·No text on this page.

·Tbe
RENAL ORIGIN
of
HYPERTENSION

·Publication Number 17
AMERICAN LECTURE SERIES
A Monographi in
ANERICA LLETURIS IN PATHOLOGY
Edited by
Paul R Cannon VD
Irofessor of Parfolos v
Um ersity of Chicano
Chicago ilmos

·The
RENAL ORIGIN
of
HYPERTENSION
by
HARRY GOLDBLATT, MD CM
Director Institute for Vedical Research
Cedars of Lebanon Hospital
Professor of Pathology
Um ersity of Southern Caliform
Los Angeles Califorint
pat
CHARLES C THOMAS PUBLISHER
Springfield Illinois USA

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PART IR
Printele Umre States of America

·PREFACL In recent years in several books (14) the present statc of our know ledge of human and experimental hypertension has been de scribed ind discussed in great detail. It is legitimate therefore to question who a written lecture on this subject should be published at this time My first impulse is to apologize for making this con tribution which is incomplete and in great part repetitious but on second thought I have considered that it may prouc of some value to those u hose interest is not sufficient to induce them to read the orig inal papers or who do not have the time to devote to the reading of books on this topic To me the whole subject continues to be fasci nating and I consider that it should be of great interest to all students of medicine and even to lay men The justification for this statement is that (1) the death rate from arteriosclerotic disease of the brun heart and kidneys issociated with the symptom of hypertension continues to be very high (about four times that of cancer) (2) tully 25 of deaths at least in males over 50 years of age is asso ciated with the existence of this condition (3) treatment has done but little to reduce these figures (4) there are no hnown methods of prei ention and (5) the initung cause or causes of the two 1ssociated conditions arteriosclerosis and hypertension are still ob scure or unknown It is my ardent hope therefore that the ad vances in our knowledge of the pathogenesis of human hypertension based on the investigations of experimental renal hypertension may vet lead to the pretention and cure of this condition which takes such a large toll of human lives

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·CONTI NTS PREF4CF INTRODUCTION Production of Experimental Renal Hypertension by Various Vethods Unulateral and bilateral nephrectomy Reduction of the amount of functioning renal tissue The effect of a nephrotic substance Irradiation with roentgen ras > Occlusion of one or both ureters Compression of the hidneys Fmbolism Passive hyperemia Permanent occlusion of the main renal artery vein and ureter Arteriovenous anastomosis Occlusion of the main renal arteries Ligauon of branches of the main renal artery Constriction of the main renal artery The administratory of sterols PRODUCTION OF EYPFRIVIF\TAL RENAL HYPERTENSION B: CONSTRIC TION OF MAN RENAL ARTERY 19 FFFECT ON BLOOD PRFSSURE OF VODERATE COVSTRICTION OF THE MAN ARTERY OF ONLY ONE KIDNEY EFFECT ON BLOOD PRESSURE OF MODERATE COVSTRICTION OF BOTH MAN RENAL ARTERIES THE BENIGN PHASE OF EXPERIMENTAL REVAL HY PERTENSION 16 EFFECT ON BLOOD PRESSURE OF GREAT COVSTRICTION OF BOTH MAIN REVAL ARTERIES THE MALIGYANT PH 4SF OF EXPERIVENTAL REVAL HYPERTENSION 77 79 PATHOLOGIC CHANGES IN TUF ORGAYS OF AVINIALS TITH PERSISTENT HYPERTENSION Pathogenesis of arteriolar necrosis Other changes in experimental renal hypertension PATHOGENESIS (MECH AVISVI OF DEVELOPMENT) OF EXPERIVENTAL RENAL HYPERTENSION Neurogenic mechanism Endocrinogenie mechanisth Tre HOVIORAL NIECH4VISVI OF EXPERI VIENTAL RENAL HYPERTENSION 37 SI LIE ·112 REVAL ORIGIN OF HYPIRTH VSION REV Chemical properties Physiological properties Fate of renin in the body lfethods for the assay of renin the art of chin HIPERTENSINOCEN \ature and properties Unit of hypertessssolen Preparation HYPERTENSIN Chemical properties Preparation and purification Physiological properties Unit of his pertensis HYPERTENY ASF ature and properties The 1st of hypertensinasc The amount of hypertensmade in the blood and various organ fechanism of action of lay pertensnase VIECHANISM vo STF OF FORTATION AND REF# OF RN "THE JU TACLOUFRL LAR API AR4TLS THE TREATE OR HYPFRTENSION Vledical Treatment Fxtracts of hidrses Antrenn treatment of his pertension by the parenteral insectton of renn Other *150consector presses and antipressor suntances and their effects Surgkal Treatment Unilateral nephrectomy for hypertensie 11 stue to underoral renal disease SLAR) OF TUF SIX INITIIS 413) Du FERI CES BETWF* Heva LSSFV714% AND TYERIVENTIL Huu HyY*T1981

·The
RENAL ORIGIN
of
HYPERTENSION

·No text on this page.

·INTRODUCTION Not infrequentlı medical historians find it difficult or even im possible to assign the origin of an ide to 1 single person Although Richard Bright knew nothing about hypertension because in his time blood pressure in man had not ver been measured yet there is litric doubt that to him should go the credit for the basic idea that hypertension may be of renal origin Although Bright did not differentiate clearl between the virious types of renal disease and although he ) new nothing of the important entity which is nou called essential hypertension vet he did make the important obser vation that in cases of cardiac hypertrophy nor obviously due to intrinsic cardiac disease or extrinsic vascular abnormaliti there is found almost without exception some disease of the kidneys Basing himself upon this observation with the intuition of a great clinician who was also greatly interested in pathology he speculared that the increased weight of the heart (hypertrophy) might be relited to the disease of the hidneys Indeed he went so far as to suggest that a chemical alteration of the blood resulting from the renal disease was probably the immediate cause of the cardiac hypertrophı effecting an increased action of the heart and what is more important by inducing u hat amounts to increased peripheral vascular resistance to the onflow of blood The latter idea is nothing short of remarkable for the time for if there is one thing that appears to be definitely settled about the basic mechanism of the state of hypertension in man it is the existence of a state of increased peripheral vascular resistance The specific parts played by arteriosclerosis and by generalized spasmi of the arterioles and the primary or secondary relationship of these changes to the hypertension still constitute i controversial subject What is not yet settled also despite all the work that has been done on the subject is the question of the renal origin of the type of hyper tension that is nou usually referred to as essential, or primary In a normal animal direct determinations of blood pressure had been made by Stephen Hales in 1733 one hundred years before Bright but in man measurements of blood pressure were not made until the end of the nineteenth century Although on the basis of other indirect methods particularlı pulpation of the pulse pulse [3] ·+ RIVE ORIGIN Ol }) PIRTISION tracings and sther bloodless methods the custence of i stitc of 123 creised vascular tension in man had been recognued crit 13 is not until the development bs Rita Rocci of 1 method to determine blood pressure (reallı bursting tension) in pneumatic cuff und 1 mercurs planometer that the custence of clerited blood pressure in man was fully recognized 10 signific ince appreciated and the stud of its pathogenesis underral on After the discover of the custence of cleared blood pressure in man it * is rcalved 11 once that the enlargement of the heirt obscried by Bright 1x ? direct coinscéjuence of the hypertension ind the problem surrched it once to the pithogeness of the increased pers pheral vascular resistance that confused the problem was the pre sous discovers by Johnson and bs Gull and Sutton of orgic de cise of the small arteries and arterioles which consisted of lichenint of the walls and reduction in the size of the lumen in ohuoush possible organic cause of increased peripheral 1 uscular resistance The direct result of this was that one group of ins estig itors 7 minority group contended with Johnson that the renal diseise was the caus of the hipertension the diffuse inscular discase and the hypertrophy of the heire while the other group asserted with the followers of Gull and Surron that the hypertension and consequent cordiac laver trophy were the direct result of the increased peripherals ascular ro sistance caused by the diffuse organic disease uluch onls mesdenrulls insolved the kidness This da ision of opinion has surını cd up to the present time with one addicion nimelt that the primary phenome non is increased peripheral vascular sesistance due to vason (neurogenic or endocrinogenic) which results in increased peripheral resistance ind his pertension and thit zil the organic changes : asculer and cardiac are secondary to the hypertension In more recent times it knas been recognsed that primary reni discase mis be associated sstth hypertension and that i causatnc re lacionsłup between the two conditions 1731 cust in such cases the presence of the renal discase is recognied usually bảy reason of renal cxcretor functsonal abnorinilities which result from pathologie changes in the hrdness These include pols cystic disease of the bed 1101s glomerulonephrir (1cute and chronic) blaterat obstruc mon of ureter' froni 3n3 causc bilateral chronic pielonephritis and other conditions which in olie considerable reduction of renal parenchima and in it fich disturbance of ercrctor function usual ·I\TRODUCTION occurs After the recognition of essentul hypertension doubt was cast upon the frequency with which renal disease might be considered the cause of the initiation of the elevated blood pressure As a matter of fact renal disease characterized by disturbance of renal excretory function has always been excluded from the definition of essential hypertension Dalton and Nuzum beliese however that the critical Statistical analysis of the data on renal excretory function in cases of essential hypertension in man does show in most cases some impar ment of ability to concentrate urine and to excrete phenolsulfonphtha lein The fact that renal excrctory functional abnormality frequently cannot be demonstrated for many vears after the onset of hyper tension and even throughout the entire course of the disease con vinced many investigators that most cases of hypertension are not on 1 renal basis As a result hyperepinephrinemia abnormal pituitars function neurogenic stimuli affecting the vasomotor mechanism and diminution of the sensitivity of the carotid sinus are some of the conditions that have been considered at various times the cause of this type of hy pertension Most students and investig itors of the subject of essential hyper tension are now in complete agreement that cardiac output, and the volume and viscosity of the blood are within the limits of normal in well established essential hy pertension It is therefore generalls agreed that with few exceptions the ultimate cause of the elevated blood pressure is increased peripheral vascular resistance Although there is still some division of opinion about whether the increased ascular resistance is ever on an organic basis vet most int estigators ire of the view that peripheral vasospasm is the physiological basis for the phenomenon That the organic changes in the peripheral blood vessels especially the arterioles are ever so widespread as to be purely mechanical cause of hypertension is not supported by the inatonical findings of pathologists Also physiologists and clinicians have shown that the peripheral arterioles exhibit normal physiological responses to physical and chemical stimuli for example the normal i sodilator response of the vessels of the forearm and hand to heat und reictie hyperenu? (Prinzmetal Pichering) and the normal de pressor response to an intravenous injection of 0 1 mg of histamine acid phosphate (Pichering and kissin) The process of vasospasm therefore can be adduced is the cause of the increased peripherl TCsistance ·RUTAL ORIGIN OF HYPERTENSION The one man sho lept the idea of the possible renal origin of some forms of human hypertension alne 1135 Volhard ti ho believed that in pale (malignant) hypertension at least the pathologic change in the kidney plays an important part in the development of the elevared blood pressure He even sought but failed to find i Masoconstrictor substance in the blood of patients with this con dieron Although there are those who still dens that the kidnews ever play a primary part in the initiation of hypertension ver it ? nou quite generalis admitted that soigie forms of renal disease may in some way be the cause of the hypertension What is not generally admitted is that essential in pertension especially the benign phase the tvge of hipertension that is usually assocrated with widespread arteriolar sclerosss and especially with nephrosclerosis but withour accompanying excretory functional abnormality is of renal origin The arguments usuallı gnen against the renal origin of essential los perrension are (3) the frequent discovery of elevated blood pressure long before there is ans recognizable sign of renal cicretory insufficiency (2) the absence of ant recognizable signs of renal excretory insufficiency tlıroughout the entire course of the hyper cension in a large percentage of cises and (3) the filure to find an zuropsy significant intrarenal ascular disease in an occasional casc of essential hypertension Liperimental proof for the fress she che hidneys play a primary part in the development of the increased peripheral vascular resistance and consequent hypertension had been sought in 1 variety of ways L»cfore our own experients on this subject began in 1928 Production of Experimental Renal Hypertension Hy Various Methods Unilateral and bilateral nephrectomy had been tried but trad not resulted in his pertension 11 the rablus cst and dog (losłer 1912 Bichman 1916 Cash 1926) Most experients of a similar ftature that have been performicd up to the present timc krac been in agreement with the earls results (farrison Bislock and l11som 1936) bur recently Grollınan his asserted that in pericnsion 1111 de clop in dogs and rats as a result of unilateral nephrectomy Reduction of the amount of functioning renal tissue by pirtni resection of cach hidney had been reported as causing slighe fuper tension in the rabbit me and dog (Cash 1924) and since 192B set ·INTRODUCTION 7 eral intestigators have noted the development of considerable hypertension in the rar but not in the dog as the result of this procedure (Ferris and Hynes 1931 Chanutin and Ferris 1932 \Vood and Ethridge 1933) In the light of our own studies on the dog and because only the rat gave a pronounced effect it is suggested that the cause of the elevation of the blood pressure in these animals was the hemodynamic disturbance in the small remnant of the kidneis caused by the scarring from the surgical operation The effect of a nephrotoxic substance such as uranium had been tried on rabbits by Bechmann (1925) and Dominguez (1928) but elevation of blood pressure was not produced consistently Since then other investigators using the same and other nephrotoxic agents have obtained contradictory results Lead salts sodium and potassium oxalate mercury bismuth and streptococcus toxin are among the other substances that have given negative or equivocal results The direct injection of trypsin into the renal artery (Freedman and Katz, 1938) failed to produce persistent hypertension It has been shown that nephrotoxic heterologous antiserum to rabbit renal substance produces glomerulonephritis and renal excretory insufficiency accom panied by slight elevation of blood pressure (Masugi 1934) This has also been accomplished in the rat (Smadel 1937) and confirmed for the rabbit but Corcoran and Page (1941) failed to observe elevation of the blood pressure in the dog with glomerulonephritis produced by a nephrotoxic serum Irradiation with roentgen rays of the hidneys of dogs caused moderate elevation of blood pressure but impairment of renal excretory function was an invariable accompaniment (Hartman and collaborators 1929) This was confirmed later by Page (1936) for the dog but Hermann Dechard and Erhard (1941) failed to ob serve indirect evidence (cardiac hypertrophy) of hypertension in the rabbit as a result of irradiation of the kidneys Occlusion of one or both ureters was first tried in 1929 by Hart wich who observed some elevation of blood pressure associated with fatal uremia in the dog as a result of bilateral occlusion of the ureters This result has been fully confirmed but most investi gators have reported failure to produce hipertension as a result of unilateral occlusion of a ureter Construction of one ureter with contralateral nephrectomy also did not result in hypertension in the dog (Eichelberger 1938) In the light of our own experiments ·8 RIVAL ORIGIT OF HIPERTF\SIO it appears probable that occlusion of a ureter muy produce a hemo di namic disturbance similar to but not as pronounced as the effect of constriction of the main renal arteri Compression of the kidneys by an oncomcter had been tried in 1909 by Alucns who reported slight immediate elevation of blood pressure in some briet experiments in cats Morc recently 1 simular effect on the hidner of a persistent type has been produced by Page and collaborators (1939) by the ens clopment of the hidnews in cellophane or silk The same effect has been obtained in rits and dogs (Greenwood Nassim and Taylor 1939 Ilcrmann Jourdan and Vial 1940) by meins of collodion painted on the surface of the lidneys and also by compression of the lidneys by means of a tape tied in a spiral form around the kidney (Grollman 194+) These methods are supposed to act by direct compression of the kidnes substance or by the compression and resultant ischemia caused by the thick periren al scar which results from the perinephritis induced by the foreign material The mun drou bach of the method is the frequent accompininent of renal excretor functional disturbancc und er en fatal uremia Embolism by the direct injection of various substances (liquid paraffine Berlin blue charcoal) directh into the renal arters of cats and dogs hird gn en consistently negatic results (Senator 1911 Cash 1924) More recenth hou eier Vaegraith and McClean (1938) reported the development of hypertension in the rabbit as the result of the injection of Lieselguhr into the main renal artery of rabbits The same substance failed to produce high blood pressure in the dog (Crestinan and Blaloch 1939) Passive hyperemia of one kidney produced by the constriction of the main renal sein had been reported by Pedersen in 1927 as cousing a transient ele ation of blood pressure in the dog This has been confirmed by Braun Menendel (1933) Diclor (1937) and Friedberg (1944) It did not prove to be a method for the produc tion of persistent hypertension on a renal basis becausc bilateral con striction of the min renal veins invariablı resulted in fatal uremia Permanent occlusion of the main renal artery, vein and ureter of both kidneys had failed to cause liy pertension in the dog (Cash 1926) Although Loesch (1933) did report hypertension in the dog as the result of intermittent occlusion of all the structures of the renal pedicle set there is reason to beliesc in the ins pertension des eloped ·1 TRODUCTIO\ 9 only when constriction of some of these structures became permi nent as the result of scirring Arteriovenous anastomosis had not been tried before 1928 In 1939 11 eber and Rumold produced hypertension accompanied by uremia in the dog by arterios enous anastomosis of one hidnes and contralateral nephrectomy This did not prove to be a method for the production of persistent hypertension Occlusion of the main renal arteries had been tried in 1905 by Katzenstein who reported an immediate slight rise of blood pressure probably of reflex origin in some brief experiments Cash in 1926 reported a rise of blood pressure in dogs that survived occlusion of both main renal arteries for several days but died in urcmia Thrs result has been confirmed since then by many other ini estigators including ourselves Although the animals de clop elevated blood pressure ct the die in uremia so this is not a good method for the production of persistent hypertension Although the animals die in urenna as in the case of bilateral nephrectomy set different from the latter clevation of blood pressure does occur 1 his is under standable in the light of our own experiments on the basis that although 1 state of profound renal ischemia exists Vet blood flow through the i idney does not cease altogether and a pressor substinec of renal origin may enter the circulation by way of the main renal cn or the lymphatics Ligation of branches of the main renal artery gave contradictors results and the hs pertension when it did occur did not persist (Jane 1913 Varl 1928 Hartu ich 1930 Friedmann and lachs muth 1930, Wolf and Heinsen 1935 honzert and Unna 1937 lernes and logt 1938) Occlusion of the main arters of only one kidney also resulted in slighe temporary elevation of blood pressure in dogs but all of these cxperiments were published after 1929 (Fried mann and Wachsmuth 1930 Hartwich 1932 Winternitz and collaboritors 1940) It is not 1 method for the production of per sistent hypertension Constriction of the main renal artery had also been tried before 1928 but harrenstein (1905) obsorsed only slight clevation proh abh of reflexorigin in a brief experiment while Bridgrian and Ilirose (1916) reported no clevation of blood pressure in dogs as 7 result of the same procedure The administration of sterols (cliolesterol) had also been trico 179 ·11) RL AL ORIGIOF HIPERTE SIO many times (Fahr 1912 vanLeersum 1912 Schonheimer 1924 Shapiro and Seccoff 192) ind Low enthal 1926) but always with the idea of producing generalized arteriosclerosis and consequent hypertension as a result of gencralized increased peripheral vascular resistance and not with the intention of proving the renal origin of hipertension The results obtained were contradictors Even the administration of vitamin D (Appelrot 1933) (Handou sh 1937) which did result in eleiation of blood pressure was based upon the same idea of generalized arteriosclerosis as a cause of hypertension but the pronounced nephrotoxic effects dreu attention to the possible renal origin of this type of hypertension In recent years it has been reported (Ham 1940 Grollman Harrison and 11 illiams 1940 Varzek orah and Reed 1942 and Sele and collaborators 1942) thar desow corticosterone induces the des elopment of hypertension and Selse has asserted that the hipertension is associated with the de elopment of nephrosclerosis in the rat and therefore may be of renal origin Some of the experiments summarized above merely proved u har is generally accepted even for man, namely the renal origin of hyper tension associated with renal excretors insufficiency as a result of great reduction of renal parenchyma fronı any cause or obstruc tion of the urinar passages However those experiments that were designed to prove the renal origin of essential hypertension failed in most instances because (1) the were brief experiments in most of which no elevation of blood pressure was demonstrated or the hiper rension u as ficeting and probably of nerous reflex origin, (2) con tradictory results were obtained by different in estigators using sim vlar methods (3) when hy pertension did result the experimental conditions did not reproduce the anatomical or what is more im porcanr the physiological state of the kidneys in benign essential hipertension and (4) the hypertension did not persistor was accompanied by renal excretory insufficiency with or without uremu This was the state of the whole problem when our onn inesti gations of the subject began in 1928 The working hypotheses of these studies were as follows (1) the pare possibls played by the kidnei in initiating, so called essential hypertension should be sus cepuble of experimental ini estigation (2) if 13scular disease lumuted to the hidners, or any other pathologic process capable of producing a similar intrarenal hemodi namic disturbance be the primarı factor ·I\TRODUCTIO 11 in the initiation of essential hy pertension then the production of the counterpart of the physiological effect of such vascular or other renal disease no matter how it may be accomplished should result 111 the development of hypertension (3) renal excretory functional disturbince should not be a necessary accompaniment of the experi mental hypertension (4) The directive thought was that since stenosing sclerosis of the smaller arteries and arterioles is the most common renal lesion associated with essential hypertension then if the consequent disturbance of renal hemodynamics is the cause of the hypertension the reproduction of this condition by any means should also result in the development of elevared blood pressure It was considered that the fulfillment of all these conditions would insu er the requirements of the definition of essential hy pertension ind signify the experimental reproduction of this condition Since there was no known was at that time of reproducing the significant anatomical abnormality namel arterial and arteriolar clerosis localized to the kidneys it was considered that the best way to reproduce the counterpart of the probable physiological effects of this intrarenal organic vascular disease would be to con Strict the main renal arteries Since the main effects of preglomerular arterial and arteriolar disease of the hidney are probably reduction of intraglomerular capillary pressure and reduction of blood flow to the functioning components of the hidney it was considered that these two effects mght be reproduced by the constriction of the main renal artery by means of a clamp It should be appreciated at once that the method decided upon was a compromise that it does not mean that it was considered that stenosing arteriosclerosis of the main renul irtery is a frequent finding in cases of human essential hypertension and that the application of the clamp was considered an exact repro duction of the anatomcıl state of the kidney in essential hyperten sion This is emphasized here and will be again because some authors ind in estigators have been guilts of this misinterpretation ·PRODUCTION OF LIPI RIVILNTAL RENAI HIPERTE VSION BI CONSTRICTION OF 1141 RENAL ARTLRY I or the purpose of constricting the main renal artery it became necessary first to devise a clamp which would fulfill the following requirements (1) it would induce little or no tissue reaction so that It miglue be left permanently on the artery (2) it would perthit I Sig i Clamps for constrictin of renal artenes Clamp with movable and removable plates and double acting scre Ordinary type (4) Side view (B) Miosable place in open position (After Goldblatt Am J Clin Part 10 40 1940 ) Clamp holder for ordinary ope clamp (hug 11A) Kreu drner to de press celerate the monable plate (B) The clamp holder with the clamp in it withour the removable plate 19 the position reads to recene che renal artery (C) The same ristrunient with the folder of the clamp holder turned over by the depression of the spring in the handle of the clamp (D) The clamp holder sith the clanip in position so that the scres uf the clamp is accessible to the scres den er for the depression of the removable plate and compression of the renal artery (E) The re movable plate held in the jaws of this special instrument It us with this special Instru ment that the removable plate is inserted into the clamp in the clamp holder After Coldblatt du Clin Path 10 40 1940 ) ()

·ft
TE
B

·14 RENIL ORIGIT OF HIPERTE SIO constriction of the arter to anı desired extene (3) It would permit increase or decrease of constriction of the arteri ind (4) it would be remos able later without injurs to the arter All these requirements ktere fulfilled by the clamp made of pure sılıer which was finally clevised for the purpose (F. 1) Specnl instruments i crc also dessed to ud in the appliu icon e>f the clamp Thes are not necessarı but the facil.cate and empe dite elic ipplication of the clup (Fig 2) The clamp the instru ments ind the surgical procedure have been described in detul in seierul publications including lledu il Physics A clamp mide of tintalum or of some of the other metals which induce little tissue reaction might he cien inore desirable than sher of the could be worked for the purpose ·CHFLCI ON BLOOD PRLSSURL OF MODERAIL CONSTRICTION OF THL MAIN ARTLRI OF ONLI ONL KIDNCI An each ind unexpected obserı ton was eles ation of the blood pressure is the result of constriction of only one main renal artery There was no immediate rise of blood pressure but within a period of 24 to 72 hours after the constriction of the main artery of only one kidney the blood pressure became elevated In the dog the hypertension usually lasted not longer than six weels and only 195 180 165 150 er 135 120 105 904 Mean Blood Pressure mm 75 60 45 15 15days! 116 3 Dog > 3> male chos young Initial velght 194 hg Lh-left main renal artery moderatel constricted = Alean blood pressure mm Hg direct method femoral artery This shows that it took about 4 hours for the blood pressure to become significantly elevated that the maximum was reached in about a week that ir remained elevated at the maximum les el for about two weeks and that it returned to the normal preoperati e level in about six weeks after the maximum hat been reachet (After Goldblatt The Hof ey Lectures 1937 38 ) (1) ] ·16 RINAL ORIGIN O WYPIRIISION 220 200 180 160 140 Direct femoral Blood Pressure mm Hg 120 100 RK 80 63 43 20 28 day Fig 4 car female age about 1 year Lk left main renal artery was moderately constricted The direct mein feniora) blood pressure remained considerably clevated for six months in the left hidney was excise 1 and within 24 hours the blood pressure returned to normal and remained at this level Rh the right main renal artery was greatly constricted The blood pressure became re eles ared bur the animal de cloped uremia and died (D) Terminally BU (blood urea nitrogen) 134 mg Cr 58 mg CO combining pou er 40 S volumes per 100 LC (After Goldblatt hahn and Lexis , Erper ved 7 97 303 1941 ) Occasionallı as long as six months Usually the pressure reached a maximum elevation in about one week remained elevated at thar level for another week and then gradually returned to normal in 4 to 6 weeks (Fig 3) It was found later that in the goar the sheep and the rnt unilateral constriction of a main renal artery resulred in hypertension that usually persisted for months (Fig 4) A significant early observation by the author and others w is the effect of the removal of the hidney with renal arteri constricted This resulted in prompt (12 34 hours) return of the blood pressure to normal (Fig45) These results dreu attention to the possibility thar human hipertension may also be caused by unilateral renal dis case and more important that the removal of the diseased kidney provided the contralateral hidney is normal might also result in the return of the blood pressure to normal This will be referred to aguin under the heading of surgical creatment

