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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 in part i a l fulfillment of the requirements for 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 in the presence of excess dietary salt. 2. Estrogen overdosage produced hypertension in rats. Castrate animals were more sensitive to the effects of estrogen. Estrogen overdosage aggravated experimental hypertension induced by nutritional choline deficiency. 3» A period of nutritional choline deficiency was followed by hypertension. Desoxycorticosterone accelerated the development of hypertension in choline deficient animals. 4. Hypertension developed in rats 2 months after a pro-longed period of inanition. Antihistamine was found to induce profound variations in the blood pressure of male rats. 6. Rats pre-treated with desoxycorticosterone acetate showed a greater pressor response to adrenaline than normal intact rats. 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 to: Dr. A.H. Hutchinson, under whose authority this work was carried out • Dr. John Allardyce, under whose personal direction this 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 for the complementary research information he made available. Thanks are equally due to: Mr. E. Eung, for his willing donation of time and valuable assistance. Miss. L. Cowie, for her gracious aid in procuring scarce material. Mr. G. Morrison and Mr. H. Radford for their co-operation as experimental subjects. TABLE OF CONTENTS The Effect of DCA on the Development of Hypertension Secondary to Renal Damage <^ tnd) Induced by Choline Avitaminosis. 7 36 /A^ (jEntroduc tion 36 ?Tl) Methods 36 / (2) Results 37 j (3) Discussion 42 (4) Conclusions 43 (5) Summary 43 The Effect of Starvation on the Blood Pressure of Wistar Rats 44 A Introduction 44 Methods 45 Results 45 Discussion 47 Conclusions 48 Summary 48 The Effects of Antihistamines on the Blood Pressure of Male Wistar Rats 49 Introduction 49 3> C (1) Methods 50 (2) Results 53 (3) Discussion 58 (4) Conclusion 62 / (5) Summary . 6 . 4 The Eaci l i t a t i o n of the Trueta Shunt by Desoxy-corticosterone Acetate and by Antihistamine 65 ^ !_Introduction 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 in the HaT 69 QO) pEntro due tion 69 (1) Methods J2) Results ,3) Discussion i(4J Conclusions 1(5) Summary Synthesis Summary Literature Cited 1 INTRODUCTION A. Historical Review Hypertension constitutes one of the most serious problems facing c i v i l i z e d man. Goldring and Chasis (25) in 1944 estimated that in the United States this condition accounts annually for more than one third of the total number of deaths. Richard Bright (5) in 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 factor i n the etiology of hypertension. It i s now clear that organic renal lesions precede the onset of hypertens-ion in a considerable number of cases, but there is a large group of cases where organic renal disease is not an obvious precursor of the hypertension. This group is comprised of the cases of so-called essential hyp-ertension. The work of Goldblatt et a l (24) in 1934 marked an epoch in the experimental investigation of experimental hypertension. They showed that transient hypertension could be produced in dogs by partially constricting the renal artery. By moderately constric-ting both renal arteries, or by constricting 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 (68), Wilson and Byrom (69), 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 in the ischemic kidney of a pressor substance which escaped into the general circulation. In 1946 Cruz - Coke (11) showed that lack of oxygen is of v i t a l importance at certain stages in the formation of pressor substance. Anoxia presumably dev-elops with decreased blood flow in the kidney. At the present time hypertensive patients are classified into two main groups, namely; those in whom organic renal disease i s recognized by a l l to be the cause of the hypertension (secondary hypertension) and those in whom no organic renal disease is apparent, and the cause of the hypertension is obscure (essential or primary hypertension). In secondary hypertension the cortical anoxia is caused from the outset by organic change but the etiology of the theoretical renal cortical anoxia of essential hypertension has remained unknown. 3. B. Theories on the Etiology of Hypertension The number of cases of hypertension in man that can be attributed to a reduction in calibre of the renal arteries by mechanical obstruction (i.e. atheroma, thrombi) is small and as an etiological factor such obstruction can be discounted. (1) Vascular Origin Goldring and Chasis (25) consider that renal arteriolosclerosis with resultant renal cortical anoxia does not precede the development of essential hyperten-sion, although i t is a concomitant of consequence of hypertension. Castleman and Smithwick (6) in 194-3 ex-amined renal biopsy specimens from one hundred hyperten-sive patients, and concluded that the evidence of renal vascular disease in more than one half of the cases was inadequate to prove this to be the sole factor in prod-ucing high blood pressure. Work done in this laboratory in 194-8 by Logan (37) showed that there was no marked vascular deg-eneration in kidneys of rats hypertensive three to eight months. However, ffloritz and Oldt (38) and E l l i s (18) reported that post-mortem findings in cases of essential hypertension almost constantly revealed intra-renal vascular damage as well as widespread arteriolar sclerosis. Child (8) suggested in 1938 that although the i n i t i a t i n g factor is unknown, induced arteriolar disease might account for the maintenance of hypertension. (2) Hormonal Origin. The role of the adrenal cortex in the induc-tion and maintenance of hypertension i s , at present, imperfectly understood. It's secretions however, are essential to the experimental establishment and mainten-ance of high blood pressure (4, 13, 23, 40). In 1942 Selye (46) produced nephