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Studies in experimental hypertension Salter, James Morley 1950

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STUDIES IN EXPERIMENTAL HYPERTENSION  James- Mar ley Salter  A thesis submitted i n p a r t i a l f u l f i l l m e n t of the requirements f o r the degree of  MASTER OE ARTS in the Department of Biology and Botany  ' '  ABSTRACT The effects of dietary and hormonal factors upon the blood pressure of male Wistar rats were investigated. 1.  Desoxycorticosterone acetate was found to increase the blood pressure -only i n the presence of excess dietary salt.  2.  Estrogen overdosage produced hypertension i n r a t s . Castrate animals were more sensitive to the effects of estrogen.  Estrogen overdosage aggravated  experimental  hypertension induced by n u t r i t i o n a l choline d e f i c i e n c y . 3»  A period of n u t r i t i o n a l choline d e f i c i e n c y was followed by hypertension.  Desoxycorticosterone accelerated the  development of hypertension i n choline deficient animals. 4.  Hypertension developed  i n r a t s 2 months after a pro-  longed period of i n a n i t i o n . Antihistamine was found to induce profound variations i n the blood pressure of male r a t s . 6.  Rats pre-treated with desoxycorticosterone acetate showed a greater pressor response  to adrenaline than  normal intact r a t s . 7«  Desoxycorticosterone and antihistamine were found to  f a c i l i t a t e the occurrence of the Trueta shunt.  ACKNOWLEDGEMENTS  The Author wishes to express his thanks t o : Dr. A.H. Hutchinson, carried out •  under whose authority this work was  Dr. John Allardyce, under whose personal d i r e c t i o n t h i s investigation was made, and whose constant advice, patience and enthusiasm made this work possible. Dr. E.C. Black, whose interest, advice and suggestions were invaluable. Dr. Wm. C. Gibson, M.D., Dr. Wm. M. McCallum, M.D., Dr. F.L. Skinner, M.D., Dr. D.S. Munroe, M.D., Dr. H. Taylor, M.D., whose co-operation and technical advice constituted an important contribution to this investigation Mr. R. Rixon f o r the complementary research information he made available. Thanks are equally due t o : Mr. E . Eung, for h i s w i l l i n g donation of time and valuable assistance. Miss. L. Cowie, f o r her gracious aid i n procuring scarce material. Mr. G. Morrison and Mr. H. Radford f o r their co-operation as experimental subjects.  TABLE OF CONTENTS  The E f f e c t of DCA on the Development of Hypertension Secondary to Renal Damage <^tnd) Induced by Choline Avitaminosis. 7 36 A^ (jEntroduc tion  36  /  ? T l ) Methods / (2) Results j (3) Discussion (4) Conclusions (5) Summary  A  36 37 42 43 43  The E f f e c t of Starvation on the Blood Pressure of Wistar Rats  44  Introduction  44  Methods Results Discussion Conclusions Summary  45 45 47 48 48  The E f f e c t s of Antihistamines on the Blood Pressure of Male Wistar Rats 49  3>  C  Introduction  (1) (2) (3) (4) / (5)  Methods Results Discussion Conclusion Summary  49 50 53 58 62 .6.4  The E a c i l i t a t i o n of the Trueta Shunt by Desoxycorticosterone Acetate and by Antihistamine ^  !_Introduction  65 65  (1) Apparatus and Methods 65 (2) Results 67 (3) Discussion 67 / (4) Conclusions 68 jL (5) Summary 68 The Effect_of_Desoxycorticosterone Acetate^S*f) (AaSiM^tration^on the Pressor Response to Adrenaline i n the HaT 69 QO)  pEntro due t i o n  69  (1) J2) ,3) i(4J 1(5)  Methods Results Discussion Conclusions Summary  Synthesis Summary Literature Cited  1  INTRODUCTION A.  H i s t o r i c a l Review Hypertension constitutes one of the most serious problems f a c i n g c i v i l i z e d man. Chasis (25)  Goldring and  i n 1944 estimated that i n the United States  this condition accounts annually f o r more than  one  third of the t o t a l number of deaths. Richard Bright (5) i n 1827 pointed out that an enlarged heat and albuminous urine accompanied a diseased condition of the kidneys and since that day the kidney has been recognized as an important i n the etiology of hypertension.  It i s now  factor  clear that  organic renal l e s i o n s precede the onset of hypertension i n a considerable number of cases, but there i s a large group of cases where organic r e n a l disease i s not an obvious precursor of the hypertension. i s comprised  This group  of the cases of so-called essential hyp-  ertension. The work of Goldblatt et a l (24) i n 1934 marked an epoch i n the experimental investigation of experimental hypertension.  They showed that transient  hypertension could be produced i n dogs by p a r t i a l l y c o n s t r i c t i n g the renal a r t e r y . By moderately  constric-  ting both renal a r t e r i e s , or by c o n s t r i c t i n g one renal  2.  artery and removing the contralateral kidney, they were able to produce chronic hypertension. Goldblatt's work was well substantiated by other investigators (Wilson and Pickering ( 6 8 ) , Wilson and Byrom ( 6 9 ) , Verney and Vogt (65)  ) who found too  that the ischemic kidney produced hypertension even when completely denervated.  They concluded from these  experiments that the hypertension was caused by the formation i n the ischemic kidney of a pressor which escaped  substance  into the general c i r c u l a t i o n .  In 1946 Cruz - Coke (11) showed that lack of oxygen i s of v i t a l importance at c e r t a i n stages i n the formation o f pressor substance.  Anoxia presumably dev-  elops with decreased blood flow i n the kidney. At the present time hypertensive patients are c l a s s i f i e d into two main groups, namely; those i n whom organic renal disease i s recognized by a l l to be the cause of the hypertension (secondary  hypertension)  and those i n whom no organic renal disease i s apparent, and the cause of the hypertension i s obscure or primary hypertension).  In secondary  (essential  hypertension  the c o r t i c a l anoxia i s caused from the outset by organic change but the etiology of the t h e o r e t i c a l renal c o r t i c a l anoxia of essential hypertension has remained unknown.  3.  B. Theories on the E t i o l o g y of Hypertension The number of cases of hypertension i n man that can be attributed to a reduction i n c a l i b r e of the renal a r t e r i e s by mechanical obstruction ( i . e . atheroma, thrombi) i s small and as an e t i o l o g i c a l factor such obstruction can be discounted. (1) Vascular Origin Goldring and Chasis (25) consider that renal a r t e r i o l o s c l e r o s i s with resultant renal c o r t i c a l anoxia does not precede the development of e s s e n t i a l hypertension, although i t i s a concomitant hypertension.  of consequence of  Castleman and Smithwick (6) i n 194-3  ex-  amined renal biopsy specimens from one hundred hypertensive patients, and concluded that the evidence of renal vascular disease i n more than one h a l f of the cases inadequate  was  to prove t h i s to be the sole factor i n prod-  ucing high blood pressure. Work done i n t h i s laboratory i n 194-8 by Logan (37) showed that there was no marked vascular degeneration i n kidneys of r a t s hypertensive three to eight months.  However, ffloritz and Oldt (38) and E l l i s  (18)  reported that post-mortem findings i n cases of essential hypertension almost constantly revealed intra-renal vascular damage as w e l l as widespread a r t e r i o l a r  s c l e r o s i s . Child (8) suggested  i n 1938 that although the  i n i t i a t i n g factor i s unknown, induced a r t e r i o l a r disease might account for the maintenance of hypertension. (2) Hormonal Origin. The role of the adrenal cortex i n the induct i o n and maintenance of hypertension i s , at present, imperfectly understood. It's secretions however, are essential to the experimental establishment and maintenance of high blood pressure (4, 13, 23, 40). In 1942  Selye (46) produced nephrosclerosis  and cardiac hypertrophy  i n chicks by overdosage with the  adrenal c o r t i c a l hormone desoxycorticosterone.  Henal  lesions included cloudy swelling of the tubules and hypertrophy and hyperplasia of both p a r i e t a l and v i s c e r a l layers of Bowman's capsule.  The blood vessels appeared  i n t a c t and blood pressure changes were not s i g n i f i c a n t . Darrow and M i l l e r (12) i n 194? observed that DCA  overdosage i n r a t s produced necrosis of the cardiac  musculature  and hypertrophy of the renal tubules. Selye et a l (47) i n 1943 produced experimen-  t a l malignant hypertension i n r a t s receiving excess dietary s a l t by administering to them large doses of desoxycorticosterone.  Later Selye (48) induced hyper-  tension with kidney disease by subjecting rats to  5* damaging agents such as prolonged exposure to c o l d . Hypertrophy of the adrenal was a c h a r a c t e r i s t i c feature of t h i s  treatment. Corcoran (9)  i n 1948  pointed out the fact that  patients manifesting "Cushing's Syndrome" are generally hypertensive and show functional l e v e l s of blood flow, glomerular f i l t r a t i o n , and tubular secretion'*to a loss of $0% of the functional and presumably structural  integrity  of the kidney. Dougherty (14) observed  that a r t e r i o s c l e r o t i c  lesions similar to those produced by administration of large amounts of desoxycorticosterone acetate were observed following d a i l y treatment of mice with adrenotrbphic hormone f o r a period of weeks. The tendency of Addisonians to develop hypertension after replacement  therapy with desoxycorticosterone  acetate (DCA) has long been recognized (49). General reports also indicate that the ACTH used f o r a r t h r i t i c therapy frequently produces hypertension.  Nephritis and  hypertension i s a common occurrence following treatment of a r t h r i t i s with cortisone (Knowlton et a l , 3&)» The precise nature of the part played by the adrenal gland, as previously mentioned, i s not known. However, the evidence that has accumulated i n recent years indicates that i t i s undoubtedly involved i n the chain of  events that terminates i n hypertension* (3) Nervous O r i g i n . The p o s s i b i l i t y that psychogenic r e n a l vasocons t r i c t i o n may be a factor i n the etiology of human essent i a l hypertension has been recognized by various workers, and a consideration of the psychological factors i n essent i a l hypertension i s given by Weiss (67).  Nevertheless  there i s considerable difference i n opinion as to whether the nervous system i s of e t i o l o g i c a l importance  i n this  condition. Garai (22) found that shipwrecked  s a i l o r s who  had suffered prolonged immersion tended to have a raised blood pressure and that they showed increased vasomotor reactions (as gauged by the cold pressor t e s t ) . He suggested that the r e f l e x c o n s t r i c t i o n of the vessels of the kidney, known to be caused by exposure to cold, had played a part i n producing hypertension.  Medoff and Bongiovanni  (39) and F a r r i s , Yeakel and Medoff (19) found that they were able to produce hypertension i n r a t s by stimulating repeatedly with intense noise.  Heymana (33) and Grimson,  Bouckaert and Heymans (29) record the production of sustained hypertension i n dogs from which they had removed the moderator nerves and the entire sympathetic  nervous  system, with the exception of the ennervation of the kidneys and adrenals.  Subsequent denervation of the kidney  resulted i n restoration of normal blood pressure. a) Renal C i r c u l a t i o n . Trueta, Barclay, Daniel, F r a n k l i n and Prichard (31) i n 194-7 made an important contribution to the physiology of the kidney and to the study of the nervous element involved i n e s s e n t i a l hypertension.  They discovered  that the blood reaching the kidney has two potential routes through that organ and, according to the circumstances, i t may pass almost exclusively by one or the other of these routes, or i n varying proportions through each of them.  