·PRODUCTIOOL HIPERTE\SO
300
Dog *2-50
280
260
240
220
RN
200!
180
160
1401
.
RK
120
100
804
601
40H
20
24days
0
116 Removal of an ischemic kidney and production of ischemia in the rem unui
hidnes Alean blood pressure in mm HE (RK) night main renal artery moderately
constricted (RV) right nephrectomy at a time when the mean blod pressure was
eles ated resulted in its prompt return to normal Lh) great constriction of
main renal artery of left hidney This was follou ed by very high elevation of
mean blood pressure the meant blood pressure at thus time was m re than
3045 mm Hg (h) killed (After Goldblatt 4nn Int Aied 11 69 1937)

·LUS w 200 260H 2404 20h 200 180 1604 1406 Blad Pre surs, mm Hg 1920 601 401 20 wechy 3) stol - Bt od Pressu e Dastoli Blood Pe sure More than 300 mm H3 118 Vinhey s lumale macaque ane ab ur ) y car at be innin í cyperiment "cruht + kilos nt beginning and three hilus at en i of ciperiment Rmun arter) right hidncy greatly constricted but not occluded 1 main artery left kidnes įreatly constricted but not Kch led Systole bil dressure Drat liell (d pressure + llore than 300 mm H. Both syst lic and diave lic presturcs be cinte elevatel and remained cleiated fs 16 months after the clamping of the sight renal artery Dunng the end facute liness which Ja ie mne dys and proned fatal no determ nations of biood pressure were made The elevatio 1 of b thule ndast lic pre ure hos th this *75 triperten in (After Coll1 tt | Ftper lled 65 671 675 1937)

·IRODUCTIO\ O IPERTI \SION
Dog 2-50
2804
260)
2401
2201
RN
200
180
160
.
140
RK
1201
1004
80
60
201
124 days
0
& 5 Removal of an ischemic kidney and production f sched in the rein unm
Ardnet 1can blood pressure in mm lig (Rh) nght main renal arter m lerarely
cfnistracted (R) neht nephrectum at a time when the meas blood pressure was
el vated resulted in its prompt return to coma Lh) great cs<SICI 37 of
»»ain renal artery of left Sidnes. This was fillosed by ion huh eleuatient f
mean blood pressure the mean hot pressure this sisse WAS tore than
mm Hg hkalle 1 (After Calablart A Int les 1879 1937

·ITFLCT ON BLOOD PRISSU'RL OI VODLRATL CON STRICTION OF BOTH VIANRLA AL ARTIRILS THL BLNIG PHASL OF I \PLRIVITAL REAL HIPLRTL\SIO In order to make the hypertension persist it was found necessary to constrict the main arters of both kidneis (Fig 6) or to constrict the main artery of one hidnes and remote the other kidnes (Fig 7) (onstriction of both mun renal arteries at the same time resulted in 1 definite rise of blood pressure usually within 24 hours with the maximum rise occurring in to ucchs or eien longer In most eu periments in inters al of a nech or longer 11 is allowed beru cen the clamping of the ruo main renal vrteries (Fig 6) The remor 11 of the 300 20 200 240! 220 200) ELK 160 140 1201 100) BDS 60 4 201 7mas. 0 May 16,193 Mar Nu928 Eg 6 Blackie short haired mongrel female agc about lier in 194 Initial reicht 14kg Rk = niderate constriction of nicht main renal arch th=m derate cr7 struction of left main renal arter Rhe = nxclusion of right main renal anten =9)stolic blox d pres urt mm Hg determined is the anl eersum carotti loop mrchad This shows that the blood pressure semaine I elevated for about 3 years after he constriction of both main renal arteries Ar no time did thus animal show any »cnificant disturbance of renal excretors function as determined by sartous type of clearance and by the chemical comportion of the bl od After Gt iblatt le Il y lecturer 193 38 ) i 18 ) ·PE VIGP 44 19 Lontralateral hidney for the purpose of uuring the hypertension persist was also performed is a rule in nor less thin 7 ucck after the constriction of the 111!! rest of one hidnas (Fig 7) » bosh gyrocedures mim imetigitors have now succeeded in producing per sistent hypertemuon in dogs monless rabbits rits cars sheep and Loats in some of the angs perustent eleiation of blood pressurt 250 220 Wu $80 141 120 10 8 ED 401 2 days! kg 7 18* 14 male bulldox soune. Instal werkt he is great constricts of left main renal arters R = nghe nephrectomy mean bi rod pressure 1983 Hg dsreer meshk d femoral artery This shows that the blood pressure may become cleated and restarn eles ared fs scseral wechs as the result of constriction of nnls cne main renal arter and that the hypertension may become persistent as a result of the subsequent com val of the contralateral Lidney (Afrer (oliblatt The Harley Lectures 1937 38 ) fras been observed for more than 6 years That this is true hi per tension has been shown by the demonscration that both systolic and drastolst pressures are eles atid (Fig 8) Immediately after the application of the clinip there is consider able reduction of the blood flow through such hidners and the blood pressure in the part of the rool arters dreal to the cup in definitely decreased l hether these two effects persist indefinirels has not yet been established In many of the animals with persistent hypertension due to mod erite constriction of both main renal arteries there was little or no decrerc of ronil excrccors funktion derectible by any of the methods ·40 3:00h 2 260) 240) 20 200) 00100 1601 1404 Blood Pres 40 20 weeks Systolic Blood Pressuc ++ O Diastolic Blood Pressure More than 300 mm FIL 8 Ilonhey 3 Ferale micaquc are about 1 year at bezain of cypliment llight + kilos at beginning and three hilos at end of Cyprenient R main artery night hidncs greatly constricted but pet occluded L main artery left kidncy urcats constricted but not occlu lcd Sy stolic blood pressure Diastolic blood pressure + Vore than 300 mm Hg Beth systolic and diastolic pressures be came elevated and remained elevated for 16 months after the clamping of the right renal artery During the penid of acute illness which Ited nine days and prosed fatal no determinations of blood pressure were made the elevation of both s stolic and diastolic pressure hons that this 1135 tnie hipertension (After Goldblatt ) Frper od 45 71 675 193 ·320 3001 280 260) 2401 20 4 wu sa poog 00 180 160} 140 BENIG PHASE 303 40 30 Urea crance c 399 sooys Tig 9 Deg 59 Inicial wehe 174 kg R = Moderate constrictiert of ant main renal arten 1 moderate construction of left 557111 renal arters Rand I constriction of night and left man renal astcsics sncreased to very great = ysk hc bkc d pressure fetermined by the lani cersum carnud kerp method This illustrates the persistent in perenylon wnhour any 355ociated disturbance nf renal er CICIOS function as derermined by the urca clearance AS Rotire in she life of this mat stas there an increase in the alacs for the non praten nitriech bloot urea or creatinine in the lead frer Cnidblatt Lynch Hanzal and Summery) } Frpey Hei 59 347 349 1934 ) ·22 RENAL ORIGIN Or HYPERTI VSION used in clinicıl medicine (Fig 9) It us shown therefore experi mentally that merely bi disturbince of the intraren i hemodynamics hy pertension was produced sluch although obviously of renal origin nei ertheless had no accompanying disturbance of renal excretory function Thus the most important of the worl ing hu pocheses was satisfied by the results of these experiments The direct application of this observation to man is perhaps not justifiable but it does offer cxperimental evidence for the view that essential human hy pertension usually associated with intrarenal arterio and arteriolo sclerosis bur without impairment of renal excretor function may also be of renil origin in recent years is the result of the work of mm in 4 300! 250 260 249 2 0 RK ats Ecod pr sure mm Hg 10 100 SIC 1 100 60 Tig 10 Doberman pinscher femiale young 18 hb Ao abdominal aorta just belo the origin of both main renal arteries greatly constricted by a clamp Ao abdominal aorta just below the origin of both main renal artertes greatly constricted by a clim loc abdominal aorta above the nam renal artertes occluded by trhtening the cam Aoc abdominal aorta below the main renal arteries occluded by tightening the clamp lh left main renal artery greatly constricted ty a clamp RK night mam rcaal artery seatly c nstricted by a clamp The figures for blood pressure which appear as solid black circles represent the carotid systolic pressure derermined by th anleepsum carotid loop method The figures which appear as open circles represent femoral snean pressure determined by the direct method This shows that the contri tion of the acrta bel the origin of the masa renal arteries has no significant effect the blood pressure in the upper part of thic bol xhereas con triction of the 2011 above the crigin of both main renal arteries results in a definite risc of pre sure which as in the case of constriction of both man rena) arteries begins in abour 14 hour after the operation Vote that ein in the femoral artery after recoicry frun the initul fall of blod pressure the final pressure 3925 Cientually higher than ni mat { After Collblatt hahn and Hanzal | Frper llet 69 69-6 4 1939) ·the blood pressure and thar the hypertension devel ped only when that are con w 8 ay w ojcow poole main renal arteries w is constricted although the mean blood pressure the main renal arteries that when the aorta above the origin of both nection with the pathogenesis of hypertension due to constriction of of elevated blood pressure (Fig 10) It is of special interest in con the origin of the renal arteries is not followed by the development blood pressure whereas constriction of the aorta immediately below site of origin of both main renal arteries results in eles ation of the It was also shown that constriction of the aorta just above the will be discussed in a later part of this monograph i estigators much evidence has accumulated to fas or this view Thus BEIGV PHASE 23 Urea clea ance ce o days of the Fig 11 Dog 60 Initial weight 18 kg SP = almost complete constriction of main splenic ar tery F = great constriction of both femoral arteries immediately belou Pouparts ligament R and L=mo lerate constriction of right and left main renal arteries respecti ely L =con triction of left nan renal artery incrcased to almost complete This control study shows that con tncti c splenic and femoral artenes in the same animal had no significant effect on the stricted This also illustrates the fact that there was no significant of renal excretory function throughout the entire experimental peno I even after the renal arteries were constncte! (After Collblatt lynch Hanzal an 1 Summers ille | Erper lied 59 347 3/9 1914 ) ·24 RENAL ORIGITOI HYPERTISO) in the femoral arteris was lower than normal for a time set et entu ith it became definitely ele, ited although not is much as in the upper part of the body In this connection Steele s obsen ition that in cases of coarcrtion of the aorta in man the diastolic arterial pressure is frequency is elevated below the site of constriction is above it is of great interest A reduced effectne renal blood flow and normal glomerular filtration rite hase also been reported in such Lises b» Friedman Selzer and Rosenblum on the basis of indirect evidence (diodrast and inulin clearances) This is similar to the conditions which obtain in essential human hypertension Other control studies were also cirried out in the same animal the splenic arter and both femoral arteries were constricted This caused no elevation of the blood pressure (Fig 11) For reasons that are difficult to understand there are those who minimize the importance of these experiments because in human hypertension the main renal artery is not commonls scenoac aod they consider therefore that the experimental constriction of the man renal artery does not reproduce euctly the state of the human kidner in essential lypertension This is adnucted of course although there Tre authors lile Yuile and Blacl man who have draun attention to the frequens existence of stenosing tersosclerosis of one or both main resad interies in association with hum in hypertension How cier what is forgotten or ignored by some writers is that con striction of the main renal artery was an expedient resorted to experi mentally because it was the only method available whereby to in duce a disturbance of the circulation of the kidner that might pos suk simulate the most probable effects not onls of stenosis of 1 main renal artery but also ot intrarenal stenosing arter and arterio li sclerosis To regard the experunenral type of hypertension 15 not exactly like human essential hipertension because the man renal artery in human beings with hipertension is not frequentl stenotic is ta misunderstand the whole problem and the mun pur pose of the experimental procedures wluch were used for the pro duction of experimental renal hypertension The recognition of the probabile simularıty is necessart to a proper understanding and evalu ution of the contributions made by the great variety of studies cir ried out on animals such experimental renal hy pertension In some of the animals with both main renal arteries moderately constricted after a period of weeks or months the blood pressure to ·SINGH MEDICAL BENIG PHASE 25 turned to a lower level or er en to the orginal normal level To re elevate the pressure it was often sufficient merels to increase the constriction of one or both main renal arteries (Fig 9) In other animals the examination of the hidners showed that the potential accessory circulation to the periphers of the hidney had become strikingly prominent with large arterial vessels entering the cortex of the kidney from the various surrounding organs and structures Decapsulation and enclosure of one or both kidneys in a fishskin condom frequently resulted in a re elevation of the blood pressure which often persisted This type of membrane did not induce the de velopment of the thick hull of connective tissuc around the kidney which is induced by wrapping cellophane collodion or silk around a hidney but it did reduce the accessori circulation to the kidney and it was thought that this induced the re elevation of the blood pressure Cellophane collodion and silh membranes (Page and others) have been wrapped around hidness and elevation of blood pressure has been observed to develop weels or months after the application of these membranes 1 he elevation of the blood pressure in these animals has been considered as due to the perinephritis and the com pression of the renal substance by the thuck hull of connective tissue which develops around the hidners That actual compression of the lidney occurs has not been proved In fact there is no proof that the mechanism of the clevated blood pressure is not due to the scar tissue which also develops around the renal pedicle with constriction of the artery vein and ureter of the kidnev Two indications of this are the passive hyperemia (venous obstruction) and hy dronephrosis (ureteral obstruction) in some degree which are almost invariably observed at autopsy in such kidneys This is a matter which should be settled in any event it is believed that the pathogenesis of the hypertension in such cases is similar to that which results from con striction of the main renal arteries The main drau bach of the method is that impairment of renal function is an almost invariable accom paniment of the hypertension and fatal uremia (the malignant phase) is a common outcome MAN LIBRARY MYS LES ·26 JC 200 280 Blood press re. 10 150 1604 REVAL ORIGI\ OF HIPERTENSION 50! Ures cicorence cc doy? Fig 12 Deg 38 female Innal weight 12 hg I great construction of left man renal artery R great constriction of nghe main rental arter) Vate the persistent reduction of ves clearance to about 50cl of normal throughout the life of this animal This was the only sign of impairment of rentl excretory functon At no time hou ever was there an accumulmuon of non protein nitrogen products in the blood (After Goldblatt Iynch Hanzal and Sommersille 1 Exner Hed 59 347 379 1934) ·EFFECT ON BLOOD PRESSURE OF GREAT CON STRICTION OF BOTH MAIN RENAL ARTERIES THE MALIGNANT PHASE OF EVPERI- MENTAL RENAL HYPERTENSION If both main renal arteries are greatly constricted from the be ginning or in some cases of moderate constriction is practiced at first and great constriction later elevation of blood pressure accompanied by variable degrees of impaired renal excretory function is the result (Fig 12) If the renal arteries are greatly constricred 320 300 280 260 240 220) Blood pressure mm Hg 200 180 19 hig 13 Dog 8 7 female Inval weight 140 kg R = almost com plete constriction of nght main renal artery L = almost complete constriction of left main renal ar tery D=Died The animal died in uremia as illustrared by the great accumulation of NPN in the blood Creatinine and blood urez nutrogen were also greatly increased and the urea clearance was greatly decreased Anatomically this ou mal showed both in the gross and DUCroscopically the typical arterio lar lesions of the malignant phase (See Plate 1) After Goldblatt Lynch Hanzal and Summerville | Etper Med 59 347 379 1934 ) 140 120 100 320 2BD 240 200 NPN mg per 100 CC 160 120 60 40 90 days 0 ·MAN SINGH MEDICAL 28 REVAL ORIGI\ OF HYPERTENSION from the beginning, and especiall of both renal arteries are occluded fatal urema results The same effect can be produced by excessive constriction of one main renal artery with contralateral nephrectomy or contralateral ureteral occlusion in those animals that develop great impairment of renal excretor function along with the hyper tension fatal con ulsite uremia occurs (Fig 13) and ar autopsy pathologic changes are found in the small arteries and arterioles u hich resemble those observed in the malignant phase of essential hyper tension More will be said about these chinges under the heading of pathologic changes Thus hypertension resembling both the benign and the malignano phases of essential hypertension has been produced experimentally in animals merely by varying the degree of constriction of the main renal arteries and the conseguent alteration in the intrarenal circula tion The exact nature of this disturbance of incrarenal hemodynamics has not yet been deterinined Vlore will be said later about the et dence that has accumulated to indicate that the benign and malig nant phases of essential hipertension in man may also be primarul of renal origin CO VVS LIBRARY 393 JAIPUP ·KA LIBRARY VIAUS 393 JAIPUR PATHOLOGIC CHANGES IN THE ORGANS OF ANIMALS WITH PERSISTENT HYPERTENSION Within the lidney the pathologic changes which result from constriction of the main renal artery are directly dependent upon the degree of constriction of this vessel in the berugn phase that is in hypertensive animals with moderate constriction of the main renal arteries and without accompanying renal excretory insufficiency the kidneys may show little if any significant gross or microscopic ab normalities detectable by the usual methods In the early stages changes in the mitochondria of the proximal convoluted tubules may be found even in those l idneys in which later no obvious anatomical changes are detectable Pathologic changes in the structure of the 1 idneys are therefore not necessary for the determination of the benign phase of experimental hypertension produced by constriction of the main renal artery Sell urt has shown that in dogs 1 considerable lowering of the systemic blood pressure alone may result in a disproportionately low renal blood flow with striking physiologic evidence of tubular damage ver without correspondingly stril ing histological alterations in the kidney depending upon the duration and degree of the anoxia This may mean that intracellular changes not detectable by the usual methods have occurred with consequent alteration in intracellular enzymes and other substances In some hypertensive animals after several months one of the lidneys may be found atrophic even though significant diminution of renal excretor function had not occurred in such animals the other 1 dney is usually hypertrophic and both in the gross and microscopically essentially normal In some of these small kidneys there is little or no interstitial fibrosis and the reduced size of the organ is due mainly to disappearance of glomeruli and of cortical tubules as well as shrinkage of the tubules which have no distinct lumen and which are lined by greatly altered epithelium in which signs of regeneration (mitoses and hyperchromatic nuclei) are com [ 29 ] ·30 REWAL ORIGIN OF HIPERTENSION mon in the liming epithelial cells This is the so called endocrine kıd ney which Selve has produced in the left kidney of rats by constric tion of the aorta between the origin of both main renal arteries Whether in such kidneys there is actual transformation of an exocrine to an endocrine type of cell and the part that these cells play in the origin of the hipertension u hich des elops remain to be determined In animals in the malignant phase especially when both main renal arteries are greatly constricted the same timc profound parenchy matous degeneration or diffuse necrosis with or without hemorrhage may occur in both lidney s In the bcnign phase in dogs even after 6 years of persistent hypertension no significant pathologic changes have been observed in the aorta or in the large or small arteries The only changes that have been detected in the vascular si stem of such animals have been slight to moderate hypertrophy of the heart and thickening of the media of the large and small arteries due to hypertrophy and hyper plasia of the muscle fibers These experiments therefore afford no proof for the vieu that hypertension by itself is a sufficient condition for the production of generalized truc simple arterial or arteriolar sclerosis In the malignant phase in animals even when it terminates farulls Plate 1 Arterial Lesions in Malignant Hypertension - Part 1 Arteriole in submucosa of large intestine Beginning subendothelial deposit of hyalin Endotheliuni well preserved Hematorylin and Losin x 65 Part 2 Artertole in submucosa of stomach Obliterative hyalınızation of inoma endothelium still recognizable but nuclei reduced in number and pknotic Hema roxylın and Fosin X 430 Part 3 Arteriole in submucosa of small intestinc Lumen completely obliterated by accumulation of hyalin contaming a few pyl notic nuclei Hematory lin and Eosin X 430 Parts 1 2 and 3 are from an animal that lived for one month after grear constriction of both main renal arteries Renal excretory function was greatly im paired Part + Artenole in submucosa of stomach Portion of entire thickness of wall necrotic Normal thichness of all and lumen natural size Hematory lin and Eosin X375 Part 5 Arteriole cut longitudinally in submucosa and mucosa of large intestine Partly hyalınızed partly necrotc with extras asated blood around it A portion of the same arteriole in the submucosa immediately proximal to the part included in this figure was entirely normal Hematorylin and Eosin x 35 (After Goldblatt, Exper ſed 67 809 1938 ) Parts 4 and 3 are from an animal that lived for one week after great constriction of both man renal arteries The animal developed con vulsive uremia

·PATHOLOGIC CHANGES IN ORGAVS OF AVIVALS
31
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PIATEJ

·32 RENAL ORIGIN OF HIPERTENSION arrer in as little as 18 to 72 hours the most profound changes has e been observed in the blood sessels of the dog monley rabbie rit sleep and goat The changes are similar to those seen in the terminal phase of human malignant hipertension In the gross the condition is man! fested by petechise in the gastro intestinal tract gall bladder urinary bladder pancreas adrenals brain pericardium and myocardium Alicroscopicalls in the aorta there is only interstitial ederna mainly of the media but the wall of small arteries and arterioles in those organs in which the perechiae occur is the seat of necrosis and fibrin old degeneration with or without i ascular and persi ascular inflamma tion characterized by the exudation of poly morphonuclear leukocytes and some limphoid cells The necrotizing and inflammatory changes in the arterioles are indistinguishable from those observed in the ter minal phase of malignant luman hypertension (Plarc 1) There is hou ever one significant difference from the malignant phase in human beings the vascular lesions do not occur in the blood vessels of the lidneis beyond the site of constriction of the niin renul Lien intrarınal necrotizing arteriolar lesions have been pro duced Greut constriction of the main arters of one kidney and liga con of the ureter of the other i idney resulted in hypertension accom panied by renal insufficiency (Goldblatt and Kihn) The arteriolar lesions of the malignant phase de eloped in the kidney with ureter occluded in huch intrarenal arterial tension was increased but nor in the lidnes with the main renal artery constricted in which the intrarenal arterial tension was undoubtedly low Pachogenesis of arteriolar necrosis Of the mode of der elopment of the degeneratie necrotizing and infiimmatory lesions of the arterioles which are found in many internal organs in the malignant phase of experimental renal hypertension nothing definite is knoun These vascular lesions are indistinguishable from those found in hu man beings in the mulignant phase of essential hy pertension and are nor to be confused with simple arteriolosclerosis observed in the benign phase of human essential hypertension In animals the arterio lac lesions are usually more sciere and more widespread than in man This may merely indicate 1 greater susceptibility of the vascular sss tem of animals to these changes 4s in human beings with malig nant hypertension some organs especially the lungs si in and sl cle tal muscles rarely show these lesions The fact that the hidneys fail to show these lesions may afford a clue to their mode of development ·PATHOLOGIC CHANGES IN ORGA'S OF AVITAIS The intravascular pressure within the hidnes beyond the site of constriction of the main renal artery is low In man even the intra renal vascular pressure is usually high because oblicerati e sclerosis of the main renal artery does not usuallı accompany the condition As a matter of fact it has never been shown even in malignant hu man hypertension that the arterioles which correspond to a larger arterial branch which is the seat of stenosing arteriosclerosis ever be come necrotic It may be that only those arterioles become necrotic that are subjected to a high bursting tension as well as to the effects of the chemical substance or substances in the blood which result from the renal damage In some cases of malignant hypertension in man necrosis of the renal arterioles does not occur 1 hese may be cases in which there is widespread stenosing arteriosclerosis of the larger in trarenal arteries or of the main renal arter with or without arteriolo sclerosis within the hidney It seems therefore that a combination of increased vascular tension and the effect of a chemical substance of renal origin the result of interference with circulation of the kidney are necessary conditions for the production of arteriolar necrosis and the associated hemorrhages That elevated intravascular pressure alone is not a sufficient condition for the production of the necrotizing arteriolar lesion is demonstrated by the absence of these lesions in the organs of animals that have had pronounced hypertension for many years without accompanying significant disturbince of renul excre tory function or in the lidneys of animals with experimental neuro genic hypertension This indicates that intense vasospasm alone is not a determinant of these lesions That the chemical factors alone is not sufficient for the production of the arteriolar lesions is demonstrated by the fact that bilaterally nephrectomized animals with profound azo temia but without hypertension do not develop the necrotizing lessons of the arterioles and the associated petechiae That the lesions of the arterioles are not due to ischemic necrosis is of course shown by their absence from the ischemic kidneys of the animals and their presence in organs in which there is no obvious ischemia Ilhat the exact nature of the chemical substance or substances is that plays the important part in the production of the anatomical lesions has not yet been elucidated by the investigations of renal hipertension that have been performed up to the present li internity and his collaborators have been able to produce lesions of a similar nature by repeated injeccions of an extract of hidneys But this does not prove that these cheinical sub ·34 RIVAL ORICT OF HIPERTISION stances, by themselves have the ability to produce these lessons because the cxtract also produced a considerable ele ation of blood pressure so that a combination of the effect of the liy pertension and of the chemical factor cannot be excluded Although remin was used in these experiments yet there is no proof that the chemical sub scance responsible for the lesions was renin or is renin in hiperren sie animals for the reruin used by Il internity and collaborrors » XS not pure The inflammatory changes around the blood vessels are probably only a reaction to the degeneration and necrosis of the walls of the arterioles but it cannot be denied that they may be caused by the same agent that produces the necrosis B repeated intravenous in jections of tyramine some ini estigators have produced lesions of arteroles uluch they consider similar to those of the malignant phase but there is cerruns no good re.ison for the belief that tiranjine is responsible for the lesions of the malignant phase of hypertension Wilson and Byrom and others have asserted thar they obscried the characteristic malignant arceriolar lesions in one hidney in rits with hypertension due to constriction of the main renal arters of the contralateral lidney lle have not been able to confirm these obsen ations in dogs rabbits monhers sheep or goats with hyper tension due to constriction of one main renal arter. The conclusion reached by Wilson and Bi rom confirmed by others that hyperten sion by itself is able to cause the characteristic malignant arteriolar lessons in the rat with hypertension due to constriction of only one main renal artery has not been substantiated in the cxperiments on any other animals and is probably based on the erroneous assumption that the contralateral lidnes was normal All the glomerular ind interstical inflammatory lesions uithin the other ise supposed) nor mai hidney, described by these authors have been observed by us in the kidneys of rats with normal blood pressure The best explanı tion of the changes in the arterioles of the contralateral kidnei ob served by it uson and Buroni and the ochers is probably that the were unaware of the frequent existence of hy dronephrosis or pyelo nephritis in onc or both kidness of adult racs and that bi constriction of onlt onc main renal artery they were really dealing in sonic of these rats such bilateral renal disease The possibilita suill remains that the rat in this respect differs from all other animals Other changes in experimental renal hypertension It was ·PATHOLOCIC CHAIGES I ORO INSOI ISuars 35 shoun cirl that the hypertension which results from constriction of the main renal arteries insoles both the su stolic and the diastolic pressures and the elevation of these has been demonstrated in 1 inriety of ways In experimental renal hipertension the pulse rare reinains unchanged and no sigmficant alteration in the output of blood from the heart has been observed in the hipertensive 2 mals The volume of the blood in hypertensive dogs shons no signut kant vanstons from the normal The pressure in the lesser circulation (the main pulmonary arteri ) is ako uiting the limes of normal which indicates that the pulmonic essels are not affected by per: pheral scular constriction in thus tipe of hypertension in the blood apart from the serention of merogenous products in the am intls in the malignant phase no significant changes hac been ob cred The pll of the blood remains within the kinues of normal 19 animals in the benign phase (lluller and Vichel) ho signific slterations in the hped and protein content of plassia have been nored bur Page did report a slight inescase of free cholesterol at the en psense of the escerified fraction o specsal significance has been at mched to this change in animals char e lubit retention of nero Senous products accumulation of the guanidine compounds akys xxccurs but since there is an accumulation of thus product in the berugn phase no special significince has bcen utached to the presente of this pressor substance in the blood esen in the malignant phase redistribution of the water content of skeletal issuscles of dogs watis experimental renal fty pertension has been found (Lichelberger) Thrs merely indicates sone cuftacellular edema hich occurs 17xech in the malgnant phase As concerns the physiologa il réactions in hipertusse anns is of interest that the carosd us and cards orti neries are wir able to effect a lonering of the blood pressure tu nomal so amals with 1113101 renal arteri concred There is some difference « <spu33&<» about the effect of occlusion of the common carotid arteries in ani inals with ciperimental renal hypertension Sonne iuthors have found 3 Grerer rise of blod pressure in such umils than in those watts normal blood pressure lle have found thar the excision of both caro fid sinuses did not alter the des clupine nt of hypertension produced o resnl ischemia and that the level of blood pressure reached br such animals was schifferent from this ut juals with caroad sinuses 15 tact It seems therefore that the regulatory si steni (of the blood pres ·N SINGH MEDICAL 36 RI VAL ORIGIN OF HIPERTENSION surc functions actn ely in cyperimental renal hypertension and that it probably acts normally though at a high level It has been found that animals with experimental renal hypertension reict in hyper sensitive fashion to injections of adrenalın tyraminc ind pitressin bur no one has suggested that these substances plus ant part in the origin of the elevated blood pressure In fact because the injection of co caine causes no fall of blood pressure in hypertensne dogs Robbers and Westenhoeffer have concluded that is ramine cannot be the cause of cyperimental ruoal by pertension It has also been shown that the dog s reaction to the cold pressor test is the same after the develop ment of hypertension is it u is in the pre hypertensie stite Van investigators have found that the presence of an infection causes a full of the blood pressure which returns to its mitual la el after the in fection has disappeared the type of infection which produces the most profound and the most lasting effect is disteniper The pro longed effect on the blood pressure is probably due to the slou re covery of animals from this type of infection This is a lcad which probably descries more attention than it has recen cd Similir effects can be obrained by the injection of bacteria or bacterial products for cxample cyphuid vaccine injected intra ehously wall producer temporary significant full of blood pressure in animis wath espera mental renal hypertension as it does also in human beings with es sencial hypertension 11 hether or not this effect is produced by the slaration of afferent arterioles and improvement of circulation of the kidneys or by rclaration of cfferent glomerular arterioles mu curense of intsaglomerular pressure has not been established LIBRARY co ·Vrts LIBRARY 3937 JAIPUR PATHIOGLNI SIS (ULCIIANISTI OF DLVLLOP\II NI) OF LIPLRIMENTAL RLMAL HYPERTL WSIO The production of the counterpart of thc benign and malign und phases of human hypertension has made possible the mi estigation of the probable prthogenesis of the high blood pressure even in nun Since the original publication of the production of experimental ronal hypertension the pathogenesis of this type of hypertension has been discussed in inint publications which have dealt muns with the possible application of the observations on animals to the problem of the mechanism of production of human essential hyper tension It is obviousls impossible to solve a problem of this kind by thic study of patients clinically or by examination of specimens of tissues obtained at autopsy Progress in the acquisition of our hnoul cdge of the pathogenesis of human hypertension has therefore been delayed because in human beings it is rarely if ever possible to study the patient before and after the development of the elevated blood pressure The arteriolar sclerosis of the kidneys which has been reported by mans authors (Fishberg Bell and Clausen Voritz and Oldt) as in almost amarnble finding in cises of human essential hypertension it zutops has been interpreted by some as proof for the sieu that the hypertension comes first and produces the renal vascular dis cise The possible causal relationship between the two conditions could concen abh be investigated by the examination of biopsy specimens of hidney obtained from the same individuals at intervals before and after the development of hypertension Since there is no u 11 of telling with any degree of certunts which persons will de velop hypertenston such a study of human beings is not feasiblc An approich to this problem has been made by the eximination of biops specimens of hidneys in cases of established human hypertension after the condition had been in eustence for 1 i ariable length of time (Castleman ind Smithuich) This study has not led to 1 sulu tion of the problem for obuous reasons ind the conclusion of the ( 37 ) ·RENAI ORIGIN OF HIPERTENSION zuthors that the results of their ini cstigation show that the ascular disease is caused by the hypertension is hurdlı justifiable In a series of patients with hypertension th it had evsted for vari ible periods biopsy specimens of the kidneys were crimined for vascular disease (Castleman and Smithwic!) In these smul speci mens in which at best only a few cross secrions of independent irterioles could be obser cd the changes were classified arbitrarılı from 0 to + + + + on the basis of hu iline thichening of the wall and stenosis of the lumen Despite the views and conclusions of the authors it is an interesting ind indeed in extraordinary face their some vascular abnormality was found in about 90° of the speci mens and that in bout 10 jt was from moderite r severe From the study of such small specimens it is obuously impossible to tell whether the ascular disease is more or less pronounced in thc rc mainder of the hidney It is hazardous therefore to extrapolate from the evaluation of such minute specimens ot hererogeneous tissue to an estimate of the average condition of a single constituent the arteriolo of the entire organ Lien if the appear ince of a fen arterioles could possibly give some estimure of the 11 erage chinge in simular vessels of the remainder of the hidney set it can give no ider of the state of the larger intrirenal vessels or of the hemods mestite of the entire kidney The lirger intrarenil uterics are rarels included in such biops, specimens because the specimens are rilen from the periphers of the corte It should be obvious that stenosis of one large intrarenal arters could account for great hemodynamic dis curbance in a large mass of kidnet substance supplied by many arterioles that are not themsch es diseased in human nephrosclerosis stenosing arteriosclerosis of large intrarenal i essels is a common 16 companiment of the arteriolar sclerosis The possible contribution of such obliterature sclerosis of the large merrenal arteries and cren of the main renal artery to the disturbince of intrarenal hemo dinamics has been underestimated Indecd Blac] min his show 1101 common it is to find in hypertensi e patients at nutopsy soc dc gree of stenosis cien of the main renal artery At no time of course has it been asserted that stenosis of the nun renal irreri un Lateral or bilaceral is a common Ljuse of or cien a frequent hind ing in, human essential has pertension It is difficult therefore te> understand u hs some authors should make a special point of emplu, sizing that in many hypertensic patients in schom pronounced stca ·PATHOGI VLSIS 39 Osis of one or both main renal arteries vis found there was also present significant intrarenal arteriolur sclerosis Thuis is to be ex pected and it is probable that in most of these cases the intrarenal disease det eloped first and determined the initial elevation of the blood pressure However the possible part played by the ob literative sclerosis of the main renul artery cannot be denied The possible mechanisms involi ed in the elevation of the blood pressure are (1) afferent nervous stimuli from the nerve endings in the kidness to the vasomotor center or simpathetic ganglia with resultant generalized vasoconstriction and consequent elevation of blood pressure (2) afferent stimulı from the kidneys with resultant output of in increased amount of some known internal secretion which produces vasoconstriction either by central or peripheral action (3) the entrance into the circulation of a primary pressor substance of renal origin or the new formation of a pressor sub stance as a result of the interaction of a renal substance with substances already present in the blood Teleologic considerations are mentioned only to be discarded because they are not susceptible of experimental proof Neurogenic mechanism The possible part played by various por tions of the nervous system was investigated first It u as soon shown that experimental renal hypertension is not caused by a nervous refle from the hidney affecting the vasomotor mechanism of the body Renal denervation (Fig 14) bilateral supradiaphragmatic ex cision of splanchnic nerves and lower dorsal sympathetic gangin (Figs 15 16) subdiaphragmatic splanchnicectomy with excision of the celiac and upper lumbar gangli, bilateral section of the an terior nerve roots from the 6th dorsal to the second lumbar inclu sive (Fig 17) pithing with destruction of the entire spinal cord and complete svmpathectomy including denervation of the heart (Fig 18) neither prevent nor abolish the hypertension which results from constriction of the main renal artery Even under anesthesia (pentothal) experinlentul renal hypertension persists whereas 1 nown neurogenic hypertension disappears These results eliminated the idei that a nervous reflex originating in the lidney is the cause of the experimental renal hypertension and indicated that a humoral niech inism was probably the cause There are those lahe Ogden however who concede that the renal humoral pressor mechanism initiates er perimental renal hy pertension but who believe that this is superseded ·40 RIA! ORIGIOI PIRTI VSIO! 325 303 279 Body weight 2301 30 Percent o per kilograms Nor-protein nitrogen 30 20 00 70 60 $0 220 Prenolsulphonephthalein Blood pressure 200 OPERATION M 100 Jycolic 160 Mrimeters of hq $40 120 100 Diastolc PO 0 0 20 40 60 00 100 120 140 160 180 200 220 240 200 200 300 320 310 Tme in days fig 14 Lffect of denervation of the kidneys and constriction of the renal arterit In the case of the blood pressure each point repre cits an ancrage of the readings Cahen ouer a period of ten days late that conil deneriation does not present the production of hipertension (After Collins Am 1 11 501 116 616 1936 ) lates by a neurogenic mechanism mediaced through the sympathetic nerous syster This view has not been established his ans (cans and much more investigation is definite indicared Endocrinogenic mechanism The French school is especialh com mutted the vics that in human essential fly pertension hiperpine phrine is a highly probable cause Although there are those who saill cling ro the idea that esseniual hi pertension is primarily endoc rinogenic and due to some disturbance of the hypophysis vcs the csperiments on animals have failed to lend support to this sick Complete his pophis sectomy does not pertinentis lower the blood pressure of a dog with experimental renal hypertension and does nor present the des elopment of this 11 pe of lpertension (I ug 19) There is no proof that the actrity of the posterior lobe of the pituitary changed in in way so experimental renal hy pertension The amount of the antidiuretic principle in the urine remains unchanged in experi ·300 250 Blood pressure mm Hg 200 LITHOGONI SIS 150 Kould be 100 Fth 13 Dag 35 femalc Inbal weight ihr 5=bilateral ceci ion of thoracic pacts ont planchine nenes and lister four dorsal sympathetic gangla R = moderate constriction of right main renal artery 1 mulcrate closericton of left main real artery The blood pressure was unattested by the excision of the netics but roes the usual way after construction tith man renal arterses and remainel elevated after constriction of the tuin aftenes Systolic blood pressure sktening lh thu I cenum caroti lop method (frer Collat cross and Iłac 2) I Frp Wet 61 13 41 1937) ·it 300 250 Blood pressure mom Hg 200 150 RIN ORIGIN OF 33 PERTENSION 30.dby 100 tag 16 Dos 2 10 male Instial serght Oh R=moderate constctim of right main renal artery I = moderate consection of teft mai renal arter) S=bulateral excsson of the imrathoracic portion of splanchnic neries an over four dorsal sympathetic gangla Tor a period of about three months following this operation the blood pressure was iery stregular and at times dropped conxaderat ly bit never reached normal levels Later she blood pressure became re elevated and remained as high as it was before Ccision of the splachrc nerses Systoke blood pressure letermined by the van 1 eersum carotid forp mechod ( \fter Golublatt Cras and lanzal / Frper tett 65 233 241 1937 1 ·300 280 260 240 20 220 € 2001 180! 160) Blood pressure mm Hg 1401 120 100! PATHOGENESIS 80 60 40 20 10days 04 Fig 17 Dog : 09 female Initial weight 107 kg NS = section of anterior spinal nerie rots from sixth dorsal to second lumbar inclusive LK - moderate constriction of might main renal artery The mcan femoral blood pressure became elevated in the usual way after the constrictin of both the min renal arteries (After Goldblatt and lart min) Errer Het 66 527 534 1937) 43 ·47 RIVAL ORIGIN OF HIPERTENSIO it my fathew cha gh - om He LANA 163 y56 A ta Do ܠܝܟ in 10 ci mgen Cmp 692 1 ltr lat ry 19 Cumpl 16 y rectomy 87 10 17 met Screet At dort niat Oct 2 -Lt net rt 19 o y 2 24 29 14 19 v Dec Hg 18 Effect of sympathectomy on deselopment of renal hypertension i ffect of constriction of the renal arteries on the systolic and diastolic pressure of a dream which both paravertebral sympathetic chains were removed from the stellare kan ? to the pelvic chain The unbroken sympathetic chains rem sed are shown in the upper part of the chart Note that sympathectoms does not present thic production of hypertension (Ifter Freeman and Page 4m Heart ) 14 406 193) mental renal hypertension but during dehydration it is increascd in both normal and hypertensn e animais [xcision of the posterior pituitary does not interfere with the dei clopment of or lower a perimental renal hypertension in the rabbit Thoroidectomy gonadectomy and pancreatectomi have no significunt effect in prci enting or lowering experimental renal in per tension in the dog The only endocrine orgin uluch 21 possibly plu significant cien if only a secondars port in cyperimental renal hypertension the adrenal Lien thus conclusion has been contested (Rogoff) in the earliest study of experiental ren ti percensson st 14 as shon » that the medulla of the adrenal plaus no pirt in the origin or main tenance of the clerated blood pressure (fig 20) Ihere is houerer some indication that the adrenal cortex m2 plat 2 secondırı pirt in this type of hypertension although there ire those who do not ·PITHOGENESI5 45 300 200 260 240 220 200 Dir et remo al Blood Pr ssure mm Hg EK 80 60 40 2012 12 day Dog "5 + 19 The effect of emplete hypophy sectomy on the development of hyperten in due to constriction of both mun renal arteries Dog 4 male middle aged che weight 11 kg H=< mplete hypophy sectomy L = Inod rate permanent Cnstriction of left main renal artery Rh = moderate permanent constriction of nght nas renal artery k=kill a Complete hypophy sectomy had no significant perma nent effect on the level of blood pressure of the normal animal and did not interfere with the d elopmn nt of hypertension due to constriction of both main renal arteries After Goldblatt Braden hahn and Hoyt I ft Sina Hosp III Jan Feb 194 ) concede even this The complete excision of both adrenals in dogs interferes with the development of hypertension due to constriction of the main renal arteries unless adequate supportive and substitution therapy is given (Figs 21 2) Ilhen only two fifths of the cortex of one adrenal is present there is no interference with the develop ment of experimental renal hypertenston in the dog (Fig 23) When both adrenals of a hypertensive animal are reftoved the blood pressure falls promptly to normal (Fig 2+) It will be shown in the discussion of the humoral mechanism that the possible mode of action of the cortical hormone is to influence the production of the pseudoglobulin in the blood which acts as the substrate for the activity of renin tu form the pressor substance hypertensin Recently Victor reported the production of hypertension in dogs by ligation of the hilar vein and of grossls visible arteries and veins it either the superior or the inferior pole of only one adrenal Jt us cvident of course that nerve fibers must have been included in the polar ligature although Victor does not mahe special mention of this

·46
RI NAI ORIGIN OF HIPI RTI VSO
320
300
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Blood pressure mm Hg
160
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120
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40
20
30 days
Fog 0 The effect of removal of one adrenal and testruction of the medulla of the
(ther adrenal on the dei clopment of hypertension due ro constriction (lth an
renal arteries Dog 8 9 Instial weight 136 hg 4 = excision of right adrenal AS
destruction of medulla and deneration of left adrenal Suction of left major ani
ttunor splanchnic nenes R and I z moderate constriction of right and left man
renal arteries, respectiel) The chronation of the medulla (f oth adrenal al
no significant effect on the deckpment of hypertension due to contrictwn of both
main renal blood arteries Systolic bl jod pressure determined by the van I cersuit
caroud loop method (After Goldblatt lynch Hanzal and Sunn muille ) rp ?
Wes 59 347 3 9 1934)

·}}THOCIVESIS 15 11 1t 1 L Fry The effect of bilateral adrenaletton on the de elopment of hypertension due to constnction of both main fenal arteries mean blood pressure mm Hg .=non protes otrogen min per 100 CC CO combnine pov er blumes per 100 cc RL4=bilateral adrenalecta y and both 13111 renal arteries moderately constncted LV=left nephrectomy += stratenou adrenal cortical extract begun adrenal cortical extract descontinued During the entire period follo ting the bilateral adrenalectomy the animal seles ed by stomach sube to tuo equal Jose (9.00am and 4 00pm ) a total of 07 sm ger hg of bod eight of sodium chlon le and 0 25 gm per his of body weight si drum incasionate Ar no cisie during the four months of survival did the animalo elevated bl od pre sure Sei eral rmc which cortical extract was discontinued the bloc 1 pre sure feilt er) tu leses hkalled (After Goldblatt Ann In sed 111937 Vo explanation of or speculation about the mechanisı of the ho per tension was given by Isctor lle he repeated these experiments in 6 dags but have failed to confirm the result in one of these dogs the operation was performed by Dr Victor himself but alus animal too failed to develop h persension Vore work wil huse to be done on this subject before ans final conclusion can be reached atrout the significance of this contribution A theory which deser es careful consideration is that of Selo (5) (General adaptation »ndsome) sho betses es that various son specific spes of stress acting by unknou n pathways on the anterior hypophysis produce an increase of the adrenal corticotrophic hor mone which in turn causes the adrenal cortex to produce an increased amount of desory corticosterone like substances (corticoid hormone) which affect the target (gans one of thich is the kidney with re sultant intrarenal arteriosclerosis and hypertension He belses es that the anterior his pophyseal substance ind che adrenal cortical substance may act independenth or sinergistically upon the kidney and that the adrenal cortical hormone was even stimulate the anterior hy po ·46 RUL ORIGI or ily PCRTI VSION 320 300 280 260 240 220 . 200 180 Blood pressure mm Hg 160 140 120 100 80 60 40 20 30 days Fug 20 The effect of removal of une adrenal and destruction of the nicdult of th other adrenal on the des clopment of hypertension due to constriction of loch min renal arteries Dog 8 9 Toitial weight 136 kg A = excrsion of right adrenal A3 destruction of medulla and denervation of lift adrenal Section of left major as minor splanchnic nenes Rand L = moderate anstriction of right and left man renal arteries respecta els The elimination of the medulla of both adrenal hal no significant effect on the deselopnient if hyperteuse due to ci nstriction of the min renal blood arteries Systolic I lood pressure determined by the van Ieruan carond loop method (Alter Goldblatt Linch Hinzal and Summerulle / Trper Ted 59 347 3 9 1934 ) ·PATHOGENESIS 19 240 Dogt 3 16 220 200 180 160) 1440) LNPA 1204 11 RKA 100 80 61 40 20 8days Fig 3 Dog 3 16 female 140 kg The effect of a remnant of adrenal cortex on the development of experimental renal hypertension == mean blood pressure mm HL =non protein nitrogen mg per 100 cc plasma LNPA = left nephrectomy and parual adrenalectomy The medulla was destroyed About two fifths of the cortex was left RKA = right adrenalectomy and right main renal artery greatly con stricted = sodium chloride (075 gm per kg of body weight) and sodium citrate (025 gm per kg of body weight) were given by stomach tube from this tunc on sodium chloride and sodium citrate discontinued No cortical extract was given at any time The blood pressure rose moderately following the constriction of the renal artery and remained eles ated when supportive treatment was discontinued This shows that the presence of a small remnant of adrenal criter adequate to help to heep the animal alive was sufficient to permit the development of hypertension after the constriction of the main renal artery of the only kidney (After Goldblatt Am Int Afed 11 69 103 1937) physis to produce a direct effect upon the lidney It is of interest that according to this author the lidney still plays a central part in the determination of the elevated blood pressure and that the hyper tension may be the result of the recognized humoral mechanism of ne month during which the dog, received substitution as well as supportive treatment 1 henes er che intravenous cortical extract was discontinued (-) the blood pressure gradually fell to a level below normal When cortical extract was begun again (+) the blood pressure gradually tose but did not reach the previous hyperten ne level D=died of pneumonia (After Goldblatt Ann Int Het 11 69 103 1937 ) ·RIIT ORIGI\ O HIPERTESIO ADRENAL G G 70 165 180 155 190 EFFECTS OF REN LISCHEMA AND B LATER LADNENALEC OMY 143 E 33 fi t CXPERIMENTS HYPERTENS ON ABOL SHED BY REMOVAL OF SECOND ADAENAL IN ALL (CON IRMS GOLDAL TTS UNPWAL SWED OBSE AT ONS) de 30 23 201 DEN LECTOMY SCHEMAT ONEY DEN LECTOM SCHEMA LT X DNE 0 ESCHTN 2 CCSD LY OA 3 DAS o 10 5 7 FIE 4 Effect on blood pressure of bilateral adrenalectomy ani renal certina Iffect on the blood pressure of remos al of both adrenals combined with bilateral renal ischemia Observe the rapid fall of blood pressure follow any rcm val the second adrenal gland (After Blaloch and Levy Ann Surg 106 8 6 193 experimental renal hypertension in addition this theori offers i possible cıplanation for the origin of the intrarenal arteriosclerosis so frequently found in association with the hypertension The experi mental work which Selye and collaborators huic published on this subject has dealt less with hypertension than uch the production of intrarenal arteriosclerosis which they accomplished by the adnunistri tion of large doses of desovs corticosterone acetate nunks to uni laterally nephrectomized rats but also to other anmuls fed on a high sodium diet Much more work on this subject is necessirs before the part that the hypophysis and adrenal may play in the origin of both vascular disease and hipertension can be considered as definitels established ·THE HUMORAL MECHANISTI OF TIPERIMENTAL RENAL HYPERTENSION The earliest indication that i humoral mechanism might be re sponsible for the elevated blood pressure in experiental renal hy per tension was the effect of tying off the renal veins in dogs with the main renal arteries constricted adequatel to produce hypertension Although these animals der eloped urema and died in from tuo to seven days et at no time did the show any elevation of the blood pressure (Fig 25) Tving off of the renal veins of hypertensive ani mals also resulted in a prompt fall of the blood pressure The gradual elimination of a possible primar part played by the nervous and endocrine systems also stimulated the search for a probable hu moral mechanism of renal origin which might be responsible for the elevation of the blood pressure in this type of hypertension ind possibly also in human essential hypertension In fict most of the recent contributions to this subject have deilt with the bumoral mechanism About this mechanism there are now two dis tinct views (1) That 1 hidnes with main renal arteri constricted or the seat of any pathologic conditions which bring about a dis turbance of the circulation similar to constriction of the main renil artery may be the source of a substance which when it enters the circulation raises the blood pressure (2) that the normal lydney in ordinarily the source of a substance the action of which prevent hypertension and that it is the absence destruction or neutralization of thus substance which results in the eles ated blood pressure (Groll man) Niost of the evidence presented to date favors the former leit In the first place it was shown that interference with the blood supply to any other organ but the kidnes does not result in either temporary or permanent elevation of the blood pressure Constric tion of the celiac axis and superior mesenteric artery of the femoral and splenic arteries (Fig 11) and of the aorta below the origin of both main renal arteries (Fig 10) does not produce a rise of blood pressure in animals It has certainly been shown that azotemia alone 151)

·52
RLMAL ORIGIV OF HIPERILNSION
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Dog 2-95
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RLVC
BIK
1401
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60
40
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2 days
OL
FIE 5 The effect of occlusion of the nun renal seins on the devel pment of hyper
tension due to moderate constriction of both man renal arteries Dok 95 female
154 kg =mean blood pressure mim Ilg Oblood urca nitrogen nig per
100 cc RI 16 = both main renal eras occluded RL = both 1722297 renal arteries
greatly constricted The animal died in uremua but the blo d pre ure did not be
come significantly eles ated The failure of the I lood pressure to rise was interpreted
a due ir nerference with the entrance of a pressor producing sulostance from the
Lidney into the si ternic blood (After Goldbatt Ann Int led 11 69 101 1937)

·FIUMORAL MECHA VISV
5.
is not a sufficient condition for the elevation of blood pressure be
cause renoval of both kidneys although profound 170tem ?
consequence is not follou ed by the des elopment of hy pertension
(Fig 26) Anastomosis ben een renal artery and renal vein although
azotenuia de elops also does not result in hypertension. It is well
I nown also that acute nephrosis with uremis produced in mals
240
Dog Y3-28
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BNI
1201
100!
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0
Fig 6 The effect of bilateral nephrectoms on the blood pres ure Dag 3 '8 male
166 kg = Mean blood pressure mm Hg = Binod urea n trogen mg per
100 cc plasma BV=bilateral nephrectom The blood pressure did not become
clevated D= died The blood pressure did not become elevated despite the great
azoremja shich develnpeł (After Goldblatt Ann Ini led 11 69 103 1997)

