erubed (17 18) rh ability of the tubule to con erje sodium simpaired even though plasma odrum level Jox While no certain conclu ion can b drawn as to its mechanı m the condition apparently differs from the alt losing yndromº attributable to an inherent tubular defect in that it dt appears on recovery from the central nervou le ion 69 ·In closing we may be permitted a few speculations although we are able only to restate questions without answering them We hall start from the Idea which of cour e is not original that the renal role in edema formation is an erces ise tubular reabsorption of sodium (with accompanying water) in relation to the filtered load Taking congestie failure as an example we may conclude that there is not primir aberration of tubular function since thu4 function returns to normal ag cardiac function improve The que tion IS What is re pon ble for this increa ed tubular activiti? We may po tu late some humoral sub tance produced in crees in conge fine failure and deficient in the cerebral salt lo in, syndrome Can this be aldo terone? Aldosterone production is known to be but little reduced after hypophy sectomy although the output of other adrenal steroid is greatly reduced(19) This 19 consi tent with the finding that hypophy ectomized dogs can main tain normal or almot normal sodium balancc (20 21) While the princi pal factor immediately responsible for the regulation of aldo terone produc tion remains unknown ap arently it is not the anterior pituitary Aldosterone excretion and pre umably production is increa ed in alt deprivation and in ede malous patients while expan ion of body fundo by water plus pitre in in sodium depleted subjects de crea is the previously hugh aldo teronc excretion and increa es odium excretion de pite hyponatremia suggesting a role of fluid volume change (22) Then pitressin 15 stopped the retained water is climinated aldo terone excretion rises and salt ercretion drops the subject has had a net loss of all There is increa ed excretion of a sodrum relatning substance probably aldo terone in nephross and in heart failure when sodium excretion is los Freretion of the presumed aldosterone dımını hes during deure is when odium excretion increase It is not found in Addı ons disca e or after bilateral adrenalectomy Is er cretion is increa ed on salt deprnation and dımını hed on luigh salt in take(23) The unexpectedly high output in sodium losing neprilis may simply mean that in this condition the tubules are in cnsite to its action It appears justifiable to entertain the hypothes that the reduction of all excretion at least in salt deprivation in the normal subject 19 the re ult and not the cau e of increased aldosterone produchion On depriving a normal subject of salt or on extrarenal lo s of alt output exceeds intake and the resultant fall in plasma level or fluid volume or both call forth inc rca ed aldosterone production with resultant low urinary (and sweat) output of alt On the other land if the kidneys are unable to conserie alt in a normal fashion perhaps becau e of in ensitivity to aldo terone negative sodium balance may persist even with high hormone production That fluid volume may be a more important factor than plasma sodium level is sugge ted by the finding that aldosterone excretion Increased greatly within a lew hours in a diabetes in spidus subject deprived of water although a rise in plasma 70 ·odium level 1 not excluded here normal men te pond to relatively small increases in sodium load with a great decres e in urinary aldosterone but heart failure and portal csisho is subjects are much less reponse Aldo terone secretion was decrea ed on increase in ECF olume and increa ed on decrea e of ECF solutie regardles of whether ECF o molality to e fell or was unchanged(21) Normal dogs excrete only traces of aldosterone while heart failure or car al contriction dogs excrete large amounts (25) Speculation that hyperaldosteronism may be an important factor in the pathogenesis of cardiac or nephrotic edema must be tempered by Conns finding (26) of primary hyperaldo teroni m due to adresocortical tumor symptomatically relieved by potassium admin tration cured by operation and characterized by hyperten ion transitory paraly es polyuria re : tant to pitressin ab ence of edema high sodium and low pota tuin pla mia les els and high sodium with low polas cum in mu cle kidney biopsy showed the tubular vacuolizanon and necrosis characteri tic of clere pola cum deple fron This is far from the picture of conge