The two routes diverge when the afferent a r t e r i o l e s  of the juxtamedullary glomeruli leave the interlobular arteries.  One route, the medullary, continues through the  juxtamedullary glomeruli, the efferent vessels of -these glomeruli and t h e i r derivative vasa recta, to the i n t e r lobular veins.  The other route, the c o r t i c a l , continues  through the interlobular a r t e r i e s , to the afferent arteri o l e s of the remaining glomeruli, these glomeruli themselves, t h e i r efferent vessels and the c o r t i c a l i n t e r tubular c a p i l l a r y network and f i n a l l y through the veins draining this network, into the interlobular veins. In the normal kidney the medulla i s poorly supplied with blood and the c o r t i c a l c i r c u l a t i o n predominates.  However,  under c e r t a i n conditions the medullary c i r c u l a t i o n predominates while c i r c u l a t i o n through the cortex a l l but ceases.  8.  The evidence i a aa follows The outer layers of the cortex of the kidneycan he blanched by stimulating the peripheral end of the cut splanchnic nerve, by stimulating the nerve plexus surrounding the renal artery, by i n j e c t i n g adrenaline, p i t u i t r i n or p i t r e s s i n and r e f l e x l y , by stimulating the central end of the cut s c i a t i c nerve, or placing a tourniquet round the thigh f o r some hours.  Sectioning of the  splanchnic nerve causes a flushing of the cortex and abolishes r e f l e x e f f e c t s . It i s d i f f i c u l t to evaluate the significance of t h i s work. - It i s pertinent however that i n the kidneys of e l d e r l y human subjects, and those suffering from hypertension, many of the juxtamedullary degenerate type.  glomeruli were of a  It seems as i f one p a r t i c u l a r c a p i l l a r y  channel i n a glomerulus can become wider and wider  ow-  ing, i t i s suggested, to the s t r a i n of repeated d i v e r s i o n of blood through t h i s part of the kidney, ^  u n t i l the  glomerulus i s no longer a functioning mechanism.  A true  short c i r c u i t of this kind i s presumed to be v i r t u a l l y out of control, so that unless a person with widespread degeneration of this type had high blood pressure, he might have very l i t t l e c o r t i c a l c i r c u l a t i o n .  I t i s sugg-  ested by Trueta et a l . that t h i s discovery points the way to a r a t i o n a l explanation of the way i n which psychologi c a l factors contribute to the induction of e s s e n t i a l  hypertension. So f a r as experimental hypertension i s concerned, i t i s suggested that c o r t i c a l ischaemia i n the intact animal, brought about by s t i m u l i of intense r e f l e x or emoti o n a l o r i g i n , or more e a s i l y i n susceptible subjects, i s equivalent to the Goldblatt clamp, and that conversely, the l a t t e r acts i n virtue of the jschaemia which i t supposedly induces i n the cortex. ( 4 ) The Nature of the Renal Pressor Mechanism. Investigators seem to be agreed that hypertension of renal o r i g i n i s due to some humoral pressor substance formed i n the kidney, but i t has not been d e f i n i t e l y established where i n the kidney t h i s substance i s produced. Opinion favors the r e n a l cortex as the source of pressor substance. Goormaghtigh ( 2 6 , 2 7 ) has described granular, a f i b r i l l a r c e l l s i n the walls of the a r t e r i o l e s of the renal cortex and i n the juxtaglomerular apparatus, and as he found that these c e l l s were larger and more numerous i n experimental animals with renal ischaemia, he suggested they secreted and liberated a pressor substance. Goormaghtigh ( 2 7 ) also observed the enlargement  of these  c e l l s i n the f a t a l crush syndrome. Eaufmann ( 3 4 ) found hypertrophy of these c e l l s i n the kidneys of patients with hypertension.  Friedman and Kaplan (21) believe, on the  10  other hand, that the pressor substance  i s formed i n the  c e l l s of the proximal convoluted tubules. It has long been known that a substance  called  renin, elaborated by the kidney, will,, causec a r i s e i n blood pressure.  This substance  i s apparently an enzyme  that acts on a plasma g l o b u l i n ( d ^ globulin) to produce a pressor substance called hypertensin.  The role renin  plays i n e s s e n t i a l hypertension i s not clear.  Repeated  injectipns of i t e l i c i t a progressively decreasing response (tachyphylaxis) and i t cannot be regularly found i n the blood of chronic hypertensives (45). Wakerlin e t a l . (66) conclude that there i s no c o r r e l a t i o n between the renal r e n i n concentration and the l e v e l of experimental r e n a l hypertension, either chronic or malignant.  Work i n recent years has indicated that  other vasodepressor  and vasoexcitor p r i n c i p l e s may be i n -  volved i n hypertension but the nature of these p r i n c i p l e s and their mode of action i s , as yet, obscure (32, 45, 53, 66, 76)  11.  APPARATUS AND METHODS USED IN DETERMINING THE SYSTOLIC PRESSURE IN RATS. : A. Apparatus. The blood pressures of the rats were measured i n d i r e c t l y by observing the pressure required on the thigh of the anaesthetized animal -ftee-e-e-ea*^- to stop the blood flow i n the c a p i l l a r i e s of an i n t e r d i g i t a l  web.  The method i s described by G r i f f i t h and F a r r i s 128), and modifications found useful i n t h i s laboratory have been reported by F i t c h ( 2 0 ) and Semple ( 5 2 ) . Photographs of the apparatus are shown i n Plate I. B. Methods. a( Anaesthesia. F i t c h ( 2 0 ) and Semple ( 5 2 ) s a t i s f a c t o r i l y standardized the use of sodium pentothal as an anaesthetic so that l i t t l e d i f f i c u l t y was technique.  encountered when applying the  The rats were anaesthetized by giving them  intraperitoneal injections of a solution of sodium pentothal. It was found that 0 . 3 5 nil* of a freshly prepared solution of 2 5 mgm.  sodium pentothal dissolved i n 1 . 0  ml. of d i s t i l l e d water injected intraperitoneal l y s u f f i c i e n t to anaesthetize a rat weighing 1 5 0 gm.  was This  12.  dose was increased 0.05 of 50 8 » m  m  l» f o r every increase i n weight  The action of the anesthetic was more r e l i a b l e  when the animals were l e f t without food f o r 2 hours before anaesthetization.  It was also observed that i f the i n i t -  i a l i n j e c t i o n did not produce a profound enough anaesthesi a that an extra 0.1 ml. of pentothal could be administered with no apparent deleterious e f f e c t on the animal.  PLATE I. The photograph on the right i l l u s t r a t e s the apparatus used in determining the systolic blood pressure of rats (see text)  The photograph on the right i s a v e r t i c a l view of the microscope stage showing the toes of the hind l e g of an anesthetized rat pinned out (with plasticene) for observation of the i n t e r d i g i t a l web. .Note the pressure cuff wrapped about the thigh.  13. THE EFFECT OF DESOXYCORTICOSTERONE OVERDOSAGE ON THE BLOOD PRESSURE OF MALE WISTAR RATS A. Introduction. Semple (52)  and F i t c h (20)  working i n this  laboratory found that one intramuscular i n j e c t i o n of 1.0 mgm. of DCA sufficed to produce a transient hypertension i n Wistar r a t s . was undertaken  The following investigation  i n order to confirm their r e s u l t s and to  note the effect of dietary s a l t supplements on the course of a hypertension thus induced. (1)  Methods.  T r i a l 1. Eight male Wistar rats $ to 7 months old, were each injected intramuscularly with 1.0 mgm. of desoxycorticosterone i n o i l .  The s y s t o l i c blood press-  ures of these animals and 8 control animals were determined d a i l y f o r 10 days. T r i a l 2. Six male Wistar rats were each given d a i l y for 6 days, intramuscular injections of 1.0 mgm. of desoxycorticosterone acetate i n o i l .  Blood pressure  determinations were made on each animal every day for 10 days and again on days 20 and 30* T r i a l 3.  14.  Eight male Wistar rats each received an intramuscular i n j e c t i o n of 1.0 mgm. of desoxycorticosterone every day f o r 14 days.  Four days "before the  experimental treatment 1% salt was added to the drinking water of the animals and supplementary given throughout  the course of i n j e c t i o n s .  i c pressures were determined  throughout  s a l t was The s y s t o l -  a period of 3°  days. (2) Results. T r i a l 1. The r e s u l t s are presented graphically i n F i g . 1. No pertinent changes i n blood pressure were observed with the exception of an i n i t i a l drop i n syst o l i c pressure averaging 14 mm/Hg.  Several repetitions  of the above procedure produced negative r e s u l t s . T r i a l 2. The r e s u l t s are presented graphically i n F i g . 2.  It i s notable that the s y s t o l i c pressure reached  an average value of 165 mm/Hg. i n 12 days and had r e t urned to a normal value i n 16 days. Trial The r e s u l t s are presented graphically i n F i g . 2.  The blood pressure of these animals was observed to  r i s e s t e a d i l y after the t h i r d i n j e c t i o n of DCA to an average value of 17^ mm./Hg. 3 days after the l a s t  r  hormone i n j e c t i o n s  The  average s y s t o l i c value  dropped t o ' 1 7 ^ mm./Hg. on the t w e n t i e t h day  and  had tended  to s t a b i l i z e at t h i s p o i n t . Histological h e a r t , l i v e r , and by Logan (37)  examination of the  a d r e n a l s of 3 of  kidneys,  the above animals  r e v e a l e d no s i g n s of p a t h o l o g i c a l change.  Systolic Blood Pressure mm/H^  FlR« 1 The s o l d l i n e r e p r e s e n t s the average s y s t o l i c blood pressure v a r i a t i o n s i n 8 male r a t s , each r e c e i v i n g 1.0 mgm. of DCA i n t r a m u s c u l a r l y on day 0. The broken l i n e r e p r e s e n t s the average s y s t o l i c pressure changes i n 8 c o n t r o l animals r e c e i v i n g ment.  blood no t r e  2  The s o l i d line represents the average s y s t o l i c blood pressure changes of 6 r a t s , each receiving 1 . 0 mgm. i n j ections of DCX d a i l y from day 0 to 5 i n c l u s i v e . The broken l i n e represents the average s y s t o l i c pressure change i n 8 male rats receiving excess dietary s a l t and 1 . 0 mgm. injections daily of BC'A from days 0 to 13 inclusive .  18. (3) D i s c u s s i o n . Semple (52) i n j e c t i o n o f 1.0  and F i t c h (20)  found  t h a t one  mgm. o f DOA produced a t r a n s i e n t hyper-  t e n s i o n l a s t i n g from 7 to 8 days•  D e s p i t e the f a c t  t h a t the r e s u l t s o f t h i s i n v e s t i g a t i o n are c o n t r a d i c t o r y to the r e s u l t s obtained by F i t c h and Semple, i t does not tend to i n v a l i d a t e t h e i r work i n t h i s author's mind. It was p u z z l i n g t o f i n d s i m u l t a n e o u s l y found  t h a t Rixon ( 6 l )  that female Wistar r a t s  (some of  which were l i t t e r m a t e s to themales used i n t h i s i n v e s t i g a t i o n ) developed  a severe and c h r o n i c h y p e r t e n s i o n  when i n j e c t e d i n t r a m u s c u l a r l y w i t h 1.0 Rixon, on r e p e a t i n g the procedure t a i n e d no response.  mgm.  o f DCA.  at a l a t e r date, ob-  I t i s not l i k e l y t h a t e r r o r s i n  blood pressure d e t e r m i n a t i o n s were i n v o l v e d , as the p r e s s u r e v a l u e s taken by each i n v e s t i g a t o r agreed when they were made on the same (4)  closely  animals.  Conclusions. Chronic  overdosage w i t h d e s o x y c o r t i c o s t e r o n e  w i l l produce h y p e r t e n s i o n i n r a t s when excess  salt is  added t o the d i e t . (5)  Summary. Male Wistar r a t s were d i v i d e d into t h r e e ex-  per M e n t a l  groups.  19.  The animals of the f i r s t group each received 1 intramuscular i n j e c t i o n of 1.0 mgm.  of DCA.  