·54 RENAT ORICIN OIII PrKTENSION los ihrious metallic poisons rarels results in ins clevation of blood pressure Also the shunting of the enous blood of 1 dog from the only hidney with renal artery constricted through the lner by means of 1 reversed I ch fistuli neither presents the development of hyper tension after constriction of the in un renui irtorics nor low ers the blood pressure in hypertensive inimals. This excludes any important cffect of the Iner on the pressor suntince of renal origin I'he possible humoral mechanism of experimental renal hyperten son uns denonstrated more directly by the trinsplantition of a kid ncy to the noch or groin of 1 biliterally nephrectomized dog or rabbit Ilhen the renul urters of the crisplanted hidnet with no nervous connection with the rest of the body 14 constricted i pressor effect resulted after the usual interul The trinsplantation of i partny or completels ischemic lydney from one dog to the 210 19 170 -156 130 -22 200 FIL 17 Pressor action from the graft of an ischemic hidney Bked pressure of tuo chloralosed recently nephrectomized dogs in which an i chenuc hidney from a hypertensive dog was grafted A) At I the kidney froni a hypertensic Ing was krafted ar' craft removed and anastomosed in dig B at graft re antst m sed B) A1 the kidnes huch had functioned in dog was grafted at Timc in minutes Blood pressure in mm Hg (After HYSSN ind I ascolo !! Soc argent de brol 13 18+ 1937 ) It was remo1c1 nech of a bilateralli nephrectoned dog resulted in in imuncdrate temporary elevation of the blood pressure when the circulition to the ischemic hodnei uns restored (Fig 27) This certainly indicated that some chemical substance from the ischemic hidncy capible of bringing about peripheral vasoconstriction had been wyshed into the circulation Il hether or not this substance in the Sidney is by itself ·HUMORAI VIECHANISM 55 vasoconstrictor or whether it becomes vasoconstrictor after entering the blood stream is not elucidated by this experiment Another indi cation of the existence of a humoral mechanism was the demonstra tion that if the entire renal pedicle was clamped so as to occlude artery sein und ureter for from five to sei en hours the sudden re moval of the clamp was followed by 1 prompt elevation of the blood pressure 11 hen such a completely schemc kidney was removed from the body without release of the clamp on the pedicle and it was then perfused with normal salıne a powerful pressor substance Nuas identified in the perfusate by the injection of the latter into the same or into another animal (Prinzmetal Lewis and Leo) It is now generally recognized that the chemical substances involved in all of the above experiments are probably identical Certainly the dem onstration of a vasoconstrictor substance in the venous blood from an ischenuc kidney (Figs 28 29) and of a vasopressor substance in the venous blood of an acutely ischemic hidney (Fig 30) and in the saline perfusate of a kidney of which the cntire pedicle had been 80 70 60 50 TTTT DROPS PER MINUTE B RINGER S 60 40 20 foon דווייןיי Fig 8 12 18 24 6 12 18 MINUTES asoconstrictor action of renal venous blood on the vascular system of the toad Bufo Arenaria hensel according to the Law en Trendelenburg method (A) enous blood plasma from normal hidneys (B) Plasma from venous blood of ischemic kidneys of hypertensie dogs The fine lines represent the greatest and leac vasoconstriction observed with each type of plasma The heavy lines represent the average action of the plasma from 15 dngs tested on 20 toads Vote the constructor action of the renal venous blood of hypertensie dogs (After Houssay and Taquini Re Soc argent de biol 145 1938 ) ·56 RIVIL ORIGIVOI HYPERTE\SION 15 с B с B 10 20 40 60 80 100 Blu Tu 19 asoconstrictor action of venous blood from an ischemuc hodney Per fusion of the denerated leg of a dog with defibrinated blood (A) Blood from the heart lung circuit after functioning one hour (B) enous blood from ischemic hidnes (C) venous blood from hidnes with normal flo Mote the marked vasoconstrictor action of the blood from the ischemic kidney (After Braun Wencoder Fascrol Leloir and Alunoz / P/ V5101 98 83 1940 ) clamped for several hours is positive evidence in favor of the bu moral mechanism These in estigations climinated the probabilie that a nerı ous reflex from the kidney affecting the 1 isomotor ippiritus plays 1 part in the origin of this type of hipertension ind helped to climinate the probability that the simpathetic nervous system plus a primary part in the origin of this type of hypertension The presence of 1 i asoconstrictor substance in the blood prisma from the renal vein of a dog with esperimental renul hipertension due to complete constriction of the main renal arteri uis demon strated by some (Figs 28 29) by the Lauen Trendelenburg rech nique in the South American toid but not bi others using other methods Some ini estigators failed to demonstrate pressor substances in the sistemic blood of hypertensie dogs or of human beings and there was also no effect of blood from hypertensie dogs on thx conus of suruni ing arterial rings But Solandt and collaborators du obsen e 1 definite rise in the blood pressure of a bilateralls nephrec tonuized dog to which was gn en a direct tranfusion from a hyperten ·HUMORAL MECHANISM 57 se dog ind Braun Menendez and Fasciolo obtained 1 pressor effect in 1 normal dog 15 7 result of the intravenous injection of 100 cc of renal venous blood from thc trinsplanted renal ischemic hidnes of another dog (Fig 30) LLL it! 116 146 020 re Fig 30 Pressor action of enous blood from an acutels ischemic kidney In vection of venous blood coming from a hidney incompletely schemic for one hour Dog of 17 lgm chloralosed and nephrectomized Femoral blood pressure in mm Hg At (1) injection of 100 cc of normal salıne into the jugular sein at (?) begin ning and end of injection of 100 cc of jugular blood at (3) beginning and end of injection of 100 cc of renal ven us blood Time in minutes Vote the pressor action of the venous blood from the scheric kidney (After Braun Wenendez and Fasciolo Re Sac argent de bic! 15 161 1939) It was soon show n that piperidomethyl benzodioxane (933F) did not have any greater effect on the blood pressure of a hypertensive animal than on thar of a normal one whereas in both the effect of epinephrine was completels rei ersed by an injection of this sub srance (Fig 31) Tlus indiciced that the effective vasoconstrictor sub stance from the hidney was not sympathicomimetic All of these in estigations pointed to a chemical agent of renal origin as the probable cause of the ele: ited blood pressure The search for this hypothetical agent began with the repetition of some old observations made by Tigerstedt and Bergman which had been con firmed by some and denied by others and consisted of the demonstra tion of a substance in the crude sılınc extract of a normal rabbit kidner which was capable of inducing a pressor effect when it was injected intravenously into a normal rabbit To this substance they gave the nanie Remn and the English word remn has now been accepted for the basic principle of the humoral mechanism of elperimental renal hypertension Prinzmetal and others found that there was a greater imount of this substance in the kidneys of dogs with experimental ·58 RLIL ORIGI\ OF HIPERTE SIO 200 El 2 Fig 11 Action of Fourneau 933 on the pressor action of venous blood from an ncurcly ischemuc hidney Tuele hgm dog anesthetized with chloralose Femoral blood pressure in mm Hg Time in minutes (1) Injection of 15 ct of control Verum into the jugular vein () fifteen cc of serum from the renal vein of an ischenuc hidnes (3) he gamma of adrenalin At the break in the curics 001 gm of Fourncau 933 per hgm of body weight was tnjected Tote that tourneau 93: docs not alter the pressor actun fenaushkund from the ischemic hidnet (After Braun Venendez and Fasc10lo Re Soc urgent de biol 15 #01 1939 ) renul hypertension and of hypertensic humın beings but not in ral» bits The stumbling block in the earlı cıperiments was the finding that this substance which scemed to possess at least some of the basic requirements for the hypotheticil pressor substince of experimental renal hypertension still licked in direct vasoconstrictor property for it hnd no effect on the visculir system when it was dissolucd in salınc and perfused through 1 part (low er portion of 1 told leg or tail of a dog) from which the blood had been washed out Two independent groups of ins estsgatars (Brtun llenender and collabo rators Page and collaborators) discovered that renin is not directls pressor and that although it is the kes substance of the humoral inechanism its effect is due to the reaction with a substrate in the blood ind resultant formation of an entirel neu substance uhucli has vasoconstrictor and therefore pressor properties To this sub) stance the South American ini estigators gic the nume Hy pertensin ·HUMOR AL ECH A VISI 50 The ci while Page and collaborators named it Angiotonın It us these earlier observations which led Landis in 1910 to write dence that renal ischema raises the blood pressure by 1 humoril imechanism seems unissailable Yet even to this das sonic observers huic concluded that there is no peripheral vasoconstrictor substance in the blood of hypertensie inimals Because in i rabbit with blood pressure hept elcı ated by the constant infusion of remin the blood pressure did not fall as a result of pithing unless the infusion was stopped while it did fall when a hypertensive rabbit not recen ing renin was pithed Doch concluded that in the latter the normal asomotor mechanısın was called into play and that vasoconstriction is therefore abolished It is it least possible that the immedite effect of the pithing was temporarik at least to abolish the outpur of the primary constituent of the humoril mechanism This should be investigated Whether or not the normal hidneys play a pirt in the homeo Stitc regulation of normal blood pressure through the humoril mechanism of renal origin which begins with the entrance of renu into the renal venous blood is still not established although evidence is accumulating that it may play such 1 part It has been shown that in shock the secretion of renın is induced and it is thought that the low blood pressure which produces renal ischemi is the cause Although the existence of renin was discovered onls about four Vears after the discovery of drenalın by Olner and Schafer and although the possible relationship of this subst ince to raised arterial pressure was obirous to the original investigators er more than 40 years pissed by before the existence of this substance w is fully established One of the reasons for this was the failure of some in estigators to corroborite the original findings of Tigerstedt and Bergman Notible among these investigations are th of Bitty Shaw but because his results with extracts of hidneys and other organs were irregular and because he obtained pressor effects at one time ind depressor 1t inother he did nor continue his investi gations et he concluded that a toxic agent leads to the libcration of sufficient renal parenchi ma or if a sufficiently large district of renal tissue is cut off from the general circulation by obliterative uscular disease the cells in olved may weld a pressor substance to the system and cause a rise of blood pressure above normal lle Slould be gren more credit for his contribution than has been done ·60 REVAL ORIGIX OF HYPERTI VSIO in the past Other ini estigators who atrached this problem here really dealing with putrefactne pressor amines not with renin when che obtained pressor effects from the intru enous snjection of furos lized but not of fresh renal pressed juice The stimulus for the renewed interest in renin came from the discovery of the method of producing persistent hy pertension mi atumals by the constriction of the main renul artery In quick stre Cession various ini cstigacors confirmed the existence of 1 subst incu like that of Tigerstedt ind Bergman in crude and cien in more puri hed extricts of hidnes Tigerstedt and Bergman had shown hou to separate the depressor from the pressor substance usually found in these extracts This is also confirmed it was also shown that the physiological effects on the circulation which result from the intri i enous injection of renin are really not due to renin itselt which is not vasoconstrictor but are due to the presence of hypertensin which is formed by the interaction of renin and a substrate in the blood plasma Thc phi siological properties of renın are theretore tho e of the end product hypertensin or angiotonin as it has been nimed by Page and collaborators The tendency at the present time is to accept the terminology suggested by the South Americans for the constituents of the hu moral mechanism which is supposed to be as follows an enzyme from the kidney enters Renin the blood stream through the renal eins and acts upon a globulin in Hypertensinogen the blood plasm to form 1 pols peptide which is the Hipertensin actie asoconstrictor substance and which can be inaccuated by an enzinc 17 the blood and Hipertensin ise in estricts of sonic or ins Agreement upon this or in other single nomenclature would be highly desirable The one given above appears entirelt accept able The follou ing are brief summaries of the chemical and physit) logical properties of the substinccs si luch play 1 pirt in the humoral niechanism of renal hypertension ·but at RLNIN Chemical properties Although renin has not ver been isolated in pure form ver all of its properties indicate that it is a protein or protein like substance or that it contains protein as 1 contaminant It is present in the press juice or in various extracts of renal cortex (not medulla) and does not occur in similar extracts of other organs It is unusually stable in solution and its physiological properties are not affected by lophilization or freezing in solution in distilled water It deteriorates rapidly but if it is dissolved in 09% to 10% sodium chloride the stability of the protein is great In the liquid form heat ing to 5) C for 15 minutes does not destroy its activity 56 C and over it is rapidly destroyed It is resistant to the action of acid and is stable at pH as low as 37 and even lower but it pH 10 or over it is rapidly inactivated The addition of ammonium sulfate to a concentration of 14 to 26 molar precipitates renin from in aqueous solution at pH 6 It may also be precipitated with 0 38 to 041 saturated ammonium sulfate at pH 5 with saturated sodium chloride at pH ' to 3 and with 0 7 to 1 0 saturation with magnesium sulfate In dilute solutions it is not precipitated by acidification alone it any pH Renin may also be precipitated from aqueous solution by the addition of 2 to 3 volumes of alcohol or acetone The following reactions for renin hue been summarized by Dexter It gives a positive biuret (peptide linkage) Millon (ty ro sine phenols) Yinthoproteil (benzene ring) Hopkins Cole (crypto phane) Lhrlich diazo (histidine ry rosine) and Sakagucht (arginine) Negative reactions were obtained with Nlolsch (carbohydrate) Sullı van (cystine cysteine) benzidine (pentose) Reactions for sulfhy dryl groups were negative even after denaturation and treatment with cyanide By fusion with sodium hou ever the presence of sul phur could be detected in the preparation The renin purified by Plentl and Page u is shown to contain carbowy peptidases pepsinases trypsinases and mino peptidases Attempts at purification of renin by chromatographic adsorption by the use of a column of calcium carbonate and by adsorption on haolin have been made Although Collings reported that passage through a Seitz filter resulted in a total 1 611 ·RLNAL ORICIO HYPERIENSION loss of the action of renin icine been unable to confirm this and others have also succeeded in filtering remin through 2 Seitz filter without significant loss of actie) Jonnard and Thompson found that renin in a crude extract migrated toward the cathode between pH 3 and 6) uhile che depressor subscances imigrated toward the anode becucen pH s ind 7, In our oun experience renin in relatnch pure form migrares toward the anode at pll76 Details of the preparation of renin haye been gren i original papers and in the book by Braun lícnende, so the will not be gnen here The result of studies on the behavior of renin subjected to precipitation sich ammonium sulfate and dualists suggests that it is pscudoglobulin bur thus his nor been established Vost imi estigt tors regard it is a proteoli eic enume extractable by 1.2810us methods from all murali in hidners and from the lidncus of other wounals Il internity and collaboritors however have asserted thar renin 111 very pure form is free of ani cari matic actuat lost exericcs uur renn icta probably contun muture of en/mes and no spe cific single enzyme with all the characteristic propertjes of renın has been solated Plent and Page hue excluded the awon of annno peptidase ind curbuus pcpridase lirious methods for the extracoon and purification of renu hate been described the preparation and Isolation of renin bi evtriction is best crned out under acrobic con ditions because anaerobic conditions favor the formation of pure facone pressor annues tu ramune isoamı lamine and probabils ethu 710int In attempt to prepare it under sterile and as a robi com ditions has not been reported hidneys from soung ruts have been reported to contain more reain chan those from old rits but old rats are said to be more sensitie to parenterally adostered reain These studies should be repeared on rats and other animals by inc of more recentes de eloped methods for the extraction ind 29.11 1f SC753 Physiological properties Repin is effcctise only when it is in jected intravenousi It is not kasaconstrictor when perfused through circulatory systein trom u buch the blood has been uashed out Most of the plı siological properties including the pressur effect of senin are due indirecrly to hipersensin u tuch results from the inter action of rerun and luy pertensinogen a glolsulin in the blood plass and which is the effectii c iasoconstrictor and trut pressor substance The hemods 12mic state of an animal after the intravenous injection ·REN 63 of renın is almost identical with that of an animal with esperimental renal hypertension The site of action of renin itself is in the blood and not on the vasomotor endings of the peripheral arterioles or di rectly on the arteriolar muscle 75 was thought at first in the rabbit the pressor effect of renin is abolished or louered by ether anesthesia but this is not true of the dog An interesting phenomenon originally reported by Tigerstedt and Bergman and confirmed more recently by other investigators who used purer renın is tachyphylaxis This means a decrease of the response of an animal to repeated intravenous injections of the same amount of renin provided these injections are made onls a few min utes apart before complere recovery from each injection has oc curred (Fig 32) This effect is independent of anesthesia the type 15 MIN. 114. 12. 1. Wir han Fig 3 Tachyphylaxis to renio Effect of the ntras enous injection of one cc of a solution of renin (R) on the lood pressure fadig te the diminished pressor effect in the second and third injection Tim in minutes Blood pressure in tim Hg (After Braun Menendez F Fascı ulo JC Leloir LF llunoz J M and Taqum AC (Translated by Leslis Dexter) Renal Hypertension Charles C Thomas Publisher Springfield 1946 of anesthetic type or method of preparation of renin and occurs cien in bilaterally nephrectomed animals 1 his phenomenon is supposed to be due to a progressive decrease of the amount of hyper tensinogen (Fig 33) but this has not been definitely established Renin produces no direct effect on the isolated perfused heart The increased force of cardiac action which results from the intra venous injection of renin is directly attributable to the effect of hyper tensen The effect of renin is not the result of the stimulation of an endocrine organ because it produces its effect in the absence of both ·64 RENAL ORIGI. Or HYPERTE\SIO 150 100 Tig 33 Disappearance of hypertensinogen from plasma by the injection of renin Hypertensinogen in the blood of a ten hgm des before (first arrow) and after (second arrow ) injection of 05 cc of renin per kgm ten cc samples of seruni incu bated ten minutes with an ercess of renio Rise in blood pressure obseried by in jection of alcoholic extracts into a chloralosed dog Blood pressure in mm Hg (After Munoz Braun Vlenendez Fasciolo and Leloir Am] 11 Sc 200 608 1940 ) hypophysis and adrenals ind acts es en in an animal with spinal cord scctioned or destroy ed It has been reported that in the rat renin acts when it is injected intraperitoneally and that it is more effects in the bilaterally nephrectomized than in the normal rat This phe nomenon has not been reported for dogs or other animals Renm has a more prolonged vasopressor effect in bilaterally nephrectomized animals probably because of the increase of hypertensinogen in the blood of such animals The effect of renin in producing deuresis and increased excretion of sodium chloride is probably attributable to the hypertensin formed The intravenous injection of renin does not produce a reduction in peripheral blood flow or a fall in the tempert ture of the surface of the skin (Landis) Many of the studıcs which have been performed on the effect of various chemicals in inhibiting or enhancing the action of renin really deal with the effect of these drugs on the hipertensin which is formed 15 1 result of the action of renin on hypertensinogen in the blood ind pull be discussed under the headmg of hypertensin In some of the earlier studies it was asserted that cvracts of the hidness of animals with experimental renul hipertension and of briefly and completeli ischemic hidney contain more remin than the Citract of the normal opposite hidnes or of the normal dncis from other animals Landis hones er was unable to corrclate the renin content of the hidney and the physiologicıl state of the hidney Ihrs work deserves more attention than it has recen ed and should be ·CU OPEXITIDI RXA 121 31 M DIT 4 DED DOG 3 111 BLOOD 1133021 111 XX KC REVIT 10 11 REXTM 11 CAT UNITS/ 10 CC will 1 PLASNA NONPROTEIN NITROGEN 124 11 PROTEIKTAIL 17 0 Cig 112 CHfect of corstriction of reml arteris on the concentratın of senin in systemic i chous blood of a les 4 RRA the right renal artery was constricted at LR 4 the Icft at C4 the caj sulir arteries were lugared Note that if the blood pressure rises considerable amic unts of renin were found in the pla ma but that despite a persistence of the biz pertension renin was no longer recocrable lv le nethod employel títer Deuter L lloy nos and Brulees C Clin In estigution 24 62 1945 ) ·06 III (TICI 01 JPERTI SIOS parents with rcpeitcd now that the methods for cutriction und 18511 franc been perfected Renin itself his nei cr becn isolated from renal icnous or systemic blood of inuals with experimental renal hypertension Tlic presence of renın his luas been inferred from the presumible demonstration of hypertensin in the blood! In most of these studies lis pertensiogen 11 is added to the blood simples ind incubited with it to enhance the action of the small amount of renin present Bi this method De rer Haynes ind bridges demonstrated the presence of rein in the systemic i enous blood of dogs at least in the earh phisc of cyperimencal renal hipertension (See rig 332 ) Bi thus indirect method Deuter and I lines have lo misured the amount of rein in the se stemc blood of human lis percensi e patients Tlies detected renin only when the blood pressure u is rising abruptl (eclamps and glomerulonephritis) and found none in the blood of benign esscntal hypertension for this reason the suggested that renin mai be ini olied out in the beginning during the dei clopment of the hypertension The presence of renn in derectiblc amounts in the renal crous blood from i hunian I dnes of which the main vern hd been occluded for 12 minures Iris bicen reported bBester and Haynes Most of the negative results that have been obtained hue probably been due to the small quantity of blood rested By the incubition of large quantities of blood suith proper precrutions to prevent the coincident action of hypertensınase "chrieben ible to demonstrate the formation of hipertensin is a result of the inter alium of the renin and hypertensinogen present in the blood of dogs with experimental rent is pertension both benign and malignans in the malignant phase in anumils there is much more hypertensin in the final product ind therefore presumably more renin in the blood (Gollan Richardson ind Goldblatt) The action of renm is not affected by hypophiscctors throu ecromy planchnicectomi gondectom splenectom piscrettet com abdominil cuisccrition or destruction of rlic spin il cord ! though bilarer al drenalcctom has no immedite effect ict it is fol Joued by i progressive decre ist in the response to the intrichou Injection of renin It his been possible bs slow intrn crous distration of ! small amount of renın to keep the blood pressure clench x lesse 30 mm abos e normal for four hours (Ilili und Pici crid) { giler ·REN 67 quantities produced untou ard circulatory disturbance Hessels as sertion that repeated injections of renin lead to pertinent hyperten sion has not been confinned and Taggart and Drun failed to produce prolonged hypertension with the continuous injection of renin The explanation for these differences is not clear but the subject is of sufficient importance to warrant more ini estigition The pressor response to an intrat enous injec son of renin is more delaved than the response to hs pertensın because the beginning of the forniation of the true i zsoconstrictor substance hypertensin has to occur during this inter al It takes about 20 seconds after the injection is completed before a rise of blood pressure begins and the risc is not steep for it tal es about two minutes for 1 unit of renin to produce its maximum rise of 30 mm Hg direct mean pressure The return to normal is gradul ind mai tahe is long as 30 minutes (lig 34) It has been shown that the action of the purest renin so far pro duced is no different from that of crude renal extract provided it does not also contain a depressor substance According to Grollman and collaborators the amount of renin in a kidney extract or its apparent concentration depends upon the core of the tissue prior to its prepa rition the method of preparation and the dur ition of time between the prepiration of the extract and its assay on a test animal The last Suitement must apply only to vers crude and probabli contaminated extract because a sample of our moderately purified sterile renin in solution in 09 saline hept at + C shou ed no significant deteriora tion during a period of 3 years Renın is not species specific for animals All mammalian renin including human when injected intrni enousls produces a pressor effect in all animals but no renin except primate renin produces ? pressor effect in man summarı of the pharmocologic and her dynamic effects of renın is given in Table 1 Fate of renin in the body The original idea of Tigerstedt and Bergman that the hidner eliminates renin has not been confirmed It has been found that only when large quantities of renin are suddenly injected intra enously does it appear in small quantity in the urine Under these conditions the maximum excretion occurs in about one hour after the injection The absence of the Inter and I idneis delays the rate of disappearance of renin injected intrat enousls Because of this Leloir and his collaborators concluded that both organs play an ·68 RENAL ORIGIN or HIPERTENSION A summary of the pharmacologic effects of senin and the arculatory dynamics in hypertensive animals as published by Dexter in the book by Braun Menendez and collaborators (4) which is a modification of the sum mary published by Lewis and Goldblact (1942) TABLET Aspect Considered Iffect of Intravenous Injection of Renin Into Nort2 Anitals I xperimenrad Renal Hypertenvoi Heart rate To change Moctanec Cardiac output To change No change Toral sympathectoms Pressor action not reduced Blood pressure not reduced Destruction of cord Pressor action not reduced Hypertension nut abolished Hypophy sectomy Pressor action not reduced Dampened but not complereh prevented or cured Thyroideccony Pressor action nor reduced Neither prevenred nor cured Conadectomy, Pressor action not reduced either presented nor cured Acute adrenalectory Pressor action nor reduced Rise of blood pressure pro duced by ischemic hidney grafts not prevented Chronic I ressor action reduced or Hypertension presented or adren iletromy abolished abolished Pressor action restored by Hypertension partially restore! desory corticosteron by desory corticosterone Bilateral nephrectomy Greater pressor effect Greater rise of blood y ressure producd by ischemic kidney grafts Peripheral blood flow Vor reduced durit rise of Not reduced hypertensie pressure rabbits Renal circulacion Cerent glomerular artersol i fferent hlonierular arteriole constricted constricted Blood pressure J Fourneau 983 Pressor effect not inserted IF 933 produces same fall of by Fourneau 933 blood pressure in normal and hypertensies 1) Cocarnc I re sor effect not mo lined (caine produces a rallor by cocaine blood pressure in dogs with hypertension from ligation of renal arteries c Pulmonary artery No rise of pressure in pul Pulnionary artery pres urL DU pressure monary artery dial d Duration of pres I crsistence of pressor action Persistence of hypertensions sor action after a single injection no after renoi asete greater than 2 hours hrines usually greater than 6 heurs e Tachyphylaxis Repeated injections produce Persistent hypertensson cachyphy laris nial or increa ed acusarts to f Permanent Permanent hypertension has Pennanent hipertent! h hypertension nec been obtained by con tinuous injcctions of rerin On the basis of differences observed bethecit the effect of refun and after tensia on the blood 1 essels of the rabbits ear (See page 79) Wylon and collax ratus hare concluded that the in to a renin effect is not adequatels explained by hyper teran fomation This subject should be pursued מגמI fe ·SINGH MEDICAL CU REVIN 69 important part in the elimination of renin from the bod: It is now considered that the main mechanism of elimination of renin from the circulation is destruction by the tissues of the body including the hidney and Iner In order that the results of all ini estigators might be directly comparable it would be well as soon as possible to de cide upon standard uruts for the various constituents of the humoril mechanism and to establish standard methods of assay Methods for the assay of renin The unit of renin In our work we have used direct intravenous injection of the test solution for the assay of renin and have defined the dog unit of renin as the quantity which when injected intrat enously into a normal un anesthetized dog will cause a rise of direct mean pressure of 30 mm Hg in at least three animals This has proved a very useful rapid method for use in purification studies Leloir ind collaborators on the contrary have defined a unit of renin as the quantity wh when incubated with hypertensinogen in excess at 37 C and pH 75 produces 0 5 unit of hypertensin in 2 hours This is an indirect and slouer method but is also satisfactory The advantage of the method is that minute amounts of renin can be detected in this was A com parison of the two methods has not yet been made A third procedure also suggested by Leloir and collaborators measures renın indirectly by the determination of the quantity of hypertensinogen which dis appears from a solution containing a hnoun amount This method has special use in the assay of human renin Full details are given in the book by Braun Venendez and collaborators (4) A method for the study of the reaction kinetics of renin has been described by Plentl and Page This also involves the determination of the amount of hypertensin formed and is also not a direct assas of the activity of renin / ARY.