tre failure it may well repre sent however an extreme xtuation where the deleterious effects of pala suum depletion are the principal manifestation The kidney cubules have suffered uch a derangement of function that the reab orption of odium and water cannat increa e in the expected way in re pon e to high aldo terone level Perhaps no one would maintain that hyperaldosteroni m is a primary factor in cardiac or nephrotic edema Some of us at leat beluese that the accumu laron of theme edemas depend principally on physcal factors durg such actumulation output of alt and water necessarily falls below intake or tated differently the diffrence between filtered and reab orbid sodium and water fall below the intake Be mu i admit that we do not know why reabsorp tron during this period is erce le relaine to the filtered load so it may still be permi able to wonder whether a humoral factor le s marked than that een in ca es such as Conn is operating During teady tale edema the ubject 1 again in balance it is not know why the relation between filtration and reab oration has agan chan,ed o that output now equals in Take and the ame considerations apply in the clearing of edema Pri stimably a balance is achueseul between the retaining effect of aldo terone and the various factors tending to promote excretion We are convinced that mere recluchon of filtration is not se ponsible for retenison Ince with ex perimental chronıc bilateral reduction of GER in otherki e normal kidneys alance 1 re e tabl hed before any demon trable edema has developed It ha leen postulated that the kz peraldo teroni so of the edema 1 a ec ondary devek z ment Tot only is the mechanim tragering the increased formone įr ductian unknoin but the effect is oppo ste to that expected Experimentally indu ed acute increa e of Bud sofume lead to dimin bed aldo lerone and mcreased sodsum escretion the seser c of the findings in ·clinical edemi ll there is any cau al relation the fluid volume changes in clinical cdema mut be the result and not the cause of the increase in aldo sterone For additional reference relating to the last five paragraphs « (27 28 29) Reference mu t al o be made to Selkurt s crcellent review (30) of the general topu of odium and safer excretion To summarize de privation of alt and water in normal suljects increa es aldosterone production while alt and water loads derst.14. The primary ment 19 a fall or nein FCF volume or odrum level or both with the result ing rise or fall in aldosterone production helping the tubules to bring about return to the normal tatus In heart failure on the other hand excess of FCF volume and of body sodium load appearing as edema is accompanied not by a fall as in the normal but Ivy a nie in aldo terone production And with the natriure is of Jearing demi aldo terone production fall in such condition the changes in aldo te rone production are not the re ult but one of the cau e of the fluid change of any can al relation and The cau e of such inerci ed aldo terone production in spite of an aree « water and odrum load remains unexplained REFERENCES > 1 Mueller ( B Surthin 1 Carlin 11 R and White 11 Glomerular and tuł ular influen es on sodium an l water er retion Am J Phyll3 421 1991 Surt hin A and Latorre C Effect of cont alateral nephrectomy on renal func non depre el by previous unilateral renal arterial con friction Am J Physjo! 182 5 1 1955 3 Barfer AC Rudolph 1 A Rokas S N an! Yates FE Chronic unilateral renal artery catheterization differential sodium ercredon in normal unine thetized dog and dog ath conge ine heart failure Fed Proc 15 8 1956 4 We on IC Jr An tow Pjr an Smith Escretion of strong ele trolyree Bull Tew York Acad Ved 24 586 1918 5 Smith II Principles of Renal Phy ology Neu York Oxford Universy Pe 1956 p 99 6 Gurt hin 1 and White II L Po tural effects on renal tubular a tauty Chan In et 35 267 1956 7 War NO BB Es enl re S Lombardo T A Wills and Harri on TR Fffect of posture and of compre son of the neck on ercretion of electolytes and glomerular filtration further tudie Carcular on 3 105 1951 8 Cort J 11 Central benou control of volume of e tracell lar fud Chekho lov fiziol 4 14 1955 9 Netrau ehf Effect of po ture an] of neck compre on on ouls of water odium and creatinine J Appl Physiol 5 11 1993 10 Filmas R A Failure f intracranial pre ure volume chang to influence renal function ) Chin Insest 32 917 1953 il Gauer O H Henry J P Szeker Hand Wendt WE Efect of negali < pressure breathing on urine llow J Clin Inse? 33 987 1951 712