They  showed no apparent pressor response over a 10 day period. Those of the second group each received tramuscular i n j e c t i o n of 1.0 mgm. ^ 5  days.  in-  DCA d a i l y f o r 6  There was a moderate transient pressor response  observed. The animals of the t h i r d group, whose drinking water contained 2% s a l t , each received X intramuscular injection of 1.0 mgm. v£ DCA d a i l y f o r 14 days. 5  The  s y s t o l i c pressure of these animals reached hypertensive levels that were sustained without further treatment.  20.  THE EFFECT OF E3TR0GEN OVERDOSAGE ON THE BLOOD PRESSURE OF INTACT MALE AND CASTRATE MALE RATS.. A. Introduction. The e f f e c t of estrogens i n mammals has been a subject of considerable debate. It i s claimed (30) that i n r a t s , hypertrophy of the kidneys, an elevation i n blood pressure and s a l t and water retention follow the d a i l y i n j e c t i o n of large doses of estrogen.  The salt and water retention i s  probably due to the adrenal corticomimetic action of this hormone (64).  Estrogens have also been claimed to  produce hydro-ureters and hydronephrosis  (30) and are  apparently involved i n producing the common phenomenon of pre-menstrual edema (62).  It i s also common know-  ledge i n medical f i e l d s that i n women s u f f e r i n g from chronic nephritis re-occurrence of the grosser symptons (extensive p i t t i n g edema, increase i n blood pressure, re-appearance  of albumin i n the urine (?)) i s associated  with the onset of mensis. Selye (50) does not agree with the statements above and states that the claim that f o l l i c u l o i d s i n crease the blood pressure i n the r a t has not been substantiated and that women with menopausal hypertension often show a decrease i n blood pressure.  Folliculoids  2-1.  exert a vasodilator effect which i s r e a d i l y v e r i f i a b l e by direct inspection (e.g., i n the rabbit ear). The vessels of the nasal mucosa, and those of the accessory sex organs are p a r t i c u l a r l y sensitive to t h i s e f f e c t . It has been assumed that the action i s due to a periphe r a l discharge of acetylcholine occasioned by the f o l l iculoids. The controversial action of estrogen  sponsored  the following investigation of i t ' s effect on the blood pressure of r a t s . ( l ) Apparatus and Methods. Apparatus and methods used for blood pressure determination as previously described. T r i a l 1. Five pressure determinations were made over a 7 day period on each of 6 male Wistar rats and the average of the readings made on each i n d i v i d u a l animal was considered to be the animal's normal s y s t o l i c blood pressure . Starting on day 0, each r a t received subcutaneously 0.5 mgm. of diovocylin. (Ciba's brand, of estr a d i o l dipropionate) dissolved i n 1.0 ml. of o i l . injections were repeated d a i l y , for 5 days. pressure of each animal was determined  The  The systolic  on days 3, 6, 8,  22 13,  2 0 , and 3 0 .  Trial 2. Five male Wistar rats castrated eight weeks previously were treated i d e n t i c a l l y as those i n T r i a l 1. T r i a l 3. a) .  Four male rats were /giren\^^^)  one  injection  of 0 . 5 mgm. of e s t r a d i o l i n o i l (diovocylin).  Their  i n d i v i d u a l s y s t o l i c pressures were determined d a i l y f o r the f i r s t f i v e days then on days 7 , 10 and 14. Six male r a t s , 3 castrates and 3 intact anim-  b) .  a l s , were each given two subcutaneous injections of ^ 0 . 5 mgm. diovocylin, one i n j e c t i o n on each of two  consecut-  ive d ays • (2)  Results.  T r i a l 1. One day a f t e r the third i n j e c t i o n of estrogen (day 3) i t  w  a  s  found that there had been an average i n -  crease i n blood pressure of 26 mm./Hg.  Determinations  made one day after the l a s t i n j e c t i o n of estrogen revealed the average blood pressure of the s i x rats to be 225 mm./Hg.  Two days l a t e r (day 8 ) the average  systolic  pressure was observed to have f a l l e n back to a value of approximately 190 mm./Hg.  Subsequent determinations  showed that the s y s t o l i c pressure rose s t e a d i l y u n t i l day 2 0 , where i t tended to s t a b i l i z e at a value of 230mm./Hg. (see F i g . 3)  23 T r i a l 2. The effects of estrogen on the "blood pressure of the castrate animals were found to be very s i m i l a r to effects i t produced  i n intact males.  However, i t i s  evident 'from the graph that the pressor response  occurs  more r a p i d l y i n the gonadectomized animal, although the elevation i n pressure i s no greater i n the castrate than the intact animal (see Fig.3) T r i a l 3. a) .  As shown i n F i g . 4, the administration of 0.5  mgm. of estrogen to 4 male rats produced i n blood pressure.  no marked change  There was a s l i g h t i n d i c a t i o n of a  t r a n s i t o r y f a l l i n s y s t o l i c pressure. b) .  The administration of 1.0 mgm. of estrogen  (0.5 mgm. on 2 consecutive days) produced, as indicated i n F i g . 4, a d e f i n i t e pressor response. The intact males showed an i n i t i a l drop i n pressure averaging 8 mm./Hg.  The smallest decrease was  4 mm/Hg., the greatest 14 mm/Hg«  Immediately following  t h i s s l i g h t depression the pressures rose by the end of day 2 to an average value of 25 mm/Hg. above normal. The pressures dropped s t e a d i l y after the second day and were found to be at normal l e v e l s by day 14. The graph ( F i g . 4) of the pressor response to 1.0  mgm. of estrogen i n castrate males i s incomplete, as  i n 2 of the 3 experimental animals a sustained pressor  24.  response was obtained. 'fhe elevated pressure of the  r t h i r d animal dropped to normal l e v e l s i n 14- days. It i s notable that i n the castrate animals no i n i t i a l f a l l i n pressure was detected.  The  systolic  pressures of the 2 animals showing the sustained elevation were found to be 165  and 190 mm/Hg. at the end of  14 days. Further Note: An error i n the anaesthetization of two r a t s (not included i n the previous discuss ion j that had each received three injections of 1.0  mgm.  three days resulted i n their death.  estrogen through Immediate autopsy  of these animals revealed a marked hyperemia of the l i v e r , and hemorrhagic adrenals and kidneys.  The r i g h t ureter  of one of these animals was markedly enlarged.  25.  TABLE I. -; • Rat. No. INTACT  1  2  3  4  5 6  CASTRATES  1 2 3  4 5  B i d . Press.  HT.WT. % Body Wt.  226  0.44  232 216 210 228  0.44  240  215 248 220 225 236  0.52  0.35 0.39  0.42  0.34  0.56 0.39  0.48 0.5  Table I. The above data represents the heart weight expressed as % body"of intact and castrate male rats made hyper« tensive by estrogen overdosage.  (Normal heart weight of rats i s 0.28% of body weight as determined by Best et a l . ( l ) )  Systolic Blood P r e s s u r e  The olic 0.5 the  mm]  s o l i d l i n e r e p r e s e n t s the average i n c r e a s e i n s y s t blood pressure of 6 male r a t s , each i n j e c t e d w i t h mgm. e s t r a d i o l d i p r o p i o n a t e at times i n d i c a t e d by arrows ( I ).  The broken l i n e r e p r e s e n t s the average i n c r e a s e i n blood pressure of 5 male c a s t r a t e r a t s i n j e c t e d w i t h 0.5 mgm. e s t r a d i o l d i p r o p i o n a t e a t times i n d i c a t e d by the arrows  J\  i  •  i  i  i  i  i  i  i  i  i  i  i_  .--  0 I 2. 3 4 Or <o 1 8 <? 10 II 12. 13 11  Days . Fig. 4 The s o l i d l i n e represents the average s y s t o l i c pressure changes occurring i n 4 male rats a f t e r 1 subcutaneous i n j e c t i o n of 0.5 mgm. of e s t r a d i o l dipropionate on day 0. The broken l i n e represents the average pressure change in 3 male rats, each receiving a subcutaneous i n j e c t i o n of 0.5 mgm. of e s t r a d i o l dipropionate on days 0 and 1. The broken and dotted l i n e represents the average syst o l i c pressure changes of 3 castrate male rats, each receiving 0.5 mgm. of e s t r a d i o l dipropionate subcutaneously on days 0 and 1.  V.  28. Retraction of the testes occurred i n a l l animals that received 2.5  mgm.  of estrogen  ( i n 0.5  mgm.  doses)  and autopsy revealed the l i v e r s to be abnormally small. (3)  Discussion. The r e s u l t s of these experiments indicate  that  e s t r a d i o l dipropionate has sustained pressor e f f e c t i n male Wistar r a t s .  The i n i t i a l decrease i n blood  pressure  found to occur after administration of this hormone i s not marked enough to be considered s i g n i f i c a n t . investigation  of this depressor  Further  e f f e c t would be of  interest. (4)  Conclusions. 1)  Sustained hypertension can be i n i t i a t e d i n i n -  tact male and castrate male Wistar rats by  estradiol  dipropionate overdosage. 2)  Castration of the male rat sensitizes the animal  to the pressor effects of this hormone. 3)  E s t r a d i o l overdosage causes a decrease i n the  size of the l i v e r . ( 5)  Summary. The administration of 0.5  mgm.  e s t r a d i o l dipro-  pionate d a i l y f o r 5 days to each of 6 intact and 6 castrate male rats produced an average increase i n their  s y s t o l i c blood pressures of 100 mm./Hg. The castrate animals were found to be more sensitive to the pressor e f f e c t s of estrogen than were the i n t a c t males. The induced hypertension was sustained and 16 days after treatment condition abating. treatment  there was no sign of the induced The heart weight made 4-0 days after  indicated that the hypertension was chronic. The administration of 0.5 mgm.  of e s t r a d i o l  dipropionate d a i l y for 2 days produced a transient i n crease i n the s y s t o l i c blood pressure of three male Wistar r a t s .  The castrate animals showed a sustained  pressor response to similar treatment.  No pressor resp-  onse was evident i n intact males each r e c e i v i n g 1 i n j e c t ion of 0.5 mgm.  of e s t r a d i o l dipropionate.  30.  THE EFFECT Off ESTROGEN UPON EXPERIMENTAL HYPERTENSION IN MALE WISTAR RATS.  (1)  Statement. This investigation was carried out as an ex-  tension of the previous study of estrogen. (2)  Methods. Four male Wistar rats i n which hypertension  had been previously induced hy renal lesions r e s u l t i n g from n u t r i t i o n a l choline deficiency (see choline deficiency and hypertension) were given•<«•**©-subcutaneous i n j e c t i o n of 0.5 mgm. of diovocylin (Ciba's brand of e s t r a d i o l dipropionate) d a i l y for 4 days. The average s y s t o l i c blood pressure of these animals had been established previously at 222 mm/Hg. The range of these elevated pressures was from 218 - 226 mm/Hg. The blood pressures following the i n i t i a l i n j e c t i o n of e s t r a d i o l were determined  d a i l y for 6 days  and again on the eighth, tenth and twentieth days. (3)  Results. The s y s t o l i c pressures of a l l 4 animals was  2IQ1  0  I  *  3  i  >  \  s5  Days  i  <b  =  ,  .  s  .  T  8  S  10  Fig. 5 This graph represents the average change i n the blood pressures of 4 hypertensive male rats following the subcutaneous administration of 0.5 mgfiu of e s t r a d i o l dipropionate to each d a i l y from days I to ^ i n c l u s i v e .  PLATE I I .  The picture on the r i g h t shows a t y p i c a l skin l e s i o n that occurs i n hypertensive r a t s . (The area around the l e s i o n has "been shaved). This animal suffered hypertension induced by renal lesions and aggravated by estrogen overdosage (The r a t was anesthetized f o r the photo).  The picture on the right of the anesthetized animal shows a t y p i c a l haemorrhage about the eye that occurs i n hypertensive r a t s . This animal i s also suffering hypertension secondary to renal lesions and aggravated by estrogen overdosage.  34-.  ©Observed  to r i s e from an average value of 222 mm/Hg. to  an average value of 290 mm/Hg. (see P i g . 5) on the f i f t h day.  (The pressures ranged from 280 - ^00 mm/Hg.) The s y s t o l i c pressures dropped from day 5 to  day 8 to an average value of 262 mm/Hg.  Observations  made on day 20 revealed no change i n the l a t t e r value (262 mm/Hg*). Heart weights of these animals are given i n Table H i TABLE I I . Rat. Ho.  HT.WT. % Body Wt.  B i d . Press.  1 2 3  290  0.61  240  0.48  265  0.53  4  250  0.5  Table I I . The data  given above  shows the heart weight expressed as  % body weight, of 4 hypertensive animals whose condition was aggravated by estrogen overdosage.  (*)  The gross appearance of these animals ed a general physical degeneration.  indicat-  There was a marked  decrease i n weight, hemorrhage about the eye, scabby skin l e s i o n s , extensive edema ( i n 1 animal), and diur e s i s and anorexia. (4)  (See P l a t e I I )  Conclusions. 1)  Hypertension secondary to renal lesions i s agg-  . i.(The heart weight of normal rats i s 0.28% as i s shown by Best et a l ( 1 ) ) *^' 8  -35-  ravated i n male Wistar r a t s by overdosage with est r a d i o l dipropionate. (5 ) Summary. Four male Wistar r a t s with hypertension secondary to renal lesions induced by n u t r i t i o n a l choline deficiency were injected subcutaneously with 0 . 5 mgm. e s t r a d i o l dipropionate daily f o r 4 days and were found to respond with a sustained increase i n s y s t o l i c pressure.  36.  THE EFFECT OF DCA ON THE DEVELOPMENT OF HYPERTENSION SECONDARY TO RENAL DAMAGE INDUCED BY CHOLINE AVITAMINOSIS.  A. Introduotion. Beat and Hartroft reported i n 194-9  ( l ) that  weanling r a t s that were fed a diet low i n choline for 6  day8 then placed on a normal food mixture for the  remaining experimental period of 4 to 7 months, tended to develop a moderate or severe degree of hypertension during the period of observation. was  The hypertension  thought to be due to the renal lesions produced by  such treatment.  In view of these results i t was decid-  ed to note the pressure changes occurring i n mature rats and the e f f e c t that desoxycorticosterone acetate might have i n animals whose renal tissue had been reduced i n such a manner. (l)  Methods. Eight mature male albino r a t s of the Wistar  s t r a i n were fed a diet (low i n choline and i t ' s precursors) i d e n t i c a l to that used by Best and Hartroft ( l ) ( 6 l ) for 5 days and were then returned to normal stock d i e t .  On the sixth day 4 of the 8 r a t s were  given intramuscular injections of 1.0 mgm. each of  37  desoxycorticosterone acetate i n o i l .  This was repeated  on days 7 said 8. The remaining 4 animals received no further (2)  treatment.  Results. The r e s u l t s are represented graphically i n  F i g . 6. The animals receiving the 3 injections of DCA showed an immediate increase i n s y s t o l i c pressure. The increase was not marked during the f i r s t 4-§- days, but had r i s e n sharply by the s i x t h day and continued to r i s e u n t i l day 10 to an average value of 222 mm/Hg• The average s y s t o l i c pressure of these animals 40 days l a t e r was 226 mm/Hg. The animals that were subjected to 5  clays  of  a choline d e f i c i e n t diet only, showed l i t t l e or no i n crease i n s y s t o l i c blood pressure after 9 days on a normal d i e t .  The pressure showed a s l i g h t increase on  day 12 and was found on day 20 to be at an average v a l ue of 226 mm/Hg. On day 25 the pressure had declined to a value of 212 mm/Hg. and 40 days l a t e r was found to be at a value of 222 mm/Hg. Heart weights are presented i n Table I I I .  38.  TABLE I I I .  Rat No.  HT.WT. % Body Wt".  B i d . Press.  1 2 3  232 218 220  O.39 0.40  5 6 7 8  216 228 222 220  0.41  4  0.45  240  0.53 0.35 0.38 0.33  Table I I I . The above data represents the heart weights expressed as % of body weight f o r male r a t s 45 days after terminating 5 days on choline d e f i c i e n t d i e t . Rats 1 to 4 received DCA the f i r s t 3 days a f t e r terminating the n u t r i t i o n a l  deficiency.  (The heart weight of normal rats i s 0.28% as i s shown by Best et a l ( l ) ) ( « °dy weight) e  1  fe  S)/5tollC  Fig.  Blood PrtSSUTfc mmH / <y  6  /  J  The s o l i d line shows the average changes i n blood pressure occurring when 4- male rats were returned to a normal diet (on day 0) after 5 days on a choline deficient -diet. The broken line represents the a v e r a g e increase i n pressure of 4 male rats that each received 1^0 mgm. a day of DCA for 3 days following t h e i r ^ r e t u r n from a choline d e f i c i e n t to a normal diet. (  42.  (3)  Discussion. Best and  Hartroft claim (1) that they cannot  consistently produce renal lesions by feeding mature rats a choline deficient d i e t .  The r a t s used i n t h i s  investigation were of the same s t r a i n as those used by Best et a l . , the diet was  prepared according to t h e i r  formula and the animals were maintained on the d e f i c i e n t diet for s i m i l a r , or shorter periods of time.  It  was  found both by Rixon ( 6 l ) and rde that choline deficiency produced renal lesions i n a l l the animals h i s t o l o g i c a l l y examined.  The renal pathology i s shown i n Plates II and  III. Hypertension was  invariably produced and dev-  eloped within 3 weeks i n the mature animals.  Best found  that i n weanlings hypertension did not generally  devel-  op for several monther. Such features  (as seen by Best) as h y a l i n i z a t -  ion of the glomerular loops and thickening of Bowman's capsule are, i n the opinion of Best ( I ) , most l i k e l y the result of high l e v e l s of intravascular pressure, and parenchymal loss i s probably attributable to the acute dietary d e f i c i e n c y .  However, a clear picture of the  pathogenesis of these renal lesions has not been given. The  influence of DCA  i n accelerating  the  4-3. development of hypertension i s not known.  Dean and  Oleson (15) have shown that there i s hypertrophy of the adrenal cortex i n weanling rats which exhibit the syndrome of hemorrhagic  kidney.  Best ( l ) suggests that t h i s  hypertrophy may contribute i n some manner to the development of hypertension.  Adrenal hypertrophy may, i n t h i s  case, occur as a direct response to the s t r e s s . (4)  Conclusions. 1)  A period of choline deficiency, followed by a  normal d i e t , w i l l produce hypertension i n male Wistar rats within 3 weeks. 2)  The administration of desoxycorticosterone w i l l  accelerate the production of hypertension i n r a t s that have survived a period of choline (5)  deficiency.  Summary. Eight male Wistar rats were maintained 5 days  on a choline d e f i c i e n t d i e t .  The animals were returned  to a normal d i e t and 4 of the 8 rats were given DCA i n jections intramuscularly. The animals r e c e i v i n g the DCA developed hypertension i n 1/3 to 1/2 the time r e quired for the control animals to develop the syndrome.  44.  THE EFFECT OP STARVATION. OH-THE BLOOD PRESSURE OF WISTAR- RATS.  A.  Introduction.  ,  Biskind and  ind (3),  Shelesnyak (2) Biskind and  Singher et a l (55)  Shipley and Gyorgy  Bisk(54)  claim to have shown that vitamin B complex factors are necessary f o r the i n a c t i v a t i o n of estrogen and  that  the s i t e of this catabolic process is. i n the l i v e r . There is considerable evidence to indicate that progesterone and desoxycorticosterone  are also inactivated  i n the l i v e r through s i m i l a r catabolic processes ( 4 3 ) . The  conclusions drawn on the r e l a t i o n s h i p  between estrogen metabolism and B complex factors has been questioned by D r i l l and P f e i f f e r (44).  They point  out that i n the foregoing work paired i n a n i t i o n cont r o l s were not used and that when paired i n a n i t i o n cont r o l s (animals which were r e c e i v i n g the same amount of food but receiving the B vitamin) were used i n t h e i r work, the controls showed the same response to estrogen as did the experimental animals.  The authors conclude  therefore that the e f f e c t of B complex deficiency i s the r e s u l t of concomitant i n a n i t i o n . With t h i s i s mind i t was  decided upon to observe the blood pressure  ects produced by administration ef DCA  eff-  to rats i n a  45.  state of general (1)  inanition,  Methods. Nine male ?/istar r a t s , 7 to 10 months o l d ,  were given no food (water ad l i b . ) for. three days. owing this they were placed on a diet consisting gms. of fox chow each (£) per day f o r 21 days.  Foll-  of 7«0 Starting  on day 8 of the enforced fast 5 animals each received an intramuscular, .injection of 1.0 mgm. desoxycorticosterone acetate d a i l y for 5 days, (The remaining 4 animals were considered controls.) The course of injections were repeated over a period of 5 days beginning on the day the animals were returned to a normal diet (days 25 to 3 0 ) . Attempts to make s y s t o l i c pressure ions during the period of starvation  determinat-  were discouraged  by the distressing e f f e c t s the anaesthetic had on the undernourished  animals.  The s y s t o l i c pressures were read  on days 31, 33» 36, and 40. (*)....The normal weight of fox chow consumed by one r a t i n a day i s approximately 20 gms. (2)  Results. Ten days after the l a s t i n j e c t i o n of DCA the  blood pressures of the animals receiving the DCA were s t i l l normal and no change i n s y s t o l i c pressure was  46  evident i n the paired i n a n i t i o n controls.  At this time  the r e s u l t s of the experiment were considered negative and no further determinations were made for a period of approximately 60 days, during which time the animals were maintained under normal conditions. It was surprising to the author to f i n d that  n  on re-checking these animals after the 60 day period, the blood pressures of both the experimental animals and the controls had reached hypertensive l e v e l s . i s presented i n the table below.  The data  It i s to be noted that  the heart weights v e r i f y these f i n d i n g s . TABLE IV. Rat Mb'.'  Bid .Press.  1 2 3 4 5 6  Ht.Wt. % Body Wt.  230 210 165 220 210 218 165 215  7 8  0.53 0.42 O.35 0.51 0.40 O.39 O.30 0.4  Table IV. In the above data the heart weights are expressed as % body weight.  The animals were found to be hypertensive  2 months after being subject to 3 weeks of a subminimal diet.  Blood pressures were determined 2 days before the  animals were s a c r i f i c e d . U) A...(the heart weight of normal r a t s i s 0.28^ as shown by Best et a l ( l ) )  of body weight  4?  At the time of writing h i s t o l o g i c a l sections of the organs have not been completed.  However, there  i s gross evidence of f a t t y i n f i l t r a t i o n i n the l i v e r j accompanied by hemorrhagic lesions and small areas of f o c a l necrosis.  There i s also gross evidence of renal  lesions and possibly enlargement of the adrenal gland.  (3) Discussion. It i s pertinent i n this experiment that both the undernourished animals receiving desoxycorticosterone acetate and the paired i n a n i t i o n controls developed hypertension.  Thus the exogenous c o r t i c a l hormone was  not apparently responsible f o r the pressure changes. It i s also of interest to note that Rixon (6l) found no such pressure changes i n female Wistar r a t s starved to a lesser degree and for a shorter period of time. The factors involved i n the production of this syndrome are not known to the author.  It would  appear reasonable to assume that the condition resulted from i r r e v e r s i b l e pathological changes, r e s u l t i n g from a general avitaminosis. In the l i g h t of recent findings of Best and Hartroft (1) and the apparent gross pathology of the l i v e r and kidneys of these animals, i t appears that the changes may be due to renal lesions  48. produced by a choline deficiency incurred during inanition. (4)  Conclusions. 1)  A prolonged period of i n a n i t i o n w i l l produce  hypertension i n male Wistar r a t s . 