·HYPI RTL SINOGEN I Typertensinogen is the substance with winch renin retets to produce the vasoconstriccar and therefore the true pressor subscance hypertensin This constituent of the humoril mechanism has been demonstrared only in the blood plasma serum and lymph Afrer the renewed interest in renin had occurred it was soll thought for 1 while that renin nas bi itself direct 1 asoconstrictor substance Although hohlstedt Helmer ind Page did find that impure ronin possessed z moderate asoconstrictor action on the isolated dog sturt ver they also showed that this action disappeared u hen the renin u as purified by diilisis They also found that it the purified renin was med with plasmız or hepırınıcd blood the tasoconstrictor action resppeared Bt the method of ultrahirrnion of the pira thes showed that the production of the i asoconstrictor action was a prop crt of the colloid part of the plasma and not of the ultruitric Ar first these authors considered that the insoconstrictor action of renn 11 is the result of its activation by a hypothetical enzyme (1 hinuse) contained in the plasma or whole blood and gave to this the 10 reinn acti ator Braun Venendez and collaborators hou cicr in 1939 concluded that a new substance which they called hypertensin and which was vasoconstrictor resulted from the incubition of a nature of renın with serum or plasti? To the hypothetical substance in the scrum with which the renin seacts they giac the name hypertcuisinio ger and the vasoconstrictor substance thes called hypertensi At abour the same time Page and Helmer discovered the sime sulyst inte to u luch they gave the name an soton. It is nou cudent from all the work that 117s been done that it is the renin si huch icts upon the hypertensinogen to produce the hipertensin Page and collaboritors huc demonstrated that the substrate is present in the .? globulin friction of the seruni Bel luse it is the substrate of renin ind bccius chus enzimatic reaction results in the formation of hipertensin the nume hypertensinogen scenis the most appropriuc for it Nature and properties li has now been slun n tut the hyperten sinogen is a prorem of the plasma therinolabile ? pseudoglobulin and ? globuhn fraction not altrafiltrable mu not (0) a constituent of the a ·NIYYRITING! dials sable Ilemoglot;ın serum zbunun isser spleen thymus testis lung heyrt skeletal muscle or vegetable proteins do not act as senin substrate Unul nos liy pertensinogen has been found only in plasm serum and lı mph It has not yet been isolated in the pure form It is precipitated from the blood seruuu bs ammonium sulpharc berwoen 0 30 and 041 stumfios pl} 68 and does not precipitate after dulu ses agunst distilled water Ileting at 60 C for 15 minutes in actRates it but it remains unchanged if lept at 10 C for 1 hour It is inacthared a pH 39 for 30 minutes 3t 37 C but not at 25 C annage is taken of this to obtun hypertensinogen free of hyper tensenase which is inactu ated at pH 39 and at 25 C for 30 minutes Hypertenssnogen from iny mamil cin serre is substrate for remin citracted from the ladness of miungis und resulrs in the for mion of hypertensin "The only onception is man Iluman renin hou eier is active on the liy pertensinogen of anı manm including man Avan hs pertensinogen does not act as a substrate for mam makan renin but forms hypertensin uuth diran renin In proportion to the amount of substrate in the blood the amount of renn required for the reaction is very small and the amount of hypertensın formed s proportion il to the amount of hypertesiumogen The roroon is hastened by incubation at 37 C but it goes on to completion at much lower temperatures mwen en at OC Other esses such as pancreatin papun and pepsin or extraces of in er and plcen do not have the sanse effect us renm on his pertensinonen Unit of hypertensinogen The assist is best defined as the amount of substrue 1 huch nith an eicess of senin ind us the absence of hypertensin 150 suzll produce one umt of hupcrionsin I he ammunt of hypertensinogen is considered propercumxl to the mount of hyper teosin formed in this rolution the presence of hipertenynasc ma result in fules determin sttons The forest rechnutie suggested in Braun Venendez ) al of scrum plasthi or globulin solution 100 unty of rehin at pl} >> {1x and lethcen » und +1) for abour 10 minutes To 230xd the concident aciun of huperiensinise the best procedure is to list uut the rectum 20 tor. hours (Spur Stein) The questits cof hyperten 118 en is out the ame in the blood of formal dogs costs and pics while the firsclun miller mint (Lcloir und collabes stars) The trut centained in Ice of plant 1 approvmituks 0 74 in huil in (* sinit rit ind u 35 ut ·72 REWAL ORIGIN OF HYPERTENSION in dog plasma It has also been shou a thac lymph contuns as much hypertensibogen as plasma In experimental renal ky pertension and in benign human hypertension no increase of hypertensinogen in the blood has been demonstrated in some cases of hunn and experi mental renal malignant hy pertension with renal insufficiency in in crease has been noted in the blood of bilaterally neplicectomized anı mals the amount of hypertensinogen is increased Hypophy sectomy does not affect the hypertensinogen content of the blood It is greatly decreased in the blood of bilaterally adrenaleccomized animals and in dogs with hemorrhagic shoch If adequate substitution therapy is gaien to adrenalectomized animals the amount of hypertensinogen in the blood returns to the normal level Adrenalectomized animals have also been found to be less sensitic to an intravenous injection of renin In human hepatic insufficiency a decrease of hypertensinogen has been reported but no change was found in one case of Addison disease (Dexter and Haynes) Repeated injections of renun reduce the hypertensinogen and in the tachy phylactic stare the blood is sard to be depleted of hypertensinogen (Fig 32) It is highlı probable chat hypertensinogen is formed in the Inver for it has been shown that the destruction of the hus er by chloroform poisoning and also hepatectomy cause the hypertensinogen to de crease in amount and even to disappear from the blood It has been demonstrated that it is significantlı decrcased in human hepatic in sufficiency but in a bilaterally nephrectomized and hepatectomized animal there is no diminution of hypertensinogen in the blood be cause no rcoin is being liberated to use up the substrate The same applies to shoch in bilateralls nephrectomized animals Preparation It has been found (Schales) thar most of the hyper censinogen can be precipitated betu cen 0 30 and 0 41 saturation with ammonium sulphate at pH 68 Saturated sodium chloride 30 plis and 2111 potassium phosphate have been used (Page) and Croxatro has advocared the addition of 311 potassium phosphate at pH 63 This precipitites both the ks porcensinogen and the hypertensinase Fur ther precipitation usith 211 phosphate then precipitates the liy perten sinogen ind ler os the hypertensinase in the filtrate in this was relatnch pure hypertensinogen is produced Full details irc gn en m the book bs Brun Menendez and collaborators (4) ·HYPERTENSIN The action of renin on hypertensinogen results in the formation of a new substance which is i asoconstrictor This is the substancc which causes the increased tonus of the smooth muscle of the arterioles and is therefore the substance which produces the pressor effect when renin is injected intravenousl or presumably enters the blood stream from the hidness of a hypertensive animal To this substance Page and Helmer gave the name anviotonin and although they described some crystalline dernatives in the form of picrites and oxalates which they considered pure vet as has been stated by Bruun Vienen dez (4) until the inelting point elemental composition relation be tu cen weight of the substance and pressor activity are determined the isolation of this substance in pure form cannot be accepted If hypertensin is finally isolated from the blood of hypertensitc animals or man the probability will become great that this is the sub) stance that causes the persistently elevated blood pressure and then hypertensin will be the more appropriate term It has been shown that when hypertensinogen is added to the plasma or serum of the blood of a totally ischemic human hidney and the two are incubated under conditions that prevent the destruction of hypertensin a sub stance results which has all the properties of hypertensin Despite some reports to the contrary evidence is accumulating that renin and hypertensin are present in the systemic blood of hypertensive animals and man This is one of the most important of the problems that still temam to be settled Chemical properties As in the case of the other constituents of the humoral mechanism the identification of hypertensin depends upon biologic methods because no specific chemical reaction for this substance has been demonstrated Some f the chemical properties of this substance are now noun It is soluble in water 96 / ethanol 75 'acetone liquid phenol glacial acetic acid and methylene glycol but it is insoluble in ethyl ether chloroform and amyl alcohol It is dialy zable and thermostable (resistant even to boiling temperature) alhalı labile (destroyed completely bı boiling for one hour ar pH 10) ind relatively acid stable because it does not become inactivated by [73] ·74 RINAL ORIGI\ OI HYPLRTE SIO boiling for tuo hours in IN HCI Its purification has proved diffi cult it can be precipitated with phosphotungstic acid is destroy cd by oudition und noctition with I ctene but is not affected by rc ducing agents. It is fluorescent and it goes the color reaction for urginine but it is not destroyed by the action of orginase Its only reiction for protein is a posici e Sal iguchi It contams tyrosine and fastidine but no custeine try prophine or prolme By the method of clectrophoresis it has been shown that hypertensin bclties 75 imphoteric electrolyte of neutral character It differs from pitressin in being more resistant to boiling with acid produces a more ripril und shorter risc of blood pressure ind docs not induce echiphylnes It differs from adrenalin in that its iction is not imierted by 9131 or by ergotamine ind it differs from ti rimine in that cucune des text pprecublilter its effect ind also because hipertensia produces 1 isoconstriction in the told while tryne docs not Iss iction in potentiated by seritol tyrimune and ephetonine That the reaction beru ecn renin and hypertensinogen i desinti brine is indicated by the fact that popsin il noun proccoli tic en /mc may replacc renin in this reaction but onls it ai cru lou ring of pH But pepsin is incare in the oprimum ringe of pl} for rlie Cours of renin ind does not produce i pressor cffect when injected inerii enousls into an rumal Thut the reaction between renin zod luu pertensinogen is enn mitic is not generally accepted the perionun is destroyed slowl bi hidrolysis and in the action of processes and peptidases It is nou generally considered that hipertensin us a pols peptide of low molecular scighe cien though Pige and liner found that it gnc ingin e buret It is destros cubi popsi fru fisiti papaine and curricrs of some organs is us ell as by fresli normal blood plasma serum ind Inhed blood corpuscles all of which contunin enzyme, hipertensin ise wuch a capable of inacın iting in peritis? The vasoconstrictor effect of hypertensin is inacta ied by 1111100 ouduse from loer of Sepia officinalis and is turoninase from Partheit? campestris (Crovatto) Cruz Coke lists number of clicmic its which parallı or complerchi inacti ite hipersensin the most imporr mi of them being 1odine It is thought that the clicct of the same is due to the transformation of the ti rosinc in hipertensin II his also drawn attention to the accelerated destruction of his pertensin !» lny pertensinise ulen oud/ed us toclirome Cindded to imture of lis pertensinogen ind renul cyrict containing hs pertensi750 ·HYPERTENSIV 75 Preparation and purification The optimum pH for the reaction between renin and its substrate is between 7 and 8 and the optimum temperature betu een 37 and 40 C The proteins are then precipitated by hert or by the addition of alcohol or acetone and the filtrate is con centrated by boiling or evaporation under reduced pressure Another method which has been described is the incubation of dulu zed renin and hypertensinogen recovery of the ultrafiltrate and concentration Sapirstein and collaborators have suggested incubation of renin and hipertensinogen at 0 C which practically eliminates the coincident action of an hypertensin ise thit may be present Up to the present time all ini estigators who have tried to purifs by pertensin hire reported lurge loss of potency during the various steps During the process for unl noun raisons it is often com pletely destroved The purification of hypertensin has been accomplished by Cruz Colc by means of anionic resin so that one unit had only 0 08 mg Cationic resin idsorbed the hypertensin but it was not possible to elute it The melting point of this substance in pure form has not yet been reported Plent ind Page studied the effect of proteolytic en 7y me on partiallı purified angiotonin but the concluded that such 1 study cannot be taken as offering proof of the structure of this substance The most important recent contribution to the study of the purification of hypertensin is by Edman whose method consists of chromatography precipitation uith nitrınılıc icid and electrodialists In this was he obtuned 2 600 700 fold purification of the actre prin ciple but the veld was only 3 This great loss he attributed to the lability of the structure of hypertensin His highly purified hypertensın is almost forts tinies more effective in ruising blood pressure than 1 comparable amount of ty ramine phosphate As little 15 05 gamma elicited an appreciable effect on the blood pressure of a cat He regarded his product as essentially pure judging by its behavior in partition chromatography on filter paper By means of electrophoresis he determined the isoelectric point to be pH 68 From the diffusion constant of this hypertensin in pure v iter he calculated the molecular y cight to be 2700 Bi means of paper chromatography and some preliminar quintitutn e determinations he found in his hypertensin the imino acids lu sine histidine glycine alanıne serine proline alıne tyrosine leucine (or isoleucine) as ·76 RLNAL ORIGIN OF HYPERTENSION pirtic acid and glurimic acid Full deruls about methods of prepira tion and purification of remin are geen in the appendn of the bool Bruun Menendez (4) WM 2 . 2 1 1 WxTts NO A FIS 34 Dragrammatic represenration and compari on of the effect of the intrasenous intection of a unit of hypertensin and a unit of renin on the direct nican fon oral blood pressure of an unanesthetized trained dog Physiological properties The characteristic pressor ctfect pro duced by an intravenous injection of hypertensia is an almost im mediare and steep rise lie that of adrenalin (Fig 34) The minimum rise from a unit of hypertensin occurs usually in one minute or less and the return to normal in three minutes or less As in the case of renın the hypertensive effect of hypertensın is not accompanied by a change in bland fou through the skin is measured by the temperature of the skin or by direct observation of the blood vessels growing in a wound of the sl in of 1 rabbits er The splecn und led ney shou a decrease in volume and there is a decrease in coronarı blood flos increase of senous pressure and decrease of renal blood flow during the period of elevated blood pressure Except for 3 forceful heart beat hy pertensin produces no significant simptoms when it is injected intru cnously into man If the sagi are cut the dog s heart rate shows no modification is a result of the injection of pertensin The continuous intra cnous injection of hypertensin produces an increase in blood pressure which is maintained during the entire period of injection (Fig 35) Hypertensin has a stimularıng effect on practically all wooch muscle and this effect on intestinal strips has been used as 1 method for its identification and even its 158 ·HYPERTE SI 77 101 ننننن 11" 11% 35 Continuous intravenous injection of hypertensin Dag 6 hem chloralsed Double vagoromy Aruficul respiration Femoral blood pressure in mm Hg Time in manures (1) intravenous injection of hypertensin is started at a rate of one unit/ min, (2) end of injection (After Braun llenundez Casciolo Telour and Aluno | Physiol 98 83 1940 ) In its pharmacological effects liv pertensın is not specific It has shown its characteristic pressor effect in dogs chickens roads and snahes Toads and snahes but no ocher animals are rapidly rendered tachyphy factic by repeated injections of hypertensin Although Page and Helmer hare reported tachypluylaxis to repeated injections of angiotonin by the method of perfusion of the rabbits ear vet it is questionable that this method can be accepted for this demonstra tion The existence of an angiotunin acinator also postulated by Page has not been confirmed The pressor effect of hypertensin is unaffected by intrat enous injections of cocaine atropine ergotamine 933F or stilbesterol It is therefore not a sympathicomimetic sub stance An intravenous injection of hypertensin into a bilateralls nephrectomized animal gues an increased rise The intru enous in jection of hypertensin produces a pronounced but transient rise in the potassium of the blood and a greater and more prolonged rise of sugar in the blood of dogs that are under the influence of chloralose No special significance has been attached to these observations and they have not been confirmed is has been said before the string and significant difference beru cen the pharmacological properties of remin and hypertensin 15 that hypertensin produces vasoconstriction when it is dissolved in Ringer s solution and perfused through an isolated organ from which the blood has been washed out while renin in Ringer s solution does not have this effect The direct effect of typertensin and the indirect effect of renin are exerted on the musculature of the peripheral blood sessels A large dose of ·78 RI\4 ORICI OF HIPERTENSIO hy perrensin injected intrii enously into norm) il persons causes a de crease in blood volume and cardiac output as measured by the ballisto cardiograph The effect of hypertensin injected intră enousi is not altered by vagotomy excision of the carorid bodies splanchnic nerves pituitarı pancreas luer adrenals destruction of the adrenal medullı rapid elimination of the central nervous system or euiscera cion in cats and dogs Page and collaborators concluded that there is in the peripheral systemic blood of hipertensive animals and man i soconstrictor angiotonin lihe substance not present in the blood of animals or min with normal blood pressure but thus finding luas not yet been con firmed There is also no proof that this hypotliccical substance is identical with renin or hypertensin Because these studies were cuir ried out by the method of perfusion of the rabbits ear the result will require confirmation by some other method before it can be ncccpred The same statement holds true for tlic demonstration of i pressor substance in blood thu had been perfused through an ISO Tired hidner wuth renal arters constricted which was demonstrated by the same method Recently Gregors and collaborators failed to demonstrate an in crease of vasoconstrictor substance in the ultrahltrate of blood plastur of human beings with essential hipertension of long duration Thiet used the method of perfusion of the lower half of the frog for the demonstration of the vasoconstrictor substance The method used as of questionable quantitate value There is some doubt therefore that the results can be accepted unequis ucalls as proof that essencial hypertension is not caused by an increased production of hy pertensin or some other soconstrictor substance Deiter and Haynes failed to demonstrate hypertensin when thes added hypercensinogen and incubated it with the sistemic blood of patients with essential hiper is a result of our own studies (Gollan Richardson anul Goldblact — unpublished) the impression has been gained that the mount of blood tested hitherto has alu 11s been too small Larger amounts of blood should be investigated the fullure of Grollmus and Rule to demonstrate a pressor effect in the normal rat of pari biotic tuins of wluch one was hypertensiuc on a renzi basis does not disprove the evstence of a humoril mechanism in this type of hypertension and does not prove the contention that the normal hidner elaborates 1 substance the absence of which results in hiper tension ·UTIRTINSI 79 tension The explanation of their results may be simply the slow pass age of the hypertensin from one animal to the other and the rapid destruction of the portion which does pass across Unit of Hypertensin le have defined this as the quantity of hypertensin which when injected intr n cnousht into thc unanes thetized trained dog will give i risc of 30 mm Ilg direct mean femoral blood pressure in te least 3 dogs (Tis 34) Braun Menendez and collaboritors have published a curse of the pressor effects of Various quantities of hypertensin from which the number of units 15 estimated by interpolation (Fig 36) It would be highly desirable to agree upon a single method ind i standard unit 60 40 X 20 yo 1 1 1 1 10 11 14 2 4 6 8 12 16 112 36 Incrcas s in bl < 1 pressure pr fuccel lyd fferent amounts of hypertensin Abscts is Units of by rtensin Ordinacs Ris of blood pressure in mm Hg (After Lraun Venendez Tasci Tel i and \lunuz | Ubysiol 98 82 1940 ) Recently Alylon and collaborators found that hypertensin is vasoconstrictor for the rabbits ear but that renin is This is contrary to the results obtuned by others asing the Lawen Trendelenburg technique in the giant toad They also found that hypertensin which is not viso constrictive when perfused through the rabbits ear becomes strongly vasoconstrictive it supplemented sith traces of epinephrine or if fresh plant is added Of 10 muno acids tested for a similar property to that of hypertensin ons tyrosine had it The introduction of iodine into the tyrosine molecule entirch abolished the vasoconstrictor action The concluded that constration of the blood vessel of the rabbits ear depends to a large degree upon traces of epinephrine and tu rosine containing compounds of spacenil configuration This subject deseries more investigation ·HIPERTENSINASI The observation by Page ind Helmer that when renın is incubared 11th plasma or with serum angiotonin (hypertensin) is formed but that continued incubation results in the destruction of the angiotonin led them to believe that the continued action of the rerın was re sponsible for the destruction of the angiotonin Alunöz and collabo rators hou eier, showed that this inactis ating effect of the renin could be eliminated while the capacity of the renın to produce the pressor substance remained unaffected This led them to postulate the existence of another enzy me associated with impure renin to which they gave the name hypertensinase Page and collaborators later conceded the existence of such in enzy zme and to correspond with their nomenclature coined the name angiotonase for this enzi me Nacure and properties Hypertensinase is a hydrolyzing enzyme or group of enzymes with the ability to destroy hypertensin 112 mitro present in blood plasma and serum in laked red blood corpuscles and in extracts of organs especially intestine kidney pancreas spleen and later Intestinal mucosa is the richest source of this en 7y me while blood serum and plasma that are not hemolyzed contain only a relatii els small amount Hypertensinase is a protein not duly zable and precipitable bu half saruration with ammonium sulfate It is acid and heat labile and in neutral solution is quichly inaccated at 60 C The optimum ac cury of hypertensinase is at pH beti een 7 and 8 s It is inactuated of hept at pH 36 to 39 for 15 to 20 minutes at 37 C even in the presence of renin and hypertensinogen 40 18 C the action of hyper tersin.se is greatly decreased and it becomes negligible at 0 Car u luch temperature the reaction beru cun renin and hypertensinogen only slightly retarded and may go on to completion It may be pro duced under anaerobic condicions (Fasciolo) and the optimum pll for the activits of hypertensinase not of renal origin is 7 to 8 (Alunāz) For renai hy pertensinase the optimum pH is 4 (Helmer) which indi cates the probability that there are at least two enzymes of thus type Its actis ity is not affected by treatment with chlorofor the mol toluol octyl alcohol potassium cyanide sodium bisulphite pim ( 80 ) ·HYPERTENSINASE 81 gallol and sodium fluoride The action of hypertensinase on hypercensin is regarded as monomolecular (Plentl and Page) Pure hypertensinase has not yet been isolated but Croxatto and collaborators have concluded that its effect on hypertensin is due to i peptidase and most probably an aminopeptidase This is in agree ment with the finding that the hypertensin inactivating effect of an extract of pancreas is due to carboxy peptidase They have concluded on the basis of inhibition experiments that the hypertensinase activity of renal extract and of lahed red blood corpuscles is partly proteolytic and partly due to an oxidase effect It is difficult to obtain hy perten sinase free of renin from renal extracts but in a solution of renin the hypertensinase may be easily destroyed by reduction of pH to 39 It is probable that the kidney may be the main source of the liy pertensinase in normal blood plasma An indication of this is the tlmost complete absence of hypertensinase from the blood plasma of bilaterally nephrectomized dogs It has also been shown that there is less hypertensinase in lymph than in plasma The smaller amount of hypertensinase in the plasma of the blood from an ischemic 1 idney may mean simply that the ischemic kidney produces less of this enzyme What part if any hypertensınase plays in the main tenance of normal or elevated blood pressure has not ver been elucı dated The unit of hypertensınase We have used as the unit of hypertensinase the smallest amount which is capable of inactivating one unit of hypertensın in 30 minutes at 37 > C For the assay variable amounts of hypertensinase are combined with a constant amount of solution known to contain one unit of hypertensin the mixture is in cubated for 30 minutes at 37 to 38 C and is then injected intra Venously into a normal unanesthetized trained dog The least amount of hypertensinase which destroys the entire unit of hypertensin so that there is no rise of blood pressure after the intravenous injection of the mixture is one unit of hypertensinase Fasciolo and collaborators define the unit of hypertensinase as the amount which destroys U5 unit of hypertensin in 4 hours at 37 C and pH 7 4 in a volume of 10 cc with one unit of hy pertensin originally present If exactly half a unit is not destroy ed the calcu late the amount by means of the graph in Fig 37 The amount of hypertensinase in the blood and in various ·82 RCNAL ORIGIN OF HIPERTENSION DETERMINATION OF HYPERTENSINASC 2 HOUR INCUBATION UNITS OF HYPERTENSIN DESTAOYED O 22 QA 0.6 as 30 1.2 34 LS 20 13 UNITS OF HYPERTENSINAS Tub 37 Determination of hypertensinase Tuo hours of incubation at 7 C curic derned by Dexrer for the calculation of units of hyperten inac onc unit destroys 3 unit of hypertensin in four hours Dots circles and squares represent experiments on different days (Aftur Dexter dan Ini Ifed 17 44 19+) organs in determinations of hypertensin ise in plasma or serum 10 count must be taken of the presence of hemolysis The la pertensinasc content of red blood corpuscles is high and a small amount of hemi oli sis can greatly increase the quantity of it in the plasma or serum This accounts for some of the varnble results that have been obtained Normal values for hypertensin ise in the plasma of patients with liy pertension or Iner and hidney disease hue been reported by Haynes and Dexter The observation of 11 einstein and collaborators of a diminution of hypertensinase in the i enous blood from an acutch ischemic kidney 1175 not confirmed bi Dexter and collaborators There is certainly no good rejson for believing that variations 117 the concentration of hypertensipase in the plasma plus a part in the course of experimental renal hypertension The number of South American units of hypertensinase present in various organs of the dek are gnen in Table : Simlar determina sions on human tissues have not been reporced Afechanism of action of hypertensinase Hypertensinase is proba ·HYPERTENSINASF 83 TABLE ? HYPERTENSINASE CONTENT OF DIFFERENT OAGANS OF THE Dox Units per grain of fr si fissare Intestinal mucosa hidney Intestine Pancreas Spleen Hemolyzed red blood cells Liver Adrenal Brain Heart Sonhemolyzed red blood cells Plasma or serum 1700-1600 800 100 800 140 180) 200) 80 10 RO 40 50) 4 8 + 4 4 1 ably a hydrolytic enzyme contained in cxtracts of tissue and in blood There may be other enzymes in the body with the ability to destroy hypertensin Because hypertensinise actiuty is not inlubired in the absence of oxygen it is obviously not an oxidizing enzyme and be cause occul alcohol inhibits amine oud ise but does not inlubit hyper tensinase the identity of these two is also excluded Although tyro sinase can inactivate hypertensin set it also in activates tyranune and adrenalin Hypertensinase is not a phenol oxidase however because it is not affected by cyanide The possibility that hypertensinisc is ? carboxypeptidase has been excluded by differences from the latter in its action on various substrates As in the case of other constituents of the humoral mechanism so also all the worl on the properties of hypertensinase will have to be repeated when it will have been uso lated in pure form ·VICII ISNI AND SITE OT TORVATION AND RI Lr45C OC RIMIN The discussion of this topic was deferred purposely until the nature and properties of the various constituents of the humoral mechanism had been described The determination of the cuact mechanism and site of forma tion or release of renın is of great imporcance yer despite the I ast amount of work that has been done on the properties of the various constituents of the humoral mechanism of experimental renal hypertension but little is I nown about this phase of the problem Although there are many she Leloir who consider that most of the i nown facts about the mechanism of action of renin are consistent with its being the basic cause of renal hypertension yet Grollauan cucn nou questions the existence of preformed renin in the kidney und considers that it is rierely the product of autolysis m ritro This can certainlı be disputed, for his experiments may merely indicate that in the renal tissue of the ring aninal there eusts 1 remun pre Cursor (prorenin) which is transforined into renin as it leaves the lan ing cell and that the same transformation can also occur in zitro Inalogous phenomeni tre known to occur in the case of orher proteoly cc enzymes of which trypsin is an excellent example Exactly whar tahes place in the kidney with man renal artery constricted adequately to gne hypertension nhich leads to the re Icase or formation of renın is not well known The observation of decreased orygen consumption by the ischemic kidney or by ischenne renal tissue has been confirmed but the significance of the result has been questioned on the ground that the reduction may have been due to the death of a certain number of cells and not to uniform interference with the function of the cells The continuous inhalation of 100% origen for 48 hours failed to lower the blood pressure of hypertensive dogs and the inhalation of 7 to 10% CO did not cause a greater rise of the blood pressure 111 such dogs This has been interpreted as unfavorable to the useu of hy pochetical ano emic factor in the pathogenesis of experimental senat 181) 3 ·a FORVATION AND RELEASE OF REVIN 85 hypertension let this is contrary to the view of Cruz Cohe who has concluded that tissue unova especialls renal plus an important pirt in the humoral mechanisin of renal hypertension The demonstration greit diminution of the cytochrome C concentration and of the ictivities of the cytochrome oudise and succinic dehydrogenase in slices and homogenates of the lidneys of hypertensive dogs may be subject to the same criticism is the cyperiments on origen consump tion Its significance cannot be evaluated at the presenruime and more work should certainly be done on this subject The experiments on the ongin of renin carried out in vitro have indicated that it originates in the cortex of the hidney and especially in the lining epithelium of the consoluted tubules The finding that the extract of an aglomerular marine fish lidney contains no renin proved of no great significance Cuscit shou n later that marine fsh kidneys which do possess glomerult also do not contain renin while the kidneys of fresh water fish do possess it in considerable umount No explanation has been offered for this difference It is of interest in this connection that renin can be produced in the kidnev of the dolphin which is a marine mammal The demonstration that the renin content of the involuting tubular portion of the mesonephros of the pig embryo decreases while that of the developing tubular portion of the metanephros increases and the failure to extract renin from hidneys in which the proximal tubules have been destroved by sodium tartrate poisoning indicate that the convoluted tubules arc most probably the site of origin (production and storage) of renin or at least of prorenin if this exsts The exact nature of the stimulus for the release of renin or prorenin has not yet been determined The idea suggested by Page and collaborators that reduction of intra renal pulse pressure rather than decreased blood flow to the hidney is what determines the release of renin and the formation of the vasoconstrictor substance depends entirely upon the demonstration of a pressor substince in the blood by the rabbits ear perfusion method This method is not accepted as a test for renın or angiotonin so it is questionable just what significance can be attached to these experiments Even the assumption of a presumable change from intermittent to continuous pressure beyond the site of the afferent glomerular arterioles is not justified for the ser reason that a pulse pressure in the glomerulus has never been proved to exist Braun Vlendenez goes so far as to state unequivocally that the idea that ·86 RTV ORIGIN OF HPIRTE510 diminished pulse pressure within the lidney causes the liberation of renin has no solid cyperimental proof The reduction of blood flou through the functioning components of the lidney (glomerular and pertubular capillaries) is nother possible stimulus for the formation of release of these substances That there is 1 reduction in the blood flow through the hidneys in most persons with essenal hyperten sion affecting both hidneys equally is well as in the cirly stages of renal hypertension is an established fact but there is still somn. question about whether perminent reduction in the blood flow is necessary for the persistence of the hipertension in animals The ansu er to this question must await better and more direct methods than are available at present for frequent determinations of renal blood flow before and after constriction of the renal artery Pige and collaborators do nor igree that some reduction of blood flow is a necessari condition for the development of hypertension merel because or indirect methods in an occasional animal they found no permanent reduction in the blood flow through the I dness although there was still a slightls increased blood pressure for the demonstration of truc renal ischemia Chasis and Redish require that the ratio of renal plisma flou (diodract clearince) to cubular excre tory mass (maximum tubular secretion of diodrast) should be calcu laced because the reduction of diodrast clearance does not necessarily mean realischerisa South and co workers stitc that the endence frvors the view that the renal ischemia so frequenth obsers ed snes sential human hipertension 15 7 sccondary event and that the pre mary cient is the circulation of a humoral substance of unknown origin which brings thout the efferent arteriolar spasm and progres sue and prallel reduction in renal blood flow which they consider characteristic of essential hypertension Others believe that the cf ferent arteriolar spasm is due to the hyperterisin produced by renia 18 che blood but in experimental renal hy pertension this begins onlı after the renal artery is constricted therefore in man it should be gin only when the renal arteries ind afferent arterioles are sufficient discased to suffer 1 reduction in the si/e of the lumen The demonstracion in utro bi Doci of a normalls perfusible vascular bed in the kidneys of human beings with benign In perten sion especially when the perfusing fluid is kerosene certainly does not justify the conclusion that the perfusion of blood through the hidnes SI LI O is normal in such inda iduals It is interesting houcier that ·PORTATIO ADRLI ISE OF RIV despite the obisous objection to the method there 1118 a great de crease in the rate of perfusion cien of kerosene through the hidness of patients with urema due to arteriolosclerosis glomerulonephritis or pielonephrts So httle is known about the anatons of the renal vascule bed and the effective circulraion through the functioning components of the kidnes that it is dangerous to draw any conclu sions from experiments of this kind about the effect of intrarcnal stenosing vascular disease or any other pathologic process capable of produling similar hemods nanuc disturbance The existence of many intrarenal large arterio arterial and arterio cenous anastomoses would mullify the significance of most perfusion experiments This phase of the problem is being investigated by Prinzmetal and collaborators who hne demonstrated the existence of large intrarenal arrento enous communications but hne nor derewed their number In this connection the recent contribution of Trueta and collab orators (6) is of great significance Although they have not con firmed the existence of large intrarenal arteriovenous anastomoses in man or animal set they have found thar ischemia of the renal cortex parral or complete may be brought about by the by passing of the peripheral cortical circulacon through the medullary and the purta medullary cortical circulation which they have found adequate to carry the entire amount of renal blood so that venous return may be normal while penpheral cortical ischemi exists The fare con cluded that renal cortical schemia may be induced even by inera renal cortical _asaspim of neurogenic origm As a result of these seydes both direct and indirect determinations of venous return from the hidnes become of questionable value as dererminants of the effectne supply of blood to the most smportant functioning com ponents of the kidnes which are situated in the correr In the light of these findings also renul perfusky experiments have little or no significance The pire the intermittent or persistenc neuro genie renal cortical sclema as play in the pathogenesis of hu man essential hypertension sail remins to be established but the authors are commuted to the view that this tiny be the common mechanism ind that this tipe of hypertension $31) therefore bye of renal origen ·THL JUTTAGLOMLRULAR APPARATUS The problem of the possible part played by the juxtaglomerular apparatus in the humoral mechanism of experimental renul and of human hypertension is by no means settled This apparatus has been described in detail by Goormaghugh and others Goorinaghrigh his reported an increase in the side of the ju\tı glomerular apparatus and in the number and size of the anbrillar and sometimes granular or vacuolated cells of this apparatus in the kid neys of rabbits and dogs with renal hypertension (Fig 38) Ile has arrived at the conclusion that these cells may have a local or even gener il secretory or humoral activity and may therefore have a direct relationship to the hypertensie principlc Afibrillar cells are com mon in the normal kidney of the rabbit but Goormaghrigh has found an increase in the number of fibrıllar and granular cells in the juxta glomerular apparatus of rabbits made hipertensa e by the constriction Y6 1 YG Fx 38 Juxtaglomerular apparatus and renal ischenua (A) afferent sos.cl (L) efferent vessel (1G) juxtaglomerular apparatus (1) intercalated segment As the left, glomerulus from normal rabbit bidney at the right glomerulus of rabbit hants after tuenty one days of slaglit ischemia Hypertrophy of the juxtaglomerular apparatus and increase in the number of granular cells (After Goormaghagh Brur let 50 1941 1939) of the main renal arteries He considers that the afibrillar cells have to do with the arteriolar cone and that the granular cells are the source of the pressor substance Dunjhue his confirmed these findings and sub scribes to the same vieus haufman his also reached a similar con clusion on the basis of an anatomical study of hidness from normal 88 ) ·CACES 147N SINGH MEDICAL JUTTAGLOMERULAR APP IRATUS 89 and hy pertensi e persons Grief und Smith hones er have drawn attention to the great variation in the appearance of the arteriolar media and the size and structure of the juxtaglomerular apparatus in normal man and animals and have cautioned that because of species differences for example the absence of granular cells in the hidnes of man and dog the interpretation of the effects of ischemia must be contingent upon a more complete study of normal kidneys The de velopment of cytologic changes in the juxtaglomerular apparatus interpreted by some ins estigators as indicative of endocrine activity does not constitute convincing proof of the origin of in endocrino genic pressor substance or precursor in this structure Up to the present time no direct convincing evidence has been offered that any special cells in the juxtaglomerular apparatus or pre glomerular arterioles are the source of a chemical factor which con stricts the afferent or efferent glomerular or peripheral systemic arterioles There is therefore no good reason for assuming that this apparitus is the regulator of glomerular blood flow or the indirect cause of the hypertension The very presence of renin in extracts of the hidneys of developing pig embryos in which a juxtaglomerular ap paratus has not been identified militates against this view More in vestigation will be required before the functional significance of the juxtaglomerular apparatus and its relationship to hypertension can be properly assessed LIBRARY. LUMES JAIPUR ·THL TRLATVILNI OF MIY PLRTENSIO Medical Treatment As soon as the production of ciperinental renal hypertension had been accomplished the most common methods for the med scal treatment of human hypertension were also tried out on hyper tensnc animals, maink the dog ind the rat It had been found that in many patients with hypertension the sntravenous admins tration of pentothal sodiuni caused a significint and sometimes a pro found fall of blood pressure This is the tipe of patient who is usually chosen for treatment bu surgical operation on the neri ous system It was found also that in the cictable hypertensne or normal dog the blood pressure did fall moderately during the period of unconscious ness after the intravenous administration of between 10 and 15 mg of pentochal sodium per hilogram of body weight The same effect was noted as a result of the intravenous injection of pentobarbystal sodium Such a fall indicated that in the excitable normal dog the pressure was probably hugh for 1 parmal animal and that in thc es cicable hypertensie dog the hipertension which had descloped after the constriction of the renal arteries was not entirch of renul origin and probably sn part at least psichogenic In most of the normal and hypertensie quict well trained animals no effect on the blood pressure was observed from the injection of the dose of penrothal or pencobrbital sodium mentioned or even after an injection of chloralosın In our oun cyperiments on the creatinent of hypertension with ini drug or method ciers animal was usuall subjccred u Icast once to in intrat enous injection of pentothal sodium or of chloralo 50. If the blood pressure did not fall significantlı during the state of inconsciousness the dog was regarded as satisfactory for the de cermination of the cffect of other agents on the hypertension of renal origin A significant full of blood pressure on the contrins 17ste garded as the indication that the clet acion of the blood pressure was duc in put at least to factors other than renal and the animal was not used for therapeutic tests Lnder these conditions forphine potassium thiocyanate minnitol hexanıtrate viscum albus (extract of mistietoe), allium satis um (garlic extract) extract of watermelon 190) ·TRT ITII \1 OF UIIIRIL\SIO 91 seed sodium bromide veratrum unde acetylcholinc cholinc chlo ride sodium chloride nicotinic acid and biotin prosed meffectic Of the various substances that have 1 fleeting cffect on human hyper tension lowering the blood pressuire bi producing peripheral vaso dilatation the nitrites are the most commonly employed In the dog with experimental renal hypertension as in man with so called es sential hypertension the inhalation of amyl nitrite (pearl) or the intravenous injection of glycerol trinitrate (1/100th grain) lowered the blood pressure almost immediatels In some animals the direct femoral mean blood pressure fell precipitously from a level well over 200 mm Hg to 30 mm or less. The effect as in man lasted only 1 few minutes with quick return to the original high level The administration of these substances at frequent intervals prolonged the effect by causing repeated falls of blood pressure but cessation of administration resulted in a prompt return of the blood pressure to the original high level Of the various drugs that have been suggested recently for con tinuous or frequent administration in cases of human hypertension potassium thiocyanate is the best 1 noun For man it has been stated that if an adequate concentration of this drug in the blood is main tained by duly administration the blood pressure may in some cases be kept at a considerably reduced level and may even fall to normal In the dog with renal hypertension it has been found that the con centration of the drug in the blood niust be at or very close to the level of intovcation before an apprecible fall of blood pressure occurs Intoxication indicated usually by anorexia vomiting and sometimes by diarrher regulirly preceded the fall of blood pressure to a lower level To obtan i concentration of 10 mg of this drug in 100 cc of blood the most cffective concentration for man the dog required a relatively larger dose than is necessary for man With draunl of the drug resulted in a slow return of the blood pressure to the previously hypertensive level the rate of return depending upon the degree of intoxication of the animal in one of our animals It tool a little more than two wechs for the return of the blood pres sure to the original high les el During the greater part of this time the animal was obviously ill Other ini estigators have also tested the effects of the injection of potassium thiocyanate in dogs with renal hypertension Davis and Barker found that it effectively lowered the blood pressure and that supradiaphragmatic removal of the thoracic ·92 RINII ORIGIT OF HIPERTENSION sympathetic trunks and splunchnic nerves rendered the animals even more sensitne to the drug Grollman Harrison and Williams found that potassium thiocy znate caused in insignificant fall u hen adminis tered orally to hypertensie rits Hamilton and his associates found that sodium thiocyanate lon ered the blood pressure of dogs with spontaneous hypertension but concluded that the serson of the ear (Sumnier) 11.75 more likely to huc ciused the reduction of the blood pressure than ut as the drug and the full persisted for tu o months ifter all the thiocyanate was cicreted Certiinks on the basis of the cxperimental evidence there is no definite indication that potassium thiocy inate is 1 highl desirable drug for the treatment of renal In pertension Thus it would scem that all the methods which hac Presiously fuled to affect human hypertension are equally unsuccess ful in experimental renal hypertension but that the difficulties Tolled in the clinical appreciition of the hypotensi e properties of different agents in essentul hypertension are greater than in experi mental renal hypertension Extracts of kidney A long time before persistent experimental renal hypertension had been produced in animals renal extraers of various types had been used empirically with variable results for the treatment of renal disease in man Organotherapy with renal sub stance extract or other type of preparation is not a new procedure for the treatment of human hypertension with or without accom panying disrurbance of renal excretors function The thought that the kidney may be in orgin of internal secretion dates back to 1893 when Brown Scquard assisted by d Arsons al was the first to pre pare an extract of hidne for the treatment of this condition Thes treated the uremia associated with the anurit due to renal disease or to bilateral nephrectomy which they regarded as in part at least in the nature of hormone deficiency but they did not determine the cffect of this treument on the blood pressure Wany other publici fions on the existence of an internal secretion of the hidnes have appeared since then ind creatment of nephritis and cclampsia uith uremia bı renal organotherap: has been the subject of mint re ports Renal opotherapı for the treatment of hipertension with renal insufficiency was first practiced by Renaut in 1903 lle used iace rated kidness and ciumed that the duli donnistration of thus mr terial had a beneficial effect on both conditions ·TREATMENT OF HYPLRTENSION 93 Actually the first organ to be extracted for the possible isolation of a substance that would lower blood pressure in mn was the kidney Renal extracts specifically for the treatment of hypertension were first tried by Gomez in 1934 In 17 of his 40 cases of hypertension there was associated renal excretory insufficiency and accumu lation of nitrogenous products in the blood He stated that there was a steady drop of blood pressure as the result of the treatment in 38 of his 40 cases and also a fall of blood urea in 16 out of the 17 cases in which there was elevated blood urea During the past few years there have been other public itions dealing with the treatment of human hypertension by renal opotherapy and injections of renal extracts of various kinds What prompted the trial of renal substance or extracts hitherto had alu ays been either pure empiricism or the idea of the substitution of a missing or deficient renal hornione or the detoxification of the poisonous substances present in the blood because of disease of the kidneys The thought that such treatment might lower the blood pressure by ulubiting the formation of or destroying or neutralizing the effect of a pressor substance of renal origin or some substance in the blood plasma which interacts with the substance of renal origin to form a pressor substance is entirely new and is based on the current theory of a humoral mechanism of hypertension of renal origin Any attempt to treat experimental renal hypertension by affect ing the humoral mechanism should take into consideration the Possi bilities that have been outlined by Alunoz and collaborators i su pression duninution or inactivation of renin 2 inhibition of the re action between renin and hypertensinogen 3 diminution of the amount of hypertensinogen 4 inhibition of the action or destruc tion of hypertensin by an increase in the aniount or activity of hy pertensinase or of some other agent capable of accomplishing this The first attempts to treat experimental renal hypertension by means of renal (and muscle) extracts were made by Harrison and collaborators who reported a lowering of the blood pressure in hyper tensite rats by renal extract given by mouth or parenterally They assumed as the basis of their treatment that in temporary hyperten sion due to unilateral constriction of the main renal artery the nor mal kidney by some humoral mechanism for example by inhibiting or destroying the pressor substance might be playing 1 part in ·94 RENAL ORICIS OI HIPERTE\SIOS eliminating the hypertensi e effect of the kidnes with the renal arter constricted There is Other evidence for this ueu 1 The re moval of a normal kidney in the presence of one with renul arteri constricted causes the blood pressure to remain permanently ele rated ? After removal of the schemc kidnet if the orher a normal the blood pressure fails to normal in 6 hours but it takes five times as long for the blood pressure to reach nomal after the removal of both kidneys when one or both are ischemic It was this which led hat2 and colliboritors and others to the ider that by counter icting or neutralizing the pressor substance the normal kid ney might play part in the elimination of the chemical mediator of experimental renal hypertension The believe that the more rapid fall of the blood pressure to the normal lesel in the presence of normal lidne tissue as contristed with the slow fall in its absence might be due to the excretion or destruction of the pressor sub Scance by the remaining normal kidney They shoucd thir un in animal with uruter il- cnous fistula on the side of the normal kidnes the removal of the opposite ischemic kidnes v is still follou ed by ripid (6 hours) fall of the blood pressure to norm The reached the conclusion that the normal renal tissue destroyed the pressor sub srince since otheru se its continued presence in the blood strejmy should hue hept the blood pressure elevated for a longer period In the opinion of Dexter and Braun Menendez the renal threshold for the excretion of renın is too high to account for the possible stabil 17ing part played bi the normal hidnet Groliman and collaborators have adopted the vien that the actre principle dered from kidnes tissue is an essential humoral agent the absence of which in the dis cased kidnet results in hypertension Thet nou beliese that the rdnunistration of this principle ou ercomes the deficienci indre Jei es the hipertension The demonstration that renal ein blood from an ischemic Lud frey contains much less fu pertefsirase tiin real rein blood from normal kidnes would throw light on the earlier experiments of Free man who found that normal dog sblood can reduce the blood pressure of dogs with experinental renal hypertension wlicrcas blood from a hypertensile dog had no such effect I he antipresor effect in this case may be due to the presence of hipertensinise in normal blood and its diminution in the blood of hipertensne animals fou ever ·TRCATUT OF HIPIRIISIO 