2)  Desoxycorticosterone does not markedly i n f l u -  ence the development or i n t e n s i t y of the hypertension thus produced. (5)  Summary. Nine male Wistar rats were placed on a sub-  minimal d i e t f o r 30 days.  Five animals received i n t r a -  muscular injections of DCA f o r 5 days during the period of i n a n i t i o n and for 5 days immediately following i t . Four animals received no hormonal treatment.  Both the  control and experimental animals were found to be hypertensive 60 days after their return from a subminimal to a normal d i e t .  49.  THE EFFECTS OF ANTIHISTAMINES ON THE BLOOD PRESSURE OF MALE WISTAR RATS. A. Introduction. Observations on parabiotic twins l e d Grollman (30) i n 1946 to the conclusion that the role of the kidney i n hypertension i s not one of a c t i v e l y secreting a pressor substance, but rather one of f a i l i n g to form an antipressor substance. "In 194? Shorr, Zweifach and Furchgolt (56) (57) (58) reported observation of an apparent renal pressor-depressor system (see - nature of pressor mechanism).  They postulated that a d i s b a l -  ance of this mechanism might account f o r either hypotension or hypertension. Histamine i s a very potent material producing marked pharmacologic  effects.  Upon intravenous i n -  j e c t i o n 0 ( y s u f f i c e s to produce a marked f a l l i n blood pressure i n ether-anaesthetized c a t s . l y ere hypotension even i n humans.  produces sev-  I t i s not therefore,  extravagant to postulate that t h i s substance may funct i o n i n normal animals as a factor: involved i n a system that controls vascular a c t i v i t y ; nor i s i t too imaginative to assume that the loss of histamine from the c i r c u l a t i n g blood may allow vasoconstriction to occur with a subsequent increase i n blood pressure.  50. It i s also notable that histamine has been used successfully to cause peripheral vasodilatation i n the treatment of c e r t a i n vascular diseases  (70).  With the information above i n mind, i t was decided to investigate the pressor changes that might occur i n r a t s a f t e r the administration of some of the commercial antihistamic compounds.  (l)  Apparatus and Methods. The apparatus and methods used i n determin-  ing blood pressures have been previously described i n this paper (see *• apparatus and methods-Introduction) Trial a)  1.  The normal pressures of white male Wistar rats  numbered 1 to 10 were determined d a i l y over a 4 day period.  The average value of the 4 readings taken on each  rat was accepted as the approximate normal s y s t o l i c pressure of the animal. On day 0, rats 1 to 5 received intraperitoneal i n jections of 1 cc. physiological saline and were thus considered as controls.  Rats 6 to 10 received i n t r a -  peritoneal injections of 1.0  mgm.  of the antihistamine,  antistine (Ciba's brand of phenylbenzylaminomethyl-imidazoline hydrochloride).  This procedure was repeated  every second day (The antistine solution was freshly  51. prepared before each injection) u n t i l 5 injections had been given each animal. b)  The procedure followed was i d e n t i c a l to that of part  a above, with the exception that 0.2 mgm. antistine were given rather than 1.0  injections of  mgm.  T r a i l 2. a)  The normal s y s t o l i c pressure of 5 male Wistar rats  was determined as i n T r i a l 1.  Each animal was then  given one i n j e c t i o n intraperitoneally of 1.0 mgm. antistine dissolved saline.  i n 1 ml. of physiological  The s y s t o l i c pressure of each r a t was  of  normal determ-  ined 1-J- hours after the .antistine i n j e c t i o n and then on days 3, 4, 7, 12, 14, 16, 18, and 20 after the i n i t i a l injection. b)  Procedure a above was repeated on 3 male r a t s , us-  ing -0.5 mgm. physiological c)  of pyribenzaraine dissolved  i n 1.0 ml. of  s a l i n e , i n place of a n t i s t i n e .  Procedure a  was repeated on 2 male Wistar rats with  the antistine injected subeutaneously, instead  of i n t r a -  peritoneal l y . T r i a l 3. Four male Wistar rats were anaesthetized and their normal s y s t o l i c pressure determined.  Each r a t then  52. received an intraperitoneal i n j e c t i o n of 1.0 mgm. of antiatine dissolved i n p h y s i o l o g i c a l l y normal s a l i n e . Blood pressure determinations were made on each animal 5 minutes after receiving the a n t i s t i n e , again at 10 minutes, and thereafter every 10 minutes throughout  the period of an hour.  A f i n a l reading was  made at the end of the second hour. T r i a l 4. a)  The normal pressure of 3 rats were determined.  The  animals then received one intramuscular i n j e c t i o n each of 0.1 mgm. of antistine dissolved i n 0«1 nil. of water. Pressure determinations were made 2, 18, 34, and 5° hours a f t e r the i n i t i a l i n j e c t i o n .  A f i n a l reading was  made on each animal 7 days l a t e r . b)  Procedure a was repeated using intramuscular i n j -  ections of 0.01 mgm. of a n t i s t i n e .  Pressure determinat-  ions were made on each of the 3 rats 2, 10, 24, 32 and 48 hours after they received the a n t i s t i n e . T r i a l 5. The normal blood pressure of 6 students (5 males and 1 female) between the ages of 22 and 30 years was established f o r each individual by taking f i v e pressure determinations at 2 hour intervals throughout a day i n which they remained r e l a t i v e l y quiet and spent most of  53 t h e i r time s i t t i n g at a desk.  On a day that their  a c t i v i t i e s were similar to those previously described, each student was given or a l l y one tablet of 100 mgm. antistine at 9 AM, at which time their blood pressure was again recorded.  Blood pressure values f o r each  student were determined 2, 6, 8, 27, and 43 hours after administration of the antistine., (2)  Results.  T r i a l 1-  (results) The r e s u l t s (as represented graphically i n  Pig. 7) show that after the i n j e c t i o n of 1.0 mgm. of a n t i s t i n e , the blood pressures of the experimental animals had r i s e n i n 24 hours to an average value of 220 mm./Hg;. from an average value of 132 mm./Hg. The greatest increase i n pressure was 100 mm./Hg. shown i n an animal whose normal pressure was 140 mm./Hg. and whose pressure reached a value of 240 mm./Hg. at the end of the f i r s t 24 hours. ure was 55 mm./Hg.  The smallest increase i n press-  (135-190 mm./Hg.). It was found  that with further injections of antistine, blood pressure variations decrease and the pressures tended to s t a b i l i z e at an average value of approximately 200 mm/Hg.  (see Pig»7 ) Porty-eight hours after the l a s t i n j e c t i o n of antistine the average s y s t o l i c pressure dropped from a  5*. value of 200 mm./Hg. to 185 mm./Hg. and rose slowly throughout  ^  a period of 6 days to s t a b i l i z e i t s e l f at an  average value of 200 mm./Hg.  The highest i n d i v i d u a l  value was 220 and the lowest 188 mm./Hg. It was also found that control animals injected several times with 1.0 ml. of saline i n place of 1.0 ml. of a l^^O^mgm. solution of a n t i s t i n e , showed no s i g - v J L - c n i f i c a n t change In blood pressure over a period of 20 days.  The greatest average v a r i a t i o n i n the s y s t o l i c  pressures of these animals was 6 mm./Hg.  The greatest  individual v a r i a t i o n was 10 mm./Hg., which occurred twice i n one animal and once in"another over a period of 20 days. b)  -  It was found that repeating procedure a but  modifying the individual doses of antistine to 0.2 mgm. produced  pressure variations which did not d i f f e r app-  r e c i a b l y from those obtained i n part a. T r i a l 2. (results) a)  It was observed  (see F i g 7) that one i n t r a -  peritoneal i n j e c t i o n of 1.0 mgm. antistine apparently produced  i t ' s maximum pressure response  i n Wistar rats  1-jjt- to 2 hours after i n j e c t i o n , at which time the average s y s t o l i c pressure of the 5 experimental animals was 225 mm./Hg.  The pressures ranged from 210 - 250 mm./Hg.  Over a period of 7 days the blood pressure dropped with decreasing r a p i d i t y to a value of 175 mm./Hg. and rose  55. slowly again during the next 7 days to an average value of 190 mm./Hg. at which point they tended to s t a b i l i z e . The pressures of the animals at the end of 20 days ranged from values of 180 - 220 mm./Hg. with the greatest number of values concentrated between values of 185 - 195 mml/Hg. It i s pertinent that one i n j e c t i o n of 1.0 mgm. antistine w i l l apparently produce an i r r e v e r s i b l e hypertension i n male Wistar rats (see also T r i a l 3 results). b)  It was found that antihistaminic  pyribenzamine  substance  produces blood pressure changes i d e n t i c a l  to those produced by a n t i s t i n e . <2)  Antistine injected subcutaneously i s as effec-  tive i n r a i s i n g the blood pressure as i t i s after i n t r a peritoneal administration. T r i a l 3 (results) Observations showed (see F i g 8) that immedi a t e l y following an intraperitoneal i n j e c t i o n of 1.0 mgm. antistine the blood pressure of a male Wistar r a t f a l l s to a value markedly below normal and then proceeds to increase over a 2 hour period to acute hypertensive levels.  The blood pressures of these experimental an-  imals f e l l to an average value of 90 mm./Hg. i n 10 minutes after which time they rose steadily f o r 2 hours  56.  to an average value of 215 mm./Hg.  The lowest pressure  recorded was 80 mm./Hg. and the highest 235 mm./Hg. The normal values were a l l 133 mm./Hg As a p a r t i a l confirmation of T r i a l 2, part a, the blood pressures of these animals were read after 23 days and found to be s t i l l at hypertensive  levels.  Trial 4.(results) a)  An intramuscular i n j e c t i o n of 0.1 mgm. of  antistine  caused an average elevation of s y s t o l i c blood  pressure i n male Wistar rats of 29 mmi/Hgi  The s y s t o l i c  pressure then dropped slowly but steadily over a period of 48 hours to a value of 14 mm./Hg. above the average normal pressure.  Pressure determinations made one week  l a t e r revealed that the s y s t o l i c pressure of one of the animals had returned to normal, one remained -10 points above normal, and the third was apparently hypertensive, ( s y s t o l i c pressure - 170 mm./Hg.) (see Fig. 9) b)  It was observed  muscular i n j e c t i o n of 0.01  that 2 hours after an i n t r a mgm. antistine  there was an  average decrease i n blood pressure of 14 mm./Hg. The s y s t o l i c pressures rose slowly and 24 hours after  treat-  ment they had reached an average value 6 mm./Hg. above normal..  At the end of 40 hours the s y s t o l i c pressures  of the 3 animals had returned to normal (See F i g . 9 ) .  57.  TABLE V.  Rat No.  6 7 8 9 10 11 12  B i d . Press.  Ht. Wt. % Body Wt,  220 210 205 195 185 200 190  0.40  O.36 O.36  0.37 0.35 O.36 O.39  Table V.  The data above represents the heart weights  expressed  as % of body weight of sone of the experimental animals treated with antihistamine. (The heart weight of normal rats i s 0.28^ as shown by Best et a l ( l ) )  of body weight  58 T r a i l 5»  (results) The oral administration of 100 mgm. antistine  apparently caused a decrease i n blood pressure of 6 humans averaging 15 mm./Hg.  The drop i n pressure was  evident at the end of three hours after which time i t rose s t e a d i l y and was found to be normal 26 hours after the drug was administered (See F i g . 9) It i s remarkable  that a seventh student (not  included i n the above t r i a l ) consistantly showed an increase i n blood pressure of 20 mm./Hg. a f t e r taking 100 mgm. antistine o r a l l y . (3)  Discussion. The pressor e f f e c t s of antihistamine are most  simply explained as occurring through the loss of the vasodepressor, histamine.  The exact nature of a n t i -  histamic action i s not known, although i t i s known that certain of these substances antagonize the action of other vasodepressors such as acetylcholine (42).  