95 this finding has not becn confirmed Vlore worh should be done on this subject The identical renal extracts used by Page and collaborators which caused a reduction of arterul blood pressure in their hypertensive animals and patients failed to have the same effect in the hands of sonic other inestigators Although Page and collaborators have tried to relate the antipressor effect of their kidney extract to its hyper tensinase content ver it has been shown that there is little hyperten sinase in it and Schales and collaborators have found that this ex tract gave the same results when its hypertensın ise was first com pletely destroyed There is certainls no proof that hypertensınase per se is absorbed into the blood stream from an intrimuscular in jection In fact it has been shown that for the antipressor effect of 1 renal cxtract for the treatment of hypertension hypertensinase is not required Harrison Grollman and Williams did not determine the existence of hypertensinase in their extracts but they reported a lowering of blood pressure in the rit dog and even man by the ad ministration both orally and intramuscularly of a renal extract which contains no hypertensinase That such effects are caused by 1 renin inhibitor as postulated by Page and collaborators has not been confirmed The possibility that all the effects on blood pressure by renal extracts hitherto reported are due to a non specific pyrogenic effect (with or without actual elevation of temperature) of a foreign or ganic material that produces a local and general reaction has already been suggested by several in estigators It is interesting in this con nection that a reduction in the severity of the local reaction as 1 result of purification of the extract also resulted in a corresponding reduction in the antipressor effect Schales Stead and Warren ob served an antipressor effect which was not specific for renal extracts and attributed all the effects they observed to the local and general reactions which occurred in their opinion this in alıdates any con clusions about the specific effect of ans renal extract The same effect on blood pressure was obtained when the extract contained little or no hypertensinase of the local and systemic reactions to the injec tions occurred The extract which Grollman Harrison and I liams used can hardly be the same as that of other investigators because they found that the active substance was dualı zable and effec ·96 RLVAL ORIGIN OI HIPIRIENSION tre by mouth in both anınals and man Most of their cyperiment il work on annals sis done on the rit ind has not yet been con firmed No orher ini estiguors hac reported 1 lowering of the blood pressure in hypertensive individuals from the oral administra non of renal evcrcts Goldring and Chasis fuiled to obserie a favor uble effect in four hipertensi c patients treated with renal cxtrict by mouth even when the administered the equn ulent of 50 kilo grims of origini hidne subst ince dando Although Page and collaborators insist that they have observed fall of blood pressure from renal e cract without accompanying local or systemic reaction yet it has been shown that all the effects can be produced by the parenteral injection of foreign organic sub stances such as milk and typhoid vacune There is certainly no clear indication that the renal extracts that have been prepared up to the present time constitute an adequate treatment for hyperten sion Perhaps the fact thu in the last 6 years there has been but little progress reported from the treatment of ly pertension by these renal extracts is an indication of the difficulties involved Vlani different types of extract ind other preparations of 17 rious organs especially of ller und pincreas hue been prepared and admmistered empirically an arriers of 71s for the trentment of human essentul hy pertension The results for the most part hase been equivocal and the clums for the value of these preparations Uy sonte lave not been substantiated by others The results of the treatment ot hypertensne animals by a great variety of subsrances that hic also been administered to man are summarized in Table> Antirenin Treatment of hypertension by the parenteral in section of renin Because renin is a protein it was to be cipected that it might be antigenic and that its parenteral injection would result in the development of an antibods in the blood plasma What properties of such in antiserum would be could not be anticipated but it was hoped thit it would at least prove to be antipressor that Is nuirenin Waherlin and collaborators u cre the first to worl on this subject and reported that in the blood serum of rabbits dogs and gunei pigs but not in the horse injected with litterologous ren!n from 12 rious species a substance or principle des cloped which was capablu of neutralizing the acute pressor effect of an intravenous injection of the ·TRIATVIE VT OI HYPIRTINSON 97 TABLE) Period of Substance Employed Απι mal Daily Route of Admin istra tion Effects on Blood Pressure Dose Treat nicnt Days 3 5 7 Rat Rat Rat Dog Rat Rat Rat 003 gm 006 bm 00) gm 008 13 0075 gon 01 gm 07 gm Oral Oral Oral Oral Oral Oral Oral 1 Nitrites and Nitrates Erythrol tetranitrare Frythrol tetranitrates) Inythroltetranitrate() Vannitol hexanıtrate! Pismuth subnitrates > Sodium nitre) Sodium matrite() Sulfocyanates Potassium sulfucyanate) Potassium sulfocyanate Potassium sulfocyanate) Potassium sulfocyanater Potassium sulfocyanate! Potassium sulfocyanate() Vone Voderate fall None None None None Moderate fall 8 Dog Rat Rat 01 07 01 02 5 11 Oral Oral Oral gm gm Rm m) 5 7 Rat Oral Fall None Voderate fall None Voderate fall Moderate fall and toxic symptoms 7 Rat Dyg Ora! Oral 10 6 None None Oral 71 44 Non None SC 5 None SC 5 Moderate fall Oral 10 None 60 Hagnesium salts Vagnesium carbonate Rat 02 gi Vlagnesium sulfate (1) Rat 005 m C) oline salts Choline chloride Dog 52 gm Acetylcholine Dog 25 mgm Acetyl methyl choline hydrochloride Rac 05 mgm Acetyl methyl choline hydrochloride Rat 10 mgm Bromides Sodium bromide Dog 80 gm Vegetable Extracts Allium sativum (garlic)) Dog 10 gm Allium sativum (garlic) Rat 10 gin Allium sativum (garlic) Rat 051 mgm Allium sativum (garlic) Dog 06 cc iscum album (mestletoe): Dog 07 g? Veratrum vinde (tincture) Dog 1 cc Watermelon seed) Dog Istanas 200 000 Vitamin A Dog to 400 000 U Vicotinic acido Dogs 0270 gm Biotint Pog 1 000 U Vitamin B ) Dos 8 12 cc Ascorbic acido Dog 10 gts Vitamin C Dog 100 mgm Orai Oral Oral Oral Vone None None None R 15 Or 1 15 None Oral 15 None None Ora! 90 180 Definice fall Oral SC Oral Oral Oral 21 10 + 100 150 None Yone Vone one Mone ·98 RIVAL ORIGIN OF HIPERTE\SION TABLE -Continued Substance Imployed Tani ma] Daily Dose | Route of Admin Period of Treat ment Days Effects on Blood Pressure Istra tion 03 gin Oral 30 15stie Extracts Pancreas (pou dered) Pancreas (pou dered) Adrenal cortex) Liver Dog Dob Dog Dos 01 CC them Холе Vone Vone Mone SC Il and I 11 6-12 cc 30 30 Dog 15 ST /kgm 30 one Pruntaryi ) Hornones Lsrrone) restosterone Pitutrin Dos Dos 01 mgm gun 75 mgm kom DUL, 10 U/kgm IN 30 30 15 Trac one Tone Each cc contained 0 15 mgm thiamin 001 mem riboflavin 0 15 mg m pyrid orine 2 mgm cortoic acid and 04 mgın pantothenic acid 1 Grollmaz2, Harrison and 11 ilhams (19402) 6 11 akerlin lfoss and Smuth (194) 2 Friedman Jarman and Varrus (1942) 7 Voss and Wakerlin (1944) 3 Goldblatt hahn and Lewis (194) Il intravenously 4 Davis and Barker (1941) 111 = Intramuscularly $ Wakerlin and Gaines (1940) SC = subcutaneously renin They found that if the antiserum was first mixed with the renin and kept for about 18 hours at about + C the mixture lost its pressor effect when injected intramuscularly into a normal dog Normal serum did not possess this property of inactnating renin They regarded this principle as analogous to an antibody an ancı enzy me or antihormone and suggested for it the name antirenin This has been produced in the rabbit by the intramuscular injection of human hog cat and dog reain in the guinea pig br the intra abdominal injection of hog cat and dog renin and in normal and renal hvpertensi e dogs by the intramuscular injection of hog and rabbit renin The injection of homologous renin or of heterologous renin preu sously inactivated by heat did not induce the formation of antirenin in either normal or hypertensic dogs Hog ln er extract failed to produce antirenin in normal or hypertensile dogs Angrenın is a protein but it is neither an enzyme nor precipitin In the dog and guinea pig cien u hen the antirenin titer is high there is no precipitin in the blood in the rabbit in which precipitin re sponses are more easılı obcained precipitins against other plasma pro reins are formed in high titer u hen these animals are gren repeated inthienous injections of impure renin The fact that the rabbit seruni ·TREATMENT OF HIPIRTE SIO 99 still retains its ability to neutralize renin after the precipitin has been removed by absorption in vitro certainly indicates that the antirenin and precipitin are not identical In our laboratory in which the existence of antirenin was con firmed Dr Yale J karz studied the chemical properties of this substance and found that it is precipitated quantitativ ely by ammo nium sulphate at a concentration of 16 molar ind pH 50 It is present in the pseudoglobulin fraction of the serum in which cir culating antibodies are usually found and this friction contains prac tically all the antirenin of the original serum Antirenin is active between PH 23 and 107 but is inactivated at pH 19 or less and 110 or more At 0 C and in the frozen or lophilized state it re mains stable for at least three montis Heating of the antiseruin at 65 C for ten minutes does not inactivate the antirenin but it is com pletely destroyed by heating at 75 C Antirenin does not neutral 17e the pressor effect of either hypertensın or pituitrin Like anti hormones antirenin is not species specific in the neutralization of renin in ito except for antirenin from rabbits induced by the in jection of human renin This specificity is also true for antihormones produced in rabbits by the injection of extracts from other human tissues Hog antirenin produced in the dog will inactivate dog cow or hog renin but not human renin Waherlin and collaborators reported a fall of blood pressure to normal in dogs with repeated intramuscular injections of hog renin into hypertensive dogs They also observed the prevention of hyper tension in dogs which recen ed similar injections before the renul arteries were constricted Both of these observations we have been able to confirm (Goldblatt H hatz Y J and Richardson E) Wakerlin and collaborators found that the intraperitoneal injection of 40 ml of dog serum containing a high titer of antirenin for her renin had no specific effect on the blood pressure of a hypertensive dog No significant changes have been observed by Ilakerlin or by us in those animals that des eloped high titers of intirenin in their plasma We have found that after a normnal or hypertensi e animal has developed a high titer of antirenin large doses of homologous or heterologous renin inay be injected intravenously into them without producing any change in blood pressure lle have injected intra tenously in one dose as much as 100 dog units of hog renin without ·100 RINAL ORIGIN OF HIPERTF\SIO! noting any eles non of the blood pressure in a dog with ten unirs of antirenin per cc of its blood serum The kidness of rabbits and dogs which had a high titer of antirenin in their blood were found to contain normal amounts of renin Il internitz and collaborators failed to confirm the produccion of antirenin but they injected the renin intravenously Friedman and collaborators did not observe a fall in blood pressure in animals that recen ed parenteral (not intrat enous) injections of renin but they probably injected an insufficient amount of renin lle too failed to detect the production of antirenin in dogs by the intru enous injec tion of as much as 25 units of hog renin a das for 12 weeks but by the subcutaneous and iner muscular injection of the same amount and even less we did succeed in producing antirenin of high titer in the scruin of norml and hypertensie dogs lle also observed a fall of blood pressure in hypertensie dogs and presented the develop ment of hypertension in dogs by repeated subcutaneous or imra muscular injections of hog renin before the renal arteries were con stricted The optimun dose for this v zs 25 units of renin per du Although IT akerlin and collaborators were the first to produce intirenin vet the nou consider that they have good cudence that It is not the anurenin which is responsible for the prevention of hypertension or for the louering of the blood pressure in dogs with renal hypertension The evidence upon a hich they 1.21e repudlared the significance of the intirenin is not conclusive Onc reson gn en is that highlı purihed liog renın is as effective as parnah purihed hog renin in stimulating the formation of antirenin bur tie it is much less effective as an anuhy pertensie agent It is highlı prob able however that this difference was due only to the smaller amount of renin injected Another reason was that in an occasional dog thuc recen ed injections of hog renin which had been inactivated by heat 1 fall of blood pressure v is also noted Not too much significance should be attached to this because in some untreated dogs the blood pressure also recurns ( or lower level and besides a non specific cffect of injections of proteins associated with the impure renin cin not be entirely excluded and may play a part in the phenomenon Ilaherlin and collaborators also found no correlation between the antirenin giter and the antihypertensile effect This finding is con trury to the results of our ou n studies It is difficult to make a com parison betu een their results and ours because they did not gne an ·TREATIETOT HYPLRIISIO 101 exact determination of the titer of antirenin attained by their animals ind our methods of assay are not directly comparable Their antı rerun titer has been based on the imount of renin extracted per gram of renal cortex which is obuousl subject to considerable variation lle have titrated the exact amount of antirenin by determining the number of units of renin inactivated by the serum Our dog unit of antirenin is the minimum quantity which neutralizes the acute pressor effect of our dog unit of renin Possible application of the results obtained in animals to the treat ment of human hypertension is beset with many difficulties Because homologous renin does not produce antirenin the injection of hu man renin into a hypertensi e pacient would probably be ineffective Whether heterologous animal renins which do not produce a pressor effect in man would nei crtheless induce the formation of antirenin is still unknown Renin prepared from the kidneys of other primates which does produce an elevation of blood pressure in man would probably induce the development of antirenin in man but the diffi culties involved in obtaining the large quantity of rentn that would be required for this test are obvious Aluch work on this subject is still required It has not yet been given the attention it deserves Other vasoconstrictor pressor and antipressor substances and their effects in any consideration of the humoral mechanism of renal hypertension mention should be made of the studies of Bing ind col laborators which although they may have no direct bearing on this mechanism yet indicate a possible way whereby a pressor substance of renal origin may be formed or released under conditions which in volve a disturbance of the intrarenal hemodynamics By perfusion ex periments these authors demonstrated that an ischemic kidney but not a normal one is capable by decarboxylation of converting dihydro wphenylalanine (dopa) a substance which possesses no pressor properties into hydroxy tv ramine which is a powerful pressor amine They showed that the amount of hydroxytyramine which is formed in the Vidney from 1 dopa under conditions of oxygen lach is pro portional to the reduction of blood flow through the perfused kid ney and also demonstrated the transformation of dopa into hydro vyty ramine in hidnes extracts in 21t10 under conditions of low oxygen tension But even without the addition of 1 dopa the de elopment of a pressor substance has been reported merely as a result of anacrobic conditions Liver spleen lang and heart muscle treated ·102 RENAL ORIGIN OF HIPERTFNSION in the same ini did not develop pressor substances Liter and in testine also contain i dopı decirbou lase jer these organs were un ible even when their circultaion was reduced to produce hydroxy ry ramine from 1 dopa which was added to the blood Ring wis also able to show that partlı or complerely ischemic cats hidners in no converted i dopa injecred intrarcnoush into hu dro ti rimine Oster and Soshın obseri ed that the intri enous injection of 1 dopo into cits with erperimenril renal lu pertension resulted in a great rise of blood pressure while no rise occurred in normal cats This is of great interest in this connection Bing ind collaborators did not conclude that hydrou tu rumme is the cause of or in any way directh inoked in the pathogenesis of experimental renal or of hunın hypertension The same conclusion has been reached about ry ramune As a result of his obscri tions Bing merch concluded that the deamination of amino acids in the lidney may be caralyzed by amine oxidases and that this process requires origen in an ischemic hidney under relatively anoicmic conditions de carbowlation without deumitiation of anjino acids would result in the formation of pressor emines in acumulation of which might result in elev sted blood pressure It has been demonstrared that the tuo pressor substances hu drow tyrumine and hypertensin tre de stroved by different fractions of renalextrict und bi different mech anisms It has also been shown thar renin does not cffect the de carboxylation of 1 dopa to convert it to hydrowerumine It Is been demonstrared that the reduction of the bloud Ans to the hud ney results in a profound alteration of the subsequent chemical evenrs The kidnes lias the capability of conucrting the amino acid which is itself without pressor properti into ? powerful pressor imine which accumulates under anterobic conditions and results un elevation of blood pressure Pressor anuncs are rapidly descrored houcier by ouditie enzı mes when the circulation is normal and acrobic conditions prev] Their wor) has prouded 2 1057 for tfic fissat thesis that the hipertension which results froin ren al ischeminin he due to diminished deamination of certain amino acids and that it may possibly play an accessors or even an important prinirs part in hypertension in some types of animal The work of Bing and collaborators has been the basis of the attempt made by others at the treatment of crperimental renrl hiper tension in rats by means of quinones and in hipertensne dogs by ·CRTATur 1 (III Y PIRTISIO 103 diketone 1-4 cyclohexandione Louering of the blood pressure 175 reported but we have not been able to confirm iny of these results by the use of the same materials in hypertensi e dogs Pressor amines certainly crist and produce their effects when in jected intravenously into animals Deamination requires oxygen The question is whether some disturbance of the hidnes may so reduce the available orygen that deamination of natural amines does not occur and that the entrance of such imincs into the blood stream results in hypertension There is as yet no available evidence from the studies on man that this mechanism plays a part in human hyper tension The problem whether there is a renal mechanism of hyper tension which is dependent upon a metabolic fault in the kidney which interferes with the utilization of melanın like substances and their phenolic precursors is not yet settled Even the possibility that such a mechanism exists in one animal the rat for example and not in other animals including mın has not been determined with cer tainty in itro The studies on the treatment of human hypertension with amine oxidases have not led to an elucidation of this problem Schroeder and collaborators found that the parenteral injection of ty rosinase a phenolic oud ise capable of oxıdızıng both mono dihy dro ow phenols and ortho hydro oxyphenols to inactive quinones reduced the blood pressure in rats and dogs with cxperimental renal hyper tension and in man with essential hypertension He show ed also that tyrosinase can inactivate renin in the presence of catechol But Prinzmetal and collaborators showed that the effect obtained by Schroeder was probably due to the local and systemic reaction induced by this material and not to the enzymatic activity of the tyrosinase because an extract containing it was also effectie when the ty rosinase activity was first destroyed Alles Blohm ind Saunders concluded that the amount of tyrosinase injected by Schroeder was much less than would be required for thc oxidation of diphenolic amines This subject deserves more investigation Croxatto and collaborators have shown that pepsin if it acts on blood globulin at pH 30 or lower can produce by peptic digestion of the protein a vasoconstrictor and pressor substance which the have called pepsitensin and which the assert 15 identical in chemical and pharmacological properties with hypertensin except that pep sitensın is not inactit ated as rapidly by hypertensinase from red blood ·104 ROVAL ORIGIN OF HIPERTENSION corpuscles This difference they attributed to impurities in pepsitensin and asserted that the purer the pepsitensin the more sensitic it is te inactivation by hypertensinase ind other proteolytic enzymes It has been found also that hy pertensin is more easily destroyed than pepsitensin by the action of pepsin This is to be expected since pepsitensın results from the action of pepsin on blood globulin The reaction is usually carried out with the hypertensinogen ac pH 35 but a pH of 5 to 6 for 30 minutes is considered best (Ileber Alujor and Lobb) and it will occur when the pH is up to 7 but not higher In this respect the action of pepsin differs from that of renin De pressor substances may also result These have caused difficulties in httempts at purification and may even mash the pressor effect Ac cording to Alonso in effect similar to that of pepsin may result from prolonged treatment with acid Ronin and pepsin also do not act upon cxactly the same substrates Plasma globulins acıdified ro pll 2 4 for 30 minutes at 25 C and then neutralized or precipitated with alcohol and redissolved no longer yield hypertensin with renin but still veld pepsitensin uuth pepsin It would seem thereforc that pepsin acting on denatured globulin is capable of producing 1 pressor substance while renin fails to do so It is of interest that hypertensinogen after treatment with renın cannot react with pep sin to form pepsitensin The eustence of pepsitensırt has been con firmed by others including ourselies Helmer and Page hue pro duced it with crystalline pepsin Croxatto has obtained pressor sub) stances from the action of pepsin on other substrates such as casein ovalbumin lactalbumun and lactoglobulin but not gelaun Renin does nor act upon these to form hypertensın Trypsin popsin and taka diastase do not have the pressor substance producing properties of pepsin Just what significance all of these experiments will have in con nection with the humoral mechanism of renal hypertension it is still difficult to estimate For the present these observations merely inu. cite the probable non specific character of the renin hypertensinogen renction and the disintegratie enzymatic nature of thus rciction which results in the formation of an acute pressor substance The observation that both hypertensin and pepsitensin ire in ictivated by in amino peptidase obtained from yt2st 119s led Crovato to conclude that the hypertensinase activity of renal extract mis al o be atmbuted to the enzyme iniino peptidisc conruined in renal tissue ·IRIATUT\T OF HIILRTE\SION 10) They hue also shown that the vasoconstrictor effect of hy pertensin tested on the perfused cold is destros cd enzymatically by the action of amine oxidase and tyrosinise In our ou n laboratory in collabora tion with Gollan and Richardson niuch work has been done on enzymes from miny plants that are capable of in ictn ating hypertensin in litro It is difficult to make prepirations that are not toxic and although antipressor effects have been obtained in hypertensive dogs yet it is difficult to estimate how much of the effect was duc specifically to the plant hypertensinise Shorr Zweifach and Furchgott in their studies of the humoral mechanism of shock hale obruined results which may prouc in part at least applicable to the humoral mechanism of renal hypertension From the kidney they have obtained a vaso excitor material (VEN) which has the ability when injected intravenousls of potentiating the vasoconstrictor effect of the topical application of adrenalin on the termunal arterioles and precapillaries of the mesoppendix of the rat VEM is not itself a direct vasoconstrictor substance and it has not yet been isolated in pure form They have found that VEA1 is also present in blood plasma in the irreversible phase of shock and in experimental renal hipertension due to constriction of the main renal arteries from slices of normal kidney VEA1 is obtained only under anaeorbic conditions but from the ischemic kidney of the hypertensive animal the extract may be obtained under acrobic con ditions as well The aerobic production of VEM from the hidness of hypertensile dogs is believed to be due to the loss of a renal mechanism for the inactivation of VEN I rom liver and sl eletal muscle these authors have also isolated a vasodepressor materal (VDM) which has the ability to inhibit the vasoconstrictor effect of the topical application of adrenalin Vaso inhibitor material (VINI) would have been a more appropriate name for this substance IDM is not itself a direct vasodilator and it has not ver been isolated in pure form from normal liver the VDMI is extractable only under anaerobic conditions from the liver 1 sub stance has also been obtained which is capable of destroying \ DM under aerobic conditions Extracts prepared from livers removed during irreversible shock or previouslı subjected to annerobic incu bation for two hours failed to inactivate IDV They have called this substance VDM Oudase which is said to consist of two com ponents a heat labile apoenzyme and a heat stable coenzyme Neither ·106 RIVAL ORIGIN OF HYPERTI SIO one of these has been isolated in pure forn Their exact nature has not ver been determined There is but little doubt that none of these subsrances is identical 112h am of the known components of the humoral mechanism of esperimental renal hypertension yer they may play an important part in either porentiating or neutralizing the issomosor effects of some of these substances The possible part they may play in the maintenance of normal blood pressure and the possible contribution to our knowledge of the pathogenesis and therapy of hypertension hich may result from these studies cannot vec be determined from 1 hat has been published This work is of the greatest interest ind importance and should be pursued by these authors as well as bu other intestigators The most recent conrribution to the subject of the humoril mechanism of hypertension has been made by Shipley Helmer and kohlstaedt and has been published only in preliminarı form These authors have discovered a pressor principle in the blood plasma of dead as the result of certain undiagnosed natural cruscs of DDI poisoning or of prolonged hypotension resulting from large with drawal of blood The intravenous injection of plasını from such animals caused a sustained elevation of blood pressure for 7 long as five hours in cats which had been bilateralli nephrectomized tuo days before but not in normal cats This effect occurred with or without anesthesia even in the pithed nephrectomized rost anima? This pressor principle appears to be distinct from renity anglotonin pepsitensin hydroxytyramine or ty ramme because of the difference 16 the contour and duration of the pressor response and the difference in the conditions under which the response is obsen ed The authors fuled to find this principle in the blood plasma of bilaterally nephree tomized cats which had been poisoned with DDT or in which pro longed hi porension had been produced by excessive bleeding or animals azotemic as a result of bilateral nephrecrom Thes ukser failed to find it in the blood plasma of norinal In ing cars or of 1971 cats which had been killed suddenly bs sarjous means the con cluded that a moderatels prolonged period of hu porcnsion (113th concomitant diminished blood flow and/or blood pressure with the hidneys) is necessary for the production of this pressor principle They have not yet isolated this substance in purc fom but fine con ·TREATMENT OF HYPERTENSIO 107 cluded that it appears to be protein in nature is het labile and does not pass through 1 dialı zing membrine or ultra filter The active substance is partlı but not completely precipitared at pH 4 by satura tion with sodium chloride or 06 situration with ammonium sulfate Although it has been demonstrated that renin does appear in the blood in the state of hypotension due to excesse bleeding yet the amount of renin present is not sufficient to account for the pro nounced and sustained pressor reaction of the plasma which would come from the hypertensin produced by the renin in the amount of plasma used in the experiments mentioned above The injection of a fresh solution of renin extracted from cat hidneys possessing the ability to produce hypertensin in zitro did not cause the same marhed or sustuned pressor response in the pithed bilaterally neph rectomized cat Of great interest is the fact recently reported by the authors (Second Conference on Factors Regulating Blood Pres sure sponsored by the Josiah Naci Junior I oundation Neu Yor] ) that this neu sustained pressor substance (SPS) is also inactii ated by antirenin produced with impure renin The fact that this new pressor substance produces such a sus tained effect is of great interest There does not appear to be any obvious connection between this pressor substance and the substances described by Short and collaborators The significance of this con tribution to the problem of the humoral mechanism of renal hyper tension and the regulation of normal blood pressure remains to be determined On the basis of experiments on renal hypertension in the rabbit Pickering has concluded that only the initial phase of this type of hypertension is due to the renin hypertensin mechanism and that the persistence of the hypertension is due not to a neurogenic mech anism as proposed by Ogden but to another humoral mechanism Because the pressor substance involved in the latter is not of renal origin it is not identical with that of Shipley and collaborators Aluch more work is required before the exact nature of the mechan ism involved in the acute and chronic phases of experimental renal hypertension can be considered as established The effect of diet on experimental renal hy pertension has not been exhaustively investigated It has been asserted that a high protein (800 grams of mert dails ) diet or 50 grams of urea daily increases ·108 RIVAL ORIGIT OF HYPERTI1510 the elevated blood pressure in dogs with experimental renal hyper tension A dict that produces a considerible gain of ucight has a similar cffcct The significance of the experiments of Calder on the production of hypertension in the rit by a diet deficient in the heat stable frac tion of the vitamin B complex is of interest His belief is that the hy pertension is of metabolic origin and due to diminished oudarne processes in the I jdney In this way he relates his results to those obtuned by constriction of the main renil arteries This work re quires conhrination The clam for the effecti eness of ascorbic acid in reducing hiper tension in min has nor been confirmed This has not been tested on lvpertensa e animals li has been reported that yun F has no effect on the blood pressure of dogs with experimental renal hyper cension This has not been tested on hypertension in man The assertion that large doses of It munn A lower the blood pressure of hypertensne human beings rats and dogs has not been substantiated by the same im estigators (Il aherlin and collaborators) who finally decided that it was not the vitamin A that produced the effect because fish body and Iner oil still contained the blood pres sure reducing substance when the vitamin A was destroyed In fact Grollman and collaborators found that a highly purified veinn A concentrate did not have the hypotensive effect and that the effect uns enhanced by the oudition of the fatty acids in the effectric marine oil The nature and mechanism of the action of this sub stance in mirine oils ure not knonin In his most recent publication on this subject Grollmın isserts that a number of refined oils de rned from marine fishes and from the seeds of the tung tree ad ministered orally reduce blood pressure in hipertensive rats logu and man l'eget ible oils were not effectie in hypertensic an mals Oudation and saponification prior to ovdation enhanced the cours of some of the actise oils The effect was independent of their original vitimin A content and was retamed after the destruc tion of thus itinun The actuc principle is soluble in water an! dialı zablc is in the case of the oralls effcctu e renal citracts with which he is nou inclined to consider this material identical Ilc states hou ever that it is still impractical to creat pitsents because there is no readily available source of large imounts of this principle It has been reported that viimin A mat zffect urca and inulin ·TRIATET OF HYPERTI SIO 109 clearances but these authors did not control their eyperiments by giving the same product with the vitamin A inactivated Vitaunn D, gnen by mouth has no cffect on the blood pressure of the hyper tensive rat (Briskın) Another sterol that has no effect on experi menal renal hypertension of the dog is testosterone (llaherlin and Gaines) As a result of experiments in which they noted 2 disequilibrium of sodium balance in hypertensive rats Grollman and collaborators tested the effect of restriction of sodium intake on hypertension in the rat and in man They noted a lowering of blood pressure in both the significance of these obsery itions especially with relation to the part plued by the corres of the adrenal renrains to be clucidated Kempner las reported the blood pressure lowering effect of a diet consisting mainly of rice and other obseri ers have confirmed tus effect in at least some cases The outstanding characteristics of this diet are the lou protein and low sodium content 11 hether the effects that have been obsen ed are attributable to the low sodium the low protein or both has not yet been established There are those who believe that the effect is due mainly if not entirelt to the low sodium content of the diet Some observers have failed to observe any significant lowering of blood pressure as a result of this dict Recently Dick reported a full of blood pressure in dogs with chronic experimental renal hypertension that had been fed the rice diet According to hesson and VicCutcheon there is no relationship between the level of blood pressure and retention of calcium in man This relationship has not been ini estigated in animals Surgical Treatment of Hypertension The various surgical procedures that have been carried out on the nervous system for the treatment of human hypertension have all failed to affect experimental renal hypertension Ei en total sy mpa thectomy of the abdomen and thorar including deneration of the heart and destruction of the spinal cord have had no permanent effect on experimental renal hy perrension in the dog (Freeman and Page) (Fig 22) The disturbance of renal hemodynamics produced by the clamp cannot be altered by these procedures but the effect on the vasomotor mechanism should be the same as in man It is at least pos ·110 RENAL ORIGIN OF HYPERTENSION sible that the reduction of the blood pressure which has been recorded in human beings as the result of surgical interference with the neri ous system may be duc in some way, and in part at least to the resultant improvement of the circulation in the lidney There is no proof however, that this improvement does occur If the lou cring of the blood pressure in man is not due to improvement of the renal circu lacion then it must be admitted that in the dog the effect on the vasomotor apparatus of various surgical procedures on the neri ous system are for reasons unknown not as effective as in man This difference may have to do with the usual orthostatic position of man as compared with the natural horizontal position of quadrupeds lt is well known that especially in the early stiges after sımpatheu tomy in nian the blood pressure falls only or to a greater extent when the erect position is assumed and that it frequently recurns to the original high level when the patient is in the horizontal position The experiments on the animals do not in any was controvert the results that have been obtained so far by sympathectomy in the treat ment of hypertension in man It is possible that in some cases of human essential hypertension stimul from the central nervous sys temy play a part even if only a secondary one in elet ating the blood pressure It may be that this is the factor that is most commonly influenced by the usual medical or surgical treatment of essential hypertension and accounts for most of the fall of blood pressure that s produced by such treatments Unilateral nephrectomy for hypertension due to unilateral renal disease Reference has already been made to the production of experi mental renal hypertension in animals by constriction of the main artery of only one kidney and to the cure of the hipertension by the release or removal of the clamp on the renal artery or excision of the hidney with renal artery clamped at a time when the blood pressure is still considerabls eles ared The resultant recognition of the exstence of human hypertension issociated with unilateral renul disease especially unilateral chronic pielonephritis and the ususł accompanying renal vascular disease or any other pathologic con dition capable of producing the sanie alteration of intraren il hemo dy namics and the cure of the hypertension in some cases box ca Lision of the diseased kidney has also been mentioned in man the first type of unilateral renal disease that was incriminated was chronit Pyelonephritis and Butier was the first to show that the removal ·111 arterio IRI ATVE\T OF AIX PERIENSION of such a diseased kidney resulted in the prompt return of the blood pressure to normal Since then other intestigarors have removed a pyelonephritic hidney, when the other kidney was considered norinal and, in some instances the blood pressure returned to normal and has remained normal for as long as 6 years In man as in some dogs and frequently in goats sheep and rats the livpertension evidently may persist for a long time on the basis of unilateral renal disease In those cases in which the blood pressure failed to return to normal it may be assumed either that the remaining hidney was also diseased bue that the disease was not recognizable on account of the absence of renal excretory impairment or thre the residual hy pertension was not of renal origin in recent years there have appeared reports of cases in which hypertension was found associated with unilateral renal disease of other types and in which removal of the diseased kidney also resulted in the return of the blood pressure to normal Congenital abnormality with stenosis of one renal artery sclerotic narrowing of the orifice of one main renal artery caused by arteriosclerosis of the aorta itself or of the first part of the renal irtery arteriosclerotic stenosis in any portion of the main renal artery thrombosis of the aorta at the mouth of the renal artery or in the main renal artery aneurysm dissecting or otherwise of the aorta with compression of the main renal artery unilateral renal panvasculitis and extrinsic tumor pressing on a mun renal artery are all illustra tions of the types of unilateral renal disease associated with hyper tension that have now been observed in man The return of the blood pressure to normal as a result of the removal of such a diseased hodnev has already been reported in cases of human hypertension in which one hidney was diseased and the other obviously normal or not significantly affected The subject has been reviewed in great detail by Abeshouse who has gren a complete bibliography of the published work on this subject in personal conmunications to the author there have now been mentioned more than 30 unpublished cases in which nephrectomy for unilateral renal disease has resulted in a return of the blood pressure to normal for periods varying from 3 months to 6 years In most of these cases the disease is as unilateral chronic pyelonephritis with the usual intrarenal stenosing vascular disease that accompanies this condition In man when the presence of disease in one hidney is established it is often difficult to dererınıne with certainty whether the other kidney is affected and especially ·112 RENAL ORIGIN OF HIPLRTEVSIO u hether it is the seat of arterial or arteriolar sclerosis All studies of the presumably normal hidney including clearance tests of various linds for renal excretor function may give results that are within the limits of normal nevertheless this kidney may be the seat of considerable vascular disease it is impossible therefore to predict with certainty in human beings the probable effect on the Inper tension of the removal of one obviously diseased hidney If the other kidney is actually normal the probability is great in the light of the experimental studies on animals and the results already obtained from unilateral nephrectomy in man that the blood pressure will rerurn to normal and remain at thar level after the removal of the diseased kidney If the other hidney is known to be diseased or if its excrctory function is found to be someu hat impaired unilateral nephrectomy is not indicated as a treatment for the hypertensioul alone It should then be practiced only if it is considered advisable for the renal disease itself This is in complete agreement with the views of others If both lidneys are diseased then the excision of the more diseased organ for the purpose of alleviating the hyper tension is certainly not justifiable lle have found that in dogs constriction of the main artery of one kidney does not result in elevation of blood pressure if the urerer of the same lidney is occluded This would indicate that in humin Iv pertension presumably on the basis of unilareral disease of the urerer of this kidney is completeh obstructed there is some prob ability that the hypertension is not being caused by the involvement of this kidney and that the other kidney may be the cause as a result of disease without detectable disturbance of renal excretory func tion or thar the hypertension has some other cause In such cases therefore the removal of the obviously diseased kidney should be undertaken only because of the other symptoms and not for the purpose of reducing the hypertension in a few cases of human ! hypertension however in which a completels hy dronephrotic had ney 11 as remoed the blood pressure promptly returned to normal ind has remained normal for many months As in the case of many discoveries in medicin there is likely to follow an exaggerated enthusiasm for any neu procedure that offers a possible cure for a patriologic condition Unfortunately in soric cases of hypertension one hidney lias been remoi ed when it is not fulls established that the other kidner was normal This has resulted ·TRETIETO NI PRISIO of curing not only sn the failure of the blood pressure to fall frut sn some cases, cren in 3n 1kgrauation of the blood pressure renal failure and a faral outcome lo remove the more diseased of two diseised hud news for the purpose pertension is cert unlı not justa fible In animals with persistent hypertension due to lateral renal sschemia the surgical production of collateral circulation to the ischeme hidner has also resulted in the return of the blood pressure 80 normal but the few attempts to do this to the hunc in human cases of fix pertension have not ict been successful Houciet up (1) the present time the attempt to produce collateral circulation has been pracseed on only one hidnes in hypertensie human beings 133 which both kidners were presumabl discascd The difference be tween the results in man and animals is due pirtly to this but it is un doubtedly also due to the fact that in the dog the intrarenal vessels are not organicalls disessed while in an in most instances it is the intrarenal and even preglomerular arterioles that are affected An anastomosis of entrarenal and intrarenal vessels could therefore prove of little or no value unless the ischemia u ere due only to dis case of the larger intrarenal vessels or better to the e\frarenal portion of the renal artery The occurrence of such cases in man has already been reported but the diagnosis in life is difficult ·SUMNVIARY OF THE SIMILARITICS AND DIFFERENCES BCTIVCEN HUMAN ESSLNTIAL AND EYPERI MENTAL HL VAN HIPIRTENSION In lo excellent recent books on the subject of hypertension almost diametrically opposite viets hue been expressed about the mechanism of the elevation of the blood pressure Goldring and Chasis (2) concluded that the weight of the evidence was against the identity of the mechanism in human essential and cxperimental renal ly pertension Ther postulated the existence of a primary hu moral mechanism of unknown origin to which a renal component may contribute a secondary and accessory effect Braun Alenendez and collaborators (4) including Dexter who translated the book into English have adopted the view that human essential hypertension in both its benign and malignant phases is of renal origin I believe as they do that experimental renal hypertension does faithfully repro duce human essential hypertension in niost respects in experimental renal hypertension is in human hypertension there may be no significant disturbance of renal escretory function the benign phase or there may be pronounced renal excretory func tional disturbance Isith uremia the malignant phase dependin, entirely in experipienral hypertension upon the degree of constric tion of the main renal arteries An increase in the concentration of guanidine in the blood of animals and of man in the malignant phase of the hypertension has been demonstrated, but this has little or no significance with relation to the hypertension because it occurs also in bilaterally nephrectomized animals that have azotemia but no Ins pertension As in human hypertension so also in expenmental renal ly pertension carduc action is increased but cardiac rate and out put, volume viscosity and peripheral flou of blood and venous pressure remain unaltered Pulmonic arterial pressure remains un altered, in both man and animals den chc hypertension is uncomp), cated by left ventricular failure as indicated by a normal right heart In the benign phase of hypertension in both man and anmals cardiac hypertrophy de elops affecting mainly the left sentricle and medal lny pertrophy of the arterial vessels also occurs in both in the malig (117) ·SUVAR 115 nant phase in both there are in many organs the identical typical vascular lesions arteriolar necrosis fibrinoid degeneration and necro tizing arteriolitis With feu exceptions the response to medical therapeutic meas ures of great variety is the same in both human and experimental renal li pertension In both man and animals hypertension associated with unilateral renal disease may be cured by the excision of the diseased kidney provided the other hidney is normal Bilateral neph rectomy does not result in a rise of blood pressure in either man or animal I have personally obsen ed one patient from the day when her only hidney was removed until death six days later with out noting any elevation of blood pressure despite the rapidly de Icloping profound azutemii Sympathectomy partial or extensa e may result in at least a temporary fall of blood pressure in human hypertensives without affecting the primary cause of the hyperten son but there is little or no effect as a result of this procedure in inimals Whether this difference exists because the dog does not assume the orthostatic position with its consequent hemodynamic effects on the vasomotor apparatus cannot be stated with certainty at present The fact that after si mpachectomy the blood pressure falls profoundly in some cases only when the patient is in the vertical position that it rises again when the horizontal position is assumed and that it returns to the original high level in a considerable per centage of the hypertensive patients favors the probability of a renal humoral mechanism in which the effect of the vasoconstrictor substance is presumed to act directly on the musculature of the peri pheral arterioles and not by way of the i asomotor nerves This is in Ieeping with the conclusions of Prinzmetal and Wilson and of Pickering as a result of their studies of the pathogenesis of human hipertension The frequent fall of blood pressure in the late stage of pregnancy in animals with experimental renal hypertension remains as uncx plained as a similar fall which has been observed by obstetricians in some hypertensne pregnant women The observation of pols dy psa and polyuria in rits with experinental renal hypertension has not been emphasized in human his pertension and bas not been reported in hypertensie does although the diuretic cficct of runin injected intravenously into dogs has been mentioned Thts descries inort investigation ·arters 116 RIVAL ORIGIV or HYPERTOSIOS Renal blood flow is reduced in most cases of hypertension in man ind in experimental renai hypertension in inimals The indirect studies of blood flow through the kidney in min do not demonstrate clearls the physiological effect of the sclerosis of the afferent arterioles be ciuse the presumible y asospasm of the cfferent arterioles which results in a high glomerular filcrition fraction tends to mask it al though the interference with afferent flou is definite in the animals and obuously brought about by the constriction of the main renal set the same indirect signs of efferent usospasnı ind high glomerular filtration fraction have been reported in the ho perten sue animals in both man and anals tlus simular cffcct ml be secondary to the primir humoril mechanism of renal origin which results from the hemodi namic disturbance produced by the pre glomerular vascular discise ind the constriction of the mun renal arter respectively The presence of resin has been demonstrated in the ren al venous blood of ischemic i idness of man ind and ind in intravenous injection of renin or hypertensta lso gnes the indirect eudence of efferent i sospasm Renin his been demonstrated in the systeme blood of recent hypertensie dogs and in patients with my pertension due to cute glomerulonephrius set the failure to demonstrite it in the sistemic blood in benign human ind in experimental renal hyperren sion may be on because the amount of blood used for the rests has been inadequate or because of the lack of sensıtı iti of the method for its detection 11 hether the humoral mechanism is citectie w only the relativ els cute stages of hypertension and whether as has been suggested there is in the later stages 1 greath increased sensi tivity to hipertensin remun to be determined Iliese murers de serve much more study The Compire summary of the pharma cologic effects of rein and of the circulatory di ninnes in Irxperten sic animals gn en in Table 3 shows that the parellclism is striking but this does not mean that the chemical mednatwn of In pertension by means of renın has been proi ed either for animal or man The pre ticipation of other pressor substinces suchi 15 epinephrine 63 rumine pitressin and guindu can be excluded from serious consideration The esidence for this has alrcids been gucn As in human his pertension to also in esperimental renai fuper tension the les el of blood pressure tends to go higher in his perten sie anmals that gain weight but it has not been proved that a high ·SUHU IRI protein dict or the ingestion of itrge imount of urca increases the blood pressure an min or anmol Although the clerice sistolic blood pressure of hperthi rod is in man is relics cd bs thus cordectomet it is doubtful that any of the known endocrine organs plus primary part in ciher essential hypertension associated with uscular disease in min of in experi mental renal hypertension in inals There is no proof that the hi pophuss plays 2 put in the pathogenesis of renal hypertension but there we definite indications that the adrenal cortical hormones dlo play a secondary part in the development and muntenance of cipermenral senil and perhaps of human hipertension The adress! cortes plius a part in influencing the production of hypertensinogen I his action is cu ident's Cyerted bs in effect on the iner which is probably the source of this protein There are so many similarities beru cen hus 113 essencial hyper tension associated with vascular discase mnd experimental renrl h per tension that it does not seem unreasonable to suggest that the former 121 also be of renal origin All of the more recent studies by Shorr and collaborators b Shiples ind Ilelmes by Truera and collabora tors by Selve ind collaborators and bs Hartrofe sell point directly to the central position occupied by the kidney in the pathogenesis of experimental and probably of human essential hipertension (ven of the renal origin of this form of renal hypertension should become established it would still remun necessary to determine the cruse of artern and artertotas sclerosis which when it affects the lidney to a sufficient degree inates the sumoni mechanısın of the hyper tension The faslure of animals to develop u despread recrul and artcriole scleroxis cien rfter leirs of hipertension without accum panungsparment of ren il cacrctor function (the benign phase) dues not lend support to the sleu that hipertension is 2 sufficient condition for the detersiunition of ascular sclerosis it must be ad med hou ever this this 1133 Shein onls that the blood vessels of inamls vc les schsite than hunn i essels to the effect of increased INIT31 34cular rension stone allough the pear to be csen more sensite to the conditions as huel determine the necrotstag scular changes of the maltynant phase of hipertension on that the probable prmırı sigmouince of renal artersland verilir sclerosis fras been indru itew hit the currerimental studies the cause of the vascular disease has become the most uportant problem for in