Res-  ponse to antihistamines varies with the species, however i t i s not generally accepted that i t w i l l e l i c i t pressor response.  Drug manufacturers  claim that with a few  exceptions* blood pressure changes have not been evident i n individuals who regularly use antihistaminic preparations•  Systolic 31oockPressure- mrn/n,  236  Days  The s o l i d l i n e r e p r e s e n t s t h e a v e r a g e s y s t o l i c p r e s s u r e c h a n g e s o f 5 male r a t s i n j e c t e d i n t r a p e r i t o n e a l l y w i t h 1.0 mgm. o f a n t i s t i n e a t time s i g n i f i e d b y t h e a r r o w s (^). [See t r i a l l a j The b r o k e n l i n e r e p r e s e n t s t h e a v e r a g e s y s t o l i c p r e s s u r e c h a n g e s o f 4 male r a t s r e c e i v i n g one i n t r a p e r i t o n e a l i n j e c t i o n o f 1.0 mgm. o f a n t i s t i n e on d a y O . l s e e trial 2a)  Fig.  8  The curve represents the average change i n s y s t o l i c press ure of 4- male rats over a 2 hour period immediately f o l l owing the intraperitonear administration of 1.0 mgm. of antistine.  "JO  20  30  ' 40  SO  Hours  gjff*  2—  The s o l i d l i n e r e p r e s e n t s t h e average ^change i n s y s t o l i c p r e s s u r e of 3 male r a t s r e c e i v i n g 0.1 mgm. of a n t i s t i n e i n t r a m u s c u l a r l y (see t r i a l 4a). The broken l i n e r e p r e s e n t s the average p r e s s u r e changes i n 3 r a t s r e c e i v i n g one i n t r a m u s c u l a r i n j e c t i o n of 0.1 mgm. of a n t i s t i n e (see t r a i l 4b). The curve c o n s i s t i n g of a broken and d o t t e d l i n e r e p r e s e n t s the average p r e s s u r e change i n 6 humans a f t e r o r a l a d m i n i s t r a t i o n of 100 mgm. of a n t i s t i n e . (see t r i & l 5)  62.  If this compound imitates the a c t i o n of cert a i n adrenal c o r t i c a l factors i t could possibly cause functional changes i n the organ (cortex) and work i n an insidious and detrimental fashion.  It appears that  the physiological response to this compound should he further  investigated. Recently, antihistamines have been used i n  the treatment of chronic nephritis because the disease exhibits c h a r a c t e r i s t i c s t y p i c a l of an a l l e r g y  (41).  H i s t o l o g i c a l sections of the kidney of animals used i n this investigation have not yet been expertly examined. However, from the general results thus far obtained, the use of antihistamines i n the treatment of nephritis is (4)  contra-indicated. Conclusions. 1. A single intraperitoneal i n j e c t i o n of 1.0 of antistine or pyribenzamine w i l l produce  mgm. chronic  hypertension i n white male Wistar r a t s . 2. Repeated injections of 1.0 mgm.  a n t i s t i n e do  not appear to markedly augment the changes induced by a single i n j e c t i o n of the same amount. 3 ' The administration  of (small) amounts of antistine  to both r a t s and humans causes a s l i g h t drop i n the s y s t o l i c blood pressure.  63. 4. The drop that precedes the elevation of blood pressure, when 1.0 mgm. antistine i s administered to r a t s , and the sustained hypotension that occurs A  after administration o f very small amounts to both rats and humans appears to be due to the i n t r i n s i c action of antistine as a vaso-depressor. 5* The elevation i n blood pressure induced by ant i s t i n e i s presumably due to the loss of histamine, i f this i s true, the loss of a vasodepressor mate r i a l from the blood i s as pertinent to the i n i t i a t i o n of hypertension as the increase i n c i r c u l ating vaso»excitor material. 6.  Indiscriminate use of antihistaminic compounds  may be exceedingly dangerous.  64.  Summary,  (as stated i n Conclusions)  65.  THE FACILITATION OF THE TRUETA SHUNT BY DESOXYCORTICOSTERONE ACETATE AND BY ANTIHISTAMINE  A. Introduction. The r e s u l t s of an experiment  o r i g i n a l l y per-  formed f o r academic interest only, led to the following investigations.  During the laboratory exercise des-  igned to i l l u s t r a t e the Trueta shunt (see Nervous Factors in Hypertension) i t was found that fardtdic stimulus of very low intensity applied to the splanchnic nerve plexus surrounding the renal artery produced a complete "blanching of the kidney of one experimental animal, while a stimulus of the same intensity e l i c i t e d no response from other animals ( r a t s ) .  The r a t showing a  marked response was an animal that had been treated a few days previously with desoxycorticosterone (for an experiment that could not be completed).  Speculation  over the p o s s i b l i t y that the hormone might have some influence on the induction of the renal shunt of Trueta led to further investigation. (1) Apparatus  and Methods.  The faradic stimulus was applied with a s i l v e r tipped electrode connected to a Harvard inductorium  66.  w h i c h was to  one  i n t u r n connected  l£ v o l t  The elicit  dry  moistened inals.  with  ondary c o i l  used was  when the  was  applied  stimulus  left  one  t h a t would  thumb and  s a l i n e and  When t h i s  a continuous  shock)  cell.  stimulus  sensation  (to g i v e  intact  had  just  i n d e x f i n g e r were  to  the  secondary  been o b t a i n e d  throughout  the  a l l the  term-  sec-  exper-  iments. O b s e r v a t i o n s were made by left ing  kidney  of a l l animals  electrode  from the  apart.  one  The  renal  applying  artery  about  the  the  stimulat-  1/8  o f an  inch  I n e a c h c a s e 3 s t i m u l i were g i v e n  kidney.  approximately ond  to the  and  exteriorizing  second  d u r a t i o n and  spaced  a n i m a l s were a n a e s t h e t i z e d  one  of  sec-  with  nembutal.  Trail a)  Five  served ney .  b)  1. i n t a c t male r a t s were t r e a t e d  for signs  of b l a n c h i n g  i n the  These a n i m a l s were c o n s i d e r e d  F i v e male r a t s t h a t  oxycorticosterone  had  surface as  preceding  the  for  renal  pallor^  c)  F i v e male r a t s were t r e a t e d  0.5  e a c h day  were s t i m u l a t e d  as  of  the  obkid-  controlse  each r e c e i v e d  intramuscularly  experiment  as above and  mgm.  for 4  and  desdays  observed  above 3 h o u r s a f t e r  67-  they had each received 1 intraperitoneal i n j e c t i o n of 0.5 mgm.  of antistine dissolved i n 0.5 ml. of physio-  l o g i c a l normal s a l i n e . (2)  Results.  T r i a l 1. a)  In no case was renal blanching obvious i n the intact  male rats after stimulation of the splanchnic  plexus.  b) and c ) In every case where the animals had received desoxycorticosterone acetate or a n t i s t i n e , marked blanching of the. surface of the kidney was  evident after stimul-  ation. (3)  Discussion. The above experiment has been through necess-  i t y , crudely performed, and  i s by no means conclusive.  However, i t does appear that on the basis of these resu l t s , further i n v e s t i g a t i o n into the matter would be of great i n t e r e s t .  Trueta (63) states that there i s  marked i n d i v i d u a l v a r i a t i o n i n the ease with which one can normally  obtain this shunt.  If the adrenal  cortical  hormones are involved i n such a manner i t would possibly elucidate the r e l a t i o n s h i p that apparently exists between hypertension  and the adrenal c o r t i c a l hormones.  68  (4)  Conclusions. Adrenal c o r t i c a l a c t i v i t y may be associated  with the mechanism c o n t r o l l i n g the "Trueta Shunt".  (5)  Summary, Animals treated with desoxycorticosterone  acetate or with antihistamine (antistine) appeared to be more responsive to a stimulus e l i c i t i n g the renal vasKcular shunt neither of these  (of Trueta) than animals receiving substances.  69.  THE EFFECT 0? DESOXYCORTICOSTERONE ACETATE ADMINISTRATION ON THE PRESSOR RESPONSE TO ADRENALINE IN THE RAT.  A.  Introduction. Adrenalectomy decreases the s i z e of the heart  and causes a f a l l In blood pressure.  It also sensitizes  animals to:the hypotensive action of various drugs (51) and p a r t i c u l a r l y to histamine (51a). It has also been observed by E l l i n g e r  (16)(17)  that mice irradiated with l e t h a l doses of X-rays, developed  c h a r a c t e r i s t i c pathological conditions, including  f a t t y degeneration of the l i v e r .  These changes, i t was  determined, were the r e s u l t of the elaboration of t o t a l body tissue breakdown products, which was histamine,  the most important of  or a histamine-like substance.  The d a i l y administration off DCA exerted a protective action and brought about a decrease i n the mortality r a t e .  F i t c h (20) and Semple (52) working i n  this laboratory, reported that the e f f e c t s of DCA overdosage could be antagonized by co-incident  administrat-  ion of histamine. It i s generally accepted that histamine w i l l antagonize the action of' adrenaline.  It was f e l t that  since DCA appeared to have antihistamic properties that  70...  i t might also augment the vascular response to pressor agents such as adrenaline.  It was  also considered that  since adrenaline w i l l e l i c i t the "Trueta Shunt" that investigations along these l i n e s might aid i n throwing some l i g h t upon the factors influencing renal vascular activity. (1)  Methods. Eight male Wistar rats were each given  one  intramuscular i n j e c t i o n of 1.0 mgm.  DCA  One day after the f i r s t dose ofT DCA  each of the 8 r a t s  was  d a i l y for 4 days.  anaesthetized and the blood pressure changes deter-  mined over aperiod of f i v e minutes immediately following  subcutaneous administration of 0.01 mgm.  -  a l i n e per kilogram of body weight.  of adren-  Pressor changes 1  subsequent to adrenaline administration were also observed on 6 control rats (not r e c e i v i n g DCA).  The  servations were repeated 4 and 6 days after the i n j e c t i o n of (2)  ob-  initial  DCA.  Results. The r e s u l t s are shown graphically i n F i g . 9*  It i s to be noted that the animals r e c e i v i n g the  DCA  showed a greater response to adrenaline than did those receiving no (3)  DCA.  Discussion.  4<V  /?0  I  1  I i  Day}  A  The blank bar represents the average increase i n blood pressure of 6 intact male rats following the subcutaneous i n j e c t i o n of adrenaline. The lined bar represents the average increase i n pressure following the subcutaneous i n j e c t i o n of adrenaline to male ratsr-pre-treated with intramuscular injections of DCA.  72.  The time duration of the pressor  response  was very short-lived and i n most cases the animals' syst o l i c pressure rose and dropped to normal l e v e l s within 5 minutes.  The animals could not he observed f o r  periods over 5 minutes after adrenaline administration, as i t tended to bring them out of the anaesthetic. A very interesting side effect was to occur.  observed  Pour of the animals receiving the DCA and  adrenaline became chronically hypertensive.  The s y s t o l i c  pressures ranged from values of'165 to 190 mm./Hg. The heart weight taken 45 days after the i n i t i a t i o n of t h i s 6  hypertension v e r i f y these findings KJey Tably V ) . l b incidence of hypertension occurred i n the 6 control animals and previous work (Effects of DCA on S y s t o l i c Pressure of Rats) shows that DCA given i n the amounts used i n this investigation w i l l not i n i t i a t e a sustained hypertension. (4)  Conclusions. Desoxycorticosterone  acetate administration  to male Wistar r a t s appears to increase the animals' pressor response (5)  to adrenaline.  Summary. The increase i n s y s t o l i c blood pressure  foll-  owing adrenaline administration was found to be greater  73  i n male Wistar rats receiving DCA than i t was not pre-treated  with  DCA.  i n rats  74.  SYNTHESIS  It i s i n t e r e s t i n g to note from t h i s work and from the work of others previously mentioned that l i v e r damage appears more or l e s s as a constant feature In the i n i t i a l stages of hypertension iology).  (regardless of i t ' s et-  The exact nature of the role played by the  l i v e r i n the " d e t o x i f i c a t i o n " of the steroid hormones i s obscure but i t i s generally accepted that i t i s the site of steroid catabolism (43). Several workers have shown that desoxycorticosterone  estrogen,  and progesterone are less active  when given v i a the l i v e r and more active i n the animal after hepatectomy.  It has also been shown that dietary  factors influence steroid metabolism and that the action of these hormones i s enhanced by general  i n a n i t i o n and  by c e r t a i n avitaminoses. It has been observed that estrogen w i l l cause a reduction i n the size of the l i v e r (see Est. and Blood Pressure), and that DCA w i l l cause degenerative changes (60)  i n the l i v e r such as f a t t y i n f i l t r a t i o n , hyperemia,  f o c a l necrosis, and hemorrhagic l e s i o n s . Demonstration of a hepatic vasodepressor substance has been claimed tigators (7, 10.  i n recent years by several inves-  56, 57t 58, 59i 72).  75.  In view of the foregoing information, the following chain of events could conceivably occur:1)  A n u t r i t i o n a l d e f i c i e n c y renders the l i v e r incapable  of metabolising c e r t a i n steroid hormones. 2") Normal concentrations of these steroids under these circumstances become toxic to the l i v e r (and possibly the kidney) and i n i t i a t e damage* 3)  The damage could constitute a stress that occasions  further steroid secretion from the adrenal cortex and aggravates the damage (vicious c y c l e ) . 4)  The damaged l i v e r becomes incapable of elaborating  vasodepressor material and subsequent vasoconstriction and hypertension occurs, and/or the f a i l u r e of the l i v e r to "detoxify" steroid hormones ( p a r t i c u l a r l y c o r t i c o i d s ) allows them to reach nephro-toxic l e v e l s .  It would be  of interest to know whether or not hypertension i s preceded by l i v e r damage or l i v e r dysfunction. There seems to be l i t t l e doubt that the inherent action of estrogen i s one of lowering the blood pressure ( v i a vasodilatation) (50).  However, the second-  ary pressor e f f e c t appears to be due to the corticomimeti c action of t h i s compound ( 6 4 )  (30).  The remarkable feature of t h i s hormone i s that  76.  i t has, i n t h i s investigation shown i t s e l f to he more active i n r a i s i n g the "blood pressure than has DCA, and that such pressor e f f e c t s are not dependent on the s a l t intake of the experimental animal.  If i t causes stim«  u l a t i o n of the entire adrenal cortex and the secretion of several c o r t i c a l factors, i t may prove true that one of these factors has a much greater pressor a c t i v i t y than has desoxycorticosterone.  In t h i s regard, i t i s  i n t e r e s t i n g to note that Selye and others have given no adequate account of why s a l t i s such an important faetor i n the production of nephrosclerosis and hypertension through DCA overdosage.  An explanation of the influence  of s a l t i s suggested below. The action of desoxycorticosterone i s to maint a i n the balance of e l e c t r o l y t e s i n the blood.  It  affects the r e t e n t i o n of sodium and the excretion of potassium  (35).  Kendall (35)  n a  tomized rats can be maintained  s shown that adrenaleci n d e f i n i t e l y under labor-  atory conditions when large s a l t supplements are added to t h e i r d i e t .  It i s l o g i c a l to assume therefore, that  the desoxycorticosterone requirements  of the organism  decrease with an increase i n s a l t intake.  If an animal  is given large amounts of sodium chloride and simultaneously overdosed with DCA i t would appear that the hormone, unless metabolized to some other compound, would induce sodium retention and that the sodium levels i n  77* the blood would r i s e r a p i d l y and v i o l e n t l y disturb water and electrolyte balance.  The e f f e c t upon the organism  would be extremely detrimental i f not f a t a l (35)»  This  l a t t e r syndrome does not occur probably because the  ex-  cess of hormone causes a metabolic mechanism to convert i t to another hormone of similar structure but with d i f f erent a c t i v i t y * It i s the f e e l i n g of this author that DCA i s not i n i t s e l f responsible for the pressor changes that are attributed to i t and that another c o r t i c a l factor i s involved.  It has previously been suggested that vascular r e a c t i v i t y may be involved i n the etiology of  hyperten-  sion (see - F a c i l i t a t i o n of Trueta Shunt, The  Influence  of DCA  on Pressor Response to Adrenaline). B r i e f l y stated, the theory suggests that a  lack of a vasodepressor material (such as histamine) the blood augments vascular a c t i v i t y and  In  facilitates  vasoconstriction, and that c o r t i c a l hormones antagonize i n some manner the vasodepressor action.  It was  observed  i n the course of these investigations, renal c o r t i c a l blanching (vasoconstriction) was more e a s i l y stimulated after the administration of DCA al and the DCA ine.  to the experimental  anim-  increased the pressor response to adrenal-  78 There may he more than a casual r e l a t i o n s h i p between these phenomena and the Trueta shunt. ion was  augmented by either DCA  I f vasoconstrict-  or a lack of histamine  (or similar substance) i t would be expected that vasoc o n s t r i c t i o n i n the cortex of the kidney would occur? more e a s i l y and more frequently, thus producing renal ischemia and consequent renal damage. Renin can be detected i n the blood during the i n i t i a l stages of hypertension, but cannot be detected during the l a t e r phases of hypertension.  It has been  claimed that pressor agents other than renin can be demonstrated i n the blood of chronic hypertensives, but the claims are not well substantiated and not at a l l convincing.  It appears as though renin functions primarily  to raise the blood pressure to the levels required to ensure; adequate renal c i r c u l a t i o n only for the time i t takes for another pressure increasing mechanism (adrenal cortex responding to stress?) to become f u n c t i o n a l .  79  SUMMARY Male Wistar rats were divided into 3 experimental groups. a)  The 8 animals of the f i r s t group each received 1  intramuscular i n j e c t i o n of 1.0 mgm. of desoxycorticosterone acetate.  Blood pressure determinations made  over a 10 day period revealed no pertinent pressor changes. b)  The 6 animals of the second group each received 1  intramuscular i n j e c t i o n of 1.0 mgm. desoxycorticosterone acetate d a i l y for 6 days.  A transient increase i n the  s y s t o l i c pressure of each r a t was observed.  The highest  pressure l e v e l was 165 mm./Hg. and occurred i n 12 days. A l l pressures had returned to normal by day 16. c)  The 8 animals of the third group whose diet contained  supplementary s a l t , were each injected intramuscularly with 1.0 mgm. of desoxycorticosterone daily for 14 days. The s y s t o l i c pressure of the animals reached an average value of 177 mm./Hg. i n 17 days, dropped to an average value of 170 mm./Hg. on the twentieth day and tended to remain at t h i s point i n d e f i n i t e l y .  . a) The administration of 0.5 mgm. of e s t r a d i o l dipropionate d a i l y f o r 5 days to each of 6 intact and 6 castrate male Wistar rats produced an average increase  8o.  i n the s y s t o l i c blood pressure of 100 mm./Hg.  The cas-  trate animals were found to he more sensitive to the pressor e f f e c t s of estrogen than were the intact males. The induced hypertension was sustained without further treatment. b)  The administration of 0.5 mgm;  pionate d a i l y f o r 2 days, produced  of e s t r a d i o l diproa transient r i s e i n  the s y s t o l i c blood pressure of 3 intact male r a t s . Castrate male rats treated s i m i l a r l y showed a sustained pressor response. c)  One i n j e c t i o n of 0.5 mgm.  of e s t r a d i o l dipropionate  to each of 4 intact male Wistar r a t s appeared  to produce  a slight, transient decrease i n blood pressure. Four male Wistar rats withhyertension secondary to renal lesions induced by a n u t r i t i o n a l choline deficiency were injected subcutaneously with 0.5 mgm. of e s t r a d i o l dipropionate d a i l y f o r 4 days and were found to respond with a sustained increase i n s y s t o l i c blood pressure. Eight male Wistar r a t s were maintained 5 days on a choline d e f i c i e n t d i e t .  The animals were returned  to a normal d i e t and 4 of the 8 rats were each given 1 i n j e c t i o n d a i l y , for 3 days, of 1.0 mgm. of desoxycorticosterone acetate.  The animals r e c e i v i n g the hormone  81.  developed hypertension i n 1/2 to 1/3 the time required for the control animals to develop the syndrome. Nine male Wistar rats were placed on a subminimal d i e t for 30 days.  Five animals received i n t r a -  muscular injections d a i l y of 1.0 mgm.  desoxycorticoster-  one acetate for 5 days during the period of i n a n i t i o n and for 5 days immediately following i t . eived no hormonal treatment.  Four animals rec-  Both the starved animals  receiving desoxycorticosterone acetate and the starved controls were found to be hypertensive (0 days after t h e i r return from the subminimal to the normal d i e t ) . The hormone apparently had no e f f e c t .  The blood press-  ure change was believed to be the r e s u l t of the r e n a l lesions that were found to be present. a)  Five rats each receiving 1 i n j e c t i o n of. 1.0 mgm.  of  the antihistamine, a n t i s t i n e , every second day u n t i l 5 i n j e c t i o n s had been given each animal, showed an immediate increase i n s y s t o l i c pressure to an average value of 220 mm./Hg* that wa3 l i t t l e affected by further a n t i histamine administration*  The blood pressure changeswas  sustained i n d e f i n i t e l y with no further treatment. b)  One intraperitoneal i n j e c t i o n of 1.0 mgm.  stine was given each of 5 male Wistar r a t s .  of a n t i It was  obser'  ved that the maximum pressure response occurred 1$ to 2 hours after i n j e c t i o n , at which time the average s y s t o l i c  82.  pressure of the 5 animals was 225 mm./Hg. Within a period of 20 days the average s y s t o l i c pressure decreased to 175 mm./Hg. and rose again to an average value of 190 mm./Hg. where i t remained.  Thus chronic hyper-  tension was produced hy 1 i n j e c t i o n of 1.0 mgm. a n t i s t i n e . C/)  The blood pressure changes i n 4 Wistar rats that  occurred immediately following antistine i n j e c t i o n were observed p e r i o d i c a l l y throughout  2 hours.  It was found  that following these injections of antistine the blood pressure dropped immediately  to abnormally low l e v e l s  arti then increased to hypertensive l e v e l s within 2 hours. d)  An intramuscular i n j e c t i o n of 0.1 mgm. of antis-  tine to each of 3 rats caused an average elevation i n s y s t o l i c blood pressure of 20 mm./Hg.  The pressures  returned to normal values within 48 hours.  An i n t r a -  muscular i n j e c t i o n of 0.01 mgm. of antistine to each of 3 male Wistar rats caused a temporary decrease i n blood pressure of 14 mm./Hg.  The s y s t o l i c pressures were  found to be normal after 40 hours. e)  The oral administration of 100 mgm. antistine to  6 humans caused an average decrease i n blood pressure of 15 mm./Hg.  The blood pressure of the subjects was  normal 26 hours after the drug was administered. f)  Pyribenzamine was found to produce the same e f f e c t s  83. as  antistine.  