·118
RENAS ORIGIN OF HIPERTEVSOV
i estigation The recent contributions to this subject of Selve an
collaborators ind of Ilartroft mu prove to be a step in the rig!
direction

·BIRLIOGRAPHIE i Fishberg A A1 Hypertension and Nephrttış Lea and Febiger Phila delphia, 1939 * Goldring Wand Chasis H Hypertension and Hypertensi e Dis ease The Compionwealth Fund Neu York 1941 ? Page H and Corcoran AC Arterial Hypertension Its Diagnosis and Trearment, The Year Book Publishers Chicago 1945 4 Braun Alenendez E Casciolo JC Leloir L F Munoz J M and Taquini A C (Translated bs Lexis Dexter) Renal Hyperten $1on Charles Thomas Publisher Springfield 1946 5 Selve Hans The General Adaptation Syndrome and the Diseases of Adaptation The Journal of Clmcil Endocrinology 6 117 1946 6 Trueta 3 Barclay AE Daniel P. Franklin & J and Prichard MI AL L Studies of the Renal Circulation Blackwell Screntific Publications Oxford 1947 * The references to the publications of most of the authors mentioned ma chis lecture are listed in the review on the Renal Origin of Hyperten sion by Harry Goldblatt Physiological Relleus 27 No 1 120 165 1947 and the remainder can be found in the books mennoned above

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·IVOLI А chemical properties of 99 Acer Icholine 18 treatment of hy phi solo.ical properties of 98 pertension 91 specificits of '99 Adaptation sindrome and patho titration of 29 genesis of hipertension #7 Unit of 95 Adrenal effect of ligation of hilar Inciscrum nephrotouc and cu eins of on blood pressure 41 perimental hypertension Adrenal correr orta abdominal effect of con influence of on production of Ytriction of on blood pressure 77 hypenensinagen 117 Irginine in hipertensin + relation of to experimental renal Irteriolar necrosis hypertension 19 11 molignant las pertension 11 Adrenal medulla effect of Cichon pathogenesis of ? of on experimental renal hiper Irteriolar sclerosis renal in pth tension 46 ngenesis of hipertension 11 Adrenalectomy bilateral Artcriolitis necrotizing 115 effect of an action of hype ten Arteriolosclerosis renal in patho sun 18 Senesis of hypertension 344 3, 137 effect of on csperimental renal hipertension 46 47 48 SO SE Ascosty acid in treatment of hy effect of on hypertensinogen in pertension 106 blood 72 Acropine effect of on actson of h Adrenalin 36 74 83 pertensin 77 Afibrillar cells of sustaglomerular Alutemia after bilateral nephrte tom 11 apparatus and pathogenesis of hypertension 88 B Alanine in his pertensin 73 Whum sun um an treatment of hi Bups: ot hodncı in essenart hs pertensions 90 pertensson 37 Imine oxidase in treatment of hs Biotin in treatment of hypertens on 01 pertensson 107 103 105 Aminopeptidase Blood fou renal in un perrens in action of renin 67 116 in action of hypertensinase *} Blood enous reng asocoNSESSE 104 is action of ) Anastomoses arterios enous intra Tengl effect of on renal aircut С tson 87 {alcium rerention of his perten Anastomosis arterios enous rens $ 109 for production of hipertensin } (uhou peptidase and hipertens Ingrotonin see his pertensin 175€ 678 Anti ens me and antirenin 98 (rotu bodies effect of excusion of Inghormone and antirenin on action of hu pertensin 8 Antipressos substances 101 (artritid Sisus and cypermintal Antirenin 96 real hypertension 35 ·Sion, 114 122 REVAL ORIGIT OF HYPERTENSION Cellophane membrane perirenal und production of experimental Dihu droxyphenylalanine and my hypertension 25 pertension 101 Diodrast clearance in hunian hi (holesterol in p/351111 in cyperi mental renal hipertension ? pertensson 86 (holine chloride in treatment of Distemper effect of on experimen tal renal hypertension 36 hipertension 91 Dolphin renın in kidnes of $9 (hromatograph in purification et hypertensin 75 E (lamp renal arter for production of hipertension 1] I lectrodialysis in purification of Clamp holder 14 hypertensin 75 (learances in experimental renal flectraphoresis and hypertensin hipertension 76 2- 7+ Cocaine effect of on action of hs Embolism renal and experimental pertensin 74 77 hypertension 8 Collodion membrane perirenal and Cphetonine porentiation of hiper production of experimental h rensın Bi 74 pertension 75 Ipinephrine { ompression of hidness and exper and experimental renal hyperten imental hypertensson 8 (onstriction potentiation of hypertensin bu of aorta effect of on blood pres 79 sure 22 Ergotamine effect of on action of of both main renal arteries effect fypertensin 77 of on blood pressure 16 ?? Ethylamine formation of in prep of one main rena) arter effect aration of renin 69 of on blood pressure 15 Luisceration, abdominal effect of of splenic arten effect of on on experimental renal hiperten blood pressure 23 Son 66 78 (clohexandione in tretmicnt of Titracts of hidney in crecient of hipertension 103 hypertension 92 ( isteine in hypertensin 74 F (tochrome Coudized effect of on action of hipertensinase 74 Fibrinod degeneration of arteri ( urochrome ovdase in ischemic oles in malignant hypertension hidne tissue 85 115 Fiscula ureteral enous effect of D on expenmental renal hyperten sion 94 Deamination of pressor amines 10 I ournean s solution (9331 ) Decarbori Jation of dihydrou effect of on hypertension 1 pheni jalanine 101 cffect of on action of hyperten Deneration Sin 77 of heart, cffect of on cyperimen cal renal hypertension, 39 renal effect of on experimental renal hypertension 39 Clomerulonephritis and esperimental hypertension, 7 Desory corticosterone and produc and human hypertension 4 tron of experimental hiperten perfusion of kidnes 87 sion 10 ·INDET 123 111 Glicine in hypertensin 75 Conadectomy effect of on esperi Diental renal hipertension 44 66 (raft of ischemic kidnei pressor 1ction from (ranular cells in justiglomerului apparatus 88 (uinidine in blood in malign int phase of hypertension 15 116 Surgical treatment of 100 cyperimental neurob CIC tomical changes in }} cyperimental renal benign phase of 'I effect of dict on 107 effect of occlusion of m1011 Tennl veins 5? cndocrinogenic michani in H Hepareccom effect of on iction of hypertensin 78 Histidine in hypertensen 74 75 Humoral mechanism of experiment tal renal hy pertension si Hydrous tyramine and hyperten sion 101 102 Hipertensin 58 73 Chemical properties of 7) in the blood 66 pharmacological effects of 17 phiu stological properties of 6 preparation and purification of 75 Lit of 79 Hypertensin.ase 60 71 80 81 82 04 an renal enous blood 0+ in systemic blood 81 in various organs 81 mechanism of action of x? nature and properties of 80 tinit of 81 Hypertensinogen 60 70 104 disappearance of from plasma 67 in blood in tachyphylactic stits 72 Reparation of 7? quantity of in systemic blood unit of 71 Ilypertension henign phase of 134 diastolic and su stolic cyperiment tal 20 essential 3 6 8 114 concentration of urine in in pregnancy 115 malınant 114 medical treatment of 90 humoral mechanism of 51 in monkei 0 in pregnancy 113 nalignant phase of 27 30 neurogenic mechanism in 39 pathologic changes in rissies 29 30 production of 6 19 18 other changes in 34 circa clearance in 26 Hyperthyroidism 117 Ilypertrophy carding in hyperteni sion 114 Ilypophy sectom cifect of on experimental renul hypertension 40 45 cffect of on hypertensinogen in the blood 77 llipophisis ind pathogenesis of renal hypertension 117 1 Infiction effect of on experimen til renal hypertension 16 Instruments for application ol clamp on renal arters 14 Ischemia renal cortical ncur) ACNIC R7 Ischemic kidney pressor substance in perfusite of 's, Isonmylimine formation of preparation of senin 67 Isoleucine in hypertensin 7 int j Jurraglomerular apparatus and pathogenesis of hypertension 88 ·12+ RIVAL ORIGI OF MIPIRTENSIO. sen 117 K for hipertensson associated with hidncis unilater il renal disease 110 compression of and experimental 117 hipertension 7 \ephirotouc antiserum ind e per embolism in und e perimental mental hypertension hypertension 8 Vephrotouc substances and exper irradiation of (rus) and es imental hypertension 7 perimental hypertension 7 Veurogenic mechanism of hyper passie hyperemia of and experi tension 107 mental hipertension \icotinic acid in treatment of hi pertension 91 L Vitrites in treatment of hyperten slon 91 i au en Trendelenburg technique for test of vasoconstrictor stabs 0 stances) Okclusion I eucine in hyperrensın of mun ienal irrers and experi I spid in plasma in experimental renal hipertension ? mental hypertension I ner of renal pedicle and ciperimental hipertension & and production of hipertensino Opothempi renul in treatment of cicision of cffect of on action hypertension 97 of lui pertensini P I snc in hypertensin 79 Pancrente tom effecr of on actwn of hyperten M Vannirol hevnitrate in treatment cffect of an experimental renal of hipertension 90 hypertension 44 66 Sembranes perirenal and produc Pithogenesis of experimental renal tion of hipertension ? hypertension 37'91 With injection of in trearment of Pathologic changes in experimental hypertension 96 renal hipertension 19 Vonher production of experimen Pepsin tal renal hipertension in ? action of on hypertensionen + Vorphine effect of on experimen cffect of on blood globulin 108 tal renal hipertension 90 104 Pepsensin 103 N Pepridase and hypertcrunase 1 lecross arteriolar experimental Perinephritis, production of cyper production of 31 mental hypertension is ? Phenol oudase and hypertension Vecrotizing arteriolitis 111 83 Tephrectomt bliteral effect of on blood pressure 6 Piperidonethi benzodiovane effect of on cıperimental renal (9331) effect of on normal and cleiated blood pressure 5 hipertension Pitressin and experimental renal Nephrectul ulatcral and hipertension in animals 6 hipertenston 16 99 116 Pitutar ablation of effect of on of ischemic hidnic effect of in action af hipertensinh blood pressure 10 SIN 76 ·1 DCY 125 Pituitrin (see pitressin Policistic disease of kidneys and hypertension + Potassium thiocyanate in tre itment of hypertension 90 92 Precipitin and antirenin 99 Pressor amines des elopment of in preparation of renin 6' 10 Pressor substances in blood 101 Proline in hypertensin 74 7) Prorenin 84 Proteases inactivation of hyper tensın by 74 Protein of plasma in experimental renal hypertension 3) Psallioata campestris tyrosinase ob tained from 7+ Pulmonic arterial pressure in hi pertension 11+ Pyelonephritis chronic and hypertension + 11? perfusability of hidnes in 97 urulateral and human hyperten sion 110 111 in humoral mechanism of ev perimental renal hypertension 59 60 in hidncı of Dolphin 8> in renal 1 enous blood 116 in sistemic blood 116 intravenous injection of effect of on surface temperature of shin 6+ mechanısın and site of formation and release of 8+ methods for the assal of 69 parenteral injection of treatment of hypertension b 96 pharmacologic effects of 68 physiological properties of 67 precursor (prorenin) 8+ pressor response to intravenous injection of 67 specificity of 61 unit of 69 soconstrictor action of 10 Rice diet in treatment of hyper tension 109 S Quunones in treatment of hyper tension 107 R Renal arteri main constriction of bilateral 18 constriction of unilateral 1) ligation of branches of 9 occlusion of 9 Renal function in experimental renal hypertension ? Renal veins occlusion of effect on fyperimental renal hipertension Renin 61 action of 6 action of on hypertensinogen "} nctii ator 70 chemical properties of 61 concentration of Sistemic venous blood 6) fate of in the body a hemodinamic effects of 68 Sction of anterior nerie roots effect of on experimental ren 11 his pertension 43 Sepia officinalis amino oudase from Iner of 74 Serine in hypertensin 7> Shock hemorrhagic effect of 01 hipertensinogen in the blood 72 Sith membrane perirenal and pro duction of experimental hyper tension 2 Sodium balance in hypertensne rats 109 Sodium bromide in treatment of hipertension 91 Splanchnicectomy effect of on action of hyperten sin 78 effect of on experimental renul hypertenston 41 Splenectomi effect of on experi mental renal hypertension 67 in ·126 RENAL ORIGIN OF HIPERTENSION Spinal cord destruction of effect Tirosinase effect of an action on experunental renal hyperten of hypertensin 10) Sion 66 Sulbesterol effect of on action of Tyrosine in hipertensin 74 75 hipertensin 77 SPS (sustained pressor substance) Lolaceral renal disease and hyper 106 107 tension 11 Sustained pressor substance(SPS) Urea în blood effect of injections 106 107 of renal curract on 93 Surgical trearment of hypertension I remia 109 in experimenmt renal hiperten Sumpithectomy sion 27 partial effect of on der elopment in human hipertension 11+ of cxperimental renal hiper Ureteral senous fistula and hyper tension + tension 9+ total effect of on experimental Ureters Occlusion of and export renal hypertension 109 110 menral hipertension 7 Lrine concentration of in even T tral hipertension V Tachyphylaxs 61 + 7 zhadiastase presser substance pro Valme in hypertensin /> cacing properties of 104 isoconstrictor substances 10 Testosterone effect of on experi Vaso excitor material (1 E) 10 mental renal hypertension 109 aso depressor material (TDV) Thyroidectomy 10 effect of an experimental renal DV 10) hypertension ++ Dli ondase 10 cffect of on hypertension due to Vegecablu ols in treatment of ev hyperthroidism, 11% perimental renal hypertension Transfusion from hypertensisco) 108 normal dog 56 VTV 105 Treatment of hypertension eratrum viride in crearnient of surgical 109 hipercension 91 medical 107 Ieritol potentiation of hyperten Tripsin pressor substance produc sin bi 74 1711 (1jso inhibitor material) 104 11properties of 104 Sum album in treatment of hy Tryptophane in hipertensin 74 pertension 90 Tung oil in treatment of hiper Vitamin in treatment of hs per tension 108 tension 105 luphold vaccine Itin B Complex in trement effect of on eepenmental rens! ot hypertension 105 hipertenyon 36 Vitamin D in trcatment of hiper in treatment of human hyperten tension TOR Iitamin E, in treatment of in per Turimne 74 tensioni 104 action of in hypertensie anu inal 36 formation of during production latermelon seed extract in tre it of renit, 67 ont of hipertension 90 sion 96 >

·PEACOL
7 bis Book
THE RENAL ORIGIN
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HYPERTENSION
BY HARRY GOIDBI ATT MD CM
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