T h e s e compounds  were a l s o f o u n d  a c t i v e when g i v e n s u b e u t a n e o u s l y  t o be a s  as when g i v e n  intra-  peritoneal ly. F i f t e e n male W i s t a r groups.  One g r o u p a c t e d  intramuscular  injections  and  received  the t h i r d  r a t s were d i v i d e d i n t o  3.  as c o n t r o l s , the second r e c e i v e d of desoxycorticosterone  an i n t r a p e r i t o n e a l  acetate  injection of  antihistamine.  The every and  animal  nerves surrounding  were  stimulated with  the e x t e r i o r i z e d  kidney  I t was f o u n d  that  received cesoxycorticosterone  the r e n a l  artery of  a weak f a r a d i c  observed  i n both acetate,  current  f o r blanching.  the animals  that  and t h e a n i m a l s ?  t h a t r e c e i v e d a n t i h i s t a m i n e marked r e n a l c o r t i c a l  blan-  c h i n g was e v i d e n t .  prev-  ious treatment  In those  animals  r e c e i v i n g no  no r e n a l c o r t i c a l b l a n c h i n g was  evident.  84. LITERATURE CITED 1.  Beat, C.H., 1949  2.  Biskind, M.S., and Shelesnyak, M.C. 1942 The r e l a t i o n s h i p between vitamin B complex deficiency and the capacity of the l i v e r to inactivate estrogens. Endocrinology, 30, 819.  3.  Biskind, M.S., and Biskind, G.R. 1942 The relationship between vitamin B Complex deficiency aid the capacity of the l i v e r to inactivate estrogen. Endocrinology, 31, 109.  4.  Blalock, H., and Levy, S.E. 1937 Studies on the etiology of renal hypertension. Ann. Surg., 106, 826.  5.  Bright, R.  6.  Castleman, B., arid Smlthwick* R.H. 1943 The r e l a t i o n of vascular disease to the hypertensive state based on the study of renal biopsies from 100 hypertensive patients. J.A.M.A., 121, 1256.  7.  Chambers, R., Sweifach, B.W., Lbwenstein, B.H., and Lee, R.E. 1944 Vasoexcitor and -depressor substances as "toxic" factors i n experimentally produced shock.. Proc. Soc. E x p t l . B i o l . and Med., 56, 127.  8.  Child, 1938  9.  and Hartroft, W.S. N u t r i t i o n , renal lesions and hypertension. Eed. P r o c , 8, 610  I836 1827  Reports Med. Gases, London Guys. Hosp. Rep., 1,.338  C.G.  Corcoran, 1948  Observations on pathological changes f o l l owing experimental hypertension produced by c o n s t r i c t i o n of the renal artery. J. E x p t l . Med./ 67, 521.  A.C. The renal pressor system and experimental and c l i n i c a l hypertension. Recent Progress i n Hormone Research.  3, 325.  85  10.  Culbertson, J.W., Wilkins, R.W., Ingelfinger, F.J., and Bradley, S.E. 194-7 The effect of the upright posture on hepatic blood flow i n normal and i n hypertensive human subjects. J . C l i n . Investigation,  26,  H78.  11.  Cruz-Coke, E. 1946 Mechanism of renal hypertension i n Goldring and others, experimental hypertension. New York: The New York Academy of Sciences  12.  Darrow, D.C., and M i l l e r , H.C. 1942 Production of cardiac lesions by repeated i n j e c t i o n of desoxycorticosterone acetate. J . C l i n . Investigation 21, 601.  13.  Dexter, Lewis 1946 Translation of Renal Hypertension: Braun-Mendez, et a l . Review of the r e l a t i o n o f the adrenal cortex to the maintenance of the hypertensive state. Charles Thomas, S p r i n g f i e l d . 219 -  227.  14.  Dougherty, T.F. 1948 Relation of adrenal c o r t i c a l stimulation to h i s t o l o g i c a l alterations i n the k i d neys and cardiovascular tissues of mice, i n : Factors regulating blood pressure. Transaction of the Second Conference. New York, N.Y. - Josiah Macy, J r . Foundation New York, N.Y.  15.  Dean. H.W., 1948  and Olson, R.E. Hypertrophy of the adrenal cortex of weanling r a t s which e x h i b i t the syndrome of hemorrhagic kidney. Anat. Rec., 100,  16.  E l l i n g e r , F. 1946  21.  Protective action of DCA against X-ray induced l i v e r damage. Science 104, 5 0 2 .  86.  17.  ibid. 194-7  Some effects of DCA on mice irradiated with X-rays. Proc. Soc. E x p t l . B i o l . Med. 64,  18.  Ellis, A 1938  31.  H i s t o l o g i c a l studies on human patients with malignant hypertension. Lancet 1, 9 7 7 .  19.  F a r r i s , E.J., Yeakel, E.H., and Medoff, H. S. 1945 Development of hypertension i n emotional gray Norway rats after a i r b l a s t i n g . Amer. J . P h y s i o l . 144, 3 3 1 .  20.  P i t c h . H.F. 1947  21.  The amelioration of experimental hyper* tension by h i s t i d i n e and ascorbic acid, Masters' Thesis, University of B r i t i s h Columbia.  Friedman, M., and Kaplan, A. 1943 Studies concerning the rate of renin formation i n the kidney IV. The r e n i n content of the mammalian kidney f o l l owing s p e c i f i c necrosis of the proximal convoluted tubular epithelium. J. E x p t l . Med. 77, 6 5 .  22.  Garai, 0 . 1945  Immersion as a factor in the development of hypertension. B r i t . Heart J . , 7, 2 0 0 .  23.  Goldblatt, H. 1937  Studies on experimental hypertension V. The pathogenesis of experimental renal hypertension due to renal ischaemia. Ann. Int. Med. 11, 6 9 .  24.  Goldblatt, H., Lynch, J . , Hanzal, R.F. and Summerv i l l e , W.W. 1934 J . E x p t l . Med. 59, 347.  87. 25»  Goldring, W., and Chasis , H. 1944 Hypertension and hypertensive disease. New York, Commonwealth Fund.  26.  Goormaghtigh, N. 1944 La fonction endocrine des arterioles renale s. Louvain, L i b r a r i e R. Fonteyn.  27.  ibid 1945  28.  Vascular and circulatory changes i n the renal cortex i n the anuric crush syndrome Proc. Soc. E x p t l . B i o l . N.Y.,  59, 303.  29*  G r i f f i t h , J.O., and F a r r i 3 , E . J . 1942 The Rat i n Laboratory Investigation Lippincott, Philadelphia 274 Grimson, K.W., Bouckaert, J . J . and Heymans, C. 1939 Production of a sustained neurogenic hypertension of renal o r i g i n . Proc. Soc. E x p t l . B i o l . , N.Y. 42, 225.  30.  Grollman, A. 1947  31.  •32.  ibid. 1948  Essentials of Endocrinology. J.B. Lippincott Co., P h i l a d e l p h i a  519  The role of the kidney i n the pathogenesis of hypertension as determined by a study of the effect of nephrectomy on the blood pressure of normal and hypertensive animals; i n factors regulating blood pressure. Transactions of the second conference, New York, N.Y. - Josiah Macy, Jr. Foundation, New York, N.Y.  Helmer, O.M. 1948 The nature of a p r i n c i p l e which e l i c i t s a sustained pressor response i n hephrectomized animals, i n Factors Regulating Blood Pressure. Transactions of the second conference, N.Y. - Josiah Macy, Jr. Foundation, New York, N.Y.  88. 33  Hey man,  1937  C,  The regulation of blood pressure and vasomotor tone. I r i s h J". Med. S c i . , Sixth series  717  34.  Kaufmann, W.  1942  The Goormaghtigh c e l l s i n normal and diseased kidney - Their possible r e l a t i o n to hypertension. Amer. J . Path.,  18, 783.  35«  Kendall, E.C,  1948  The influence of the adrenal cortex on the metabolism of water and e l e c t r o l y t e s . Vitamins and Hormones  277.  36.  Knowlton, et a l . Development of hypertension and nephritis 1949 in normal and adrenalectomized rats treated with cortisone. Proc. Soc. Expt. B i o l . Med.  72, 722.  37.  Logan, J..R.  38.  Moritz,  1949  A.R.  1937  H i s t o l o g i c a l Studies i n Hypertensive Rats. Masters* Thesis. University of B r i t i s h Columbia. and uidt, M.R. A r t e r i o l a r s c l e r o s i s i n hypertensive and non-hypertensive i n d i v i d u a l s . Am. J . Path.,  20, 155  39.  Medoff,  1945  a.W.  and Bongiovanni, A.M. Blood pressure i n rats subject to audiogenic stimulation. Am. J . P h y s i o l .  300  40.  Page, I.H.  1938  The effects of b i l a t e r a l adrenalectomy on a r t e r i a l blood pressure of dogs with experimental hypertension. Am. J . P h y s i o l .  122, 352.  41.  (Personal communications with Dr. Munro, M.D. i a l i s t of internal medicine.)  - spec-  89 42.  ( P e r s o n a l communications w i t h D r . Wood, D e a n o f Pharmacy, U n i v e r s i t y o f B r i t i s h Columbia)  43,  P i n c u s , G., 1948  44.  Pfeiffer, 194-6  and Thimann, K.U. The Hormones, V o l . I, p.4^3 and p.602 Academic P r e s s I n c . P u b l i s h e r s , flew ¥ork  C.A., and D r i l l , V.A. On t h e r e l a t i o n o f v i t a m i n B c o m p l e x d e f i c i e n c y and i n a n i t i o n t o t h e i n a c t i v a t i o n o f estrogens i n the l i v e r . Endocrinology  38, 300.  45.  Schroeder, 1948  H.A., O l s e n , U.S., and Goldman, M.L. P r e s s o r s u b s t a n c e s i n human h y p e r t e n s i v e blood - i n f a c t o r s r e g u l a t i n g blood pressure. Transactions o f the second conference J o s i a h Macy - J r . F o u n d a t i o n , l e w * o r k .  118.  46.  S e l y e , H. 1942  P r o d u c t i o n o f n e p h r o s c l e r o s i s by o v e r dosage w i t h DCA J.A.M.A.  47, 515  47.  S e l y e , H., H a l l , C.F., and R o w l e y , R.M. 1943 Pathology of desoxycorticosterone dosage I n v a r i o u s s p e c i e s . Arch. Path.  over-  36, 19.  48.  S e l y e , H. 1943  On t h e p r o d u c t i o n o f m a l i g n a n t h y p e r t e n s i o n b y c h r o n i c e x p o s u r e t o v a r i o u s damaging agents. Rev. C a n a d . De B i o l . 2,  501.  49.  S e l y e , H. 1948  Endocrinology - Montreal, Acta Endrocrinologica, U n i v e r s i t e de M o n t r e a l  159.  50.  ibid:  359  51.  ibid:  122  51a  ibid:  112  Canada  90. Semple, R,  1946  The amelioration of experimental hyper* tension by h i s t i d i n e and ascorbic acid, Masters * t h e s i 3 . University of B r i t i s h Columbia.  Shipley, R.E. 1948 The presence i n the blood of a p r i n c i p l e which e l i c i t s a sustained pressor response i n nephrectomized animals - i n , Factors regulating blood pressure. Transactions of the second conference Josiah Macy - J r . Foundation, N.Y.  159  Shipley, R.A., and Gyorgy, P. 1944 On the r e l a t i o n of l i v e r to the i n a c t i v ation of estrogens; Proc. Soc. E x p t l . B i o l . Med.  57, 52.  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Vasotropic content of blood i n chronic hypertension (man, dogs) Fed. Proc.  7, 115.  91. Sinaiko, E., and Necheles, H. 1949 Liver damage induced "by DCA Science,  109, 37.  Rixon, R. 1950  Experimental hypertension Masters' Thesis University of B r i t i s h Columbia.  Thorn, G.W., Nelson, R. K., and Thorn, D.W. 1936 The mechanism of edema associated with menstruation. Endocrinology,  22, 155.  Trueta, J . Barclay, A.E., Daniel, P.M. Franklin, K.J., and Prichard, * . L . 1947 Studies of the renal c i r c u l a t i o n Charles C. Thomas, S p r i n g f i e l d , I l l i n o i s . Turner, 1948  CD. General Endocrinology W.B. Saunders Co. Philadelphia 344  Vernez, E.B., arid Vogt, M. 1948 An experiment al investigation into hypertension of renal o r i g i n , with sone observations on convulsive uremia. Quart. J . E x p t l . P h y s i o l .  28, 253.  Wakerlin, G.E.; Marshall, J . Minatoya, H. 1948 Reniri concentration of the kidney i n experimental hypertension - i n Factors regulating blood pressure - p; 6 l . Transactions of the second conference,N.Y. Josiah Macy * J r . Foundation, N.Y. Weiss, E . 1942  Psychosomatic J.A.M.A.  aspects of hypertension.  120, 1081  Wilson, C , and Pickering,.. G.W. 1938 Acute a r t e r i a l lesions i n rabbits with experimental renal hypertension. Clin Sci.  3, 343.  92. 69.  Wilson, C , and Byrom, J J ' . B . The Y i c i o u s c i r c l e i n chronic Bright's " disease. Quart. J . Med., 21".S.  10, 65.  70.  Wirtschafter, Z.T., and Weidman, R. 1947 The elaboration of histamine i n vivo. J.A.M.A.  133, 604  71.  Zweifach, B.W., and bhorr, is. 1948 Hepato-renal vasotropic factors i n blood of patients with e s s e n t i a l hypertension i n Factors regulating blood pressure Transactions of second conference B.Y. Josiah Macy - J r . Foundation, H.Y.  /72.  Zweifach, B.W., Shorr, E . , and Baez, S. 1947 Hepato-renal f a c t o r s i n c i r c u l a t o r y homeostasis XI. A vasoexcitor p r i n c i p l e i n the blood of hypertensive dogs. Fed. Proc.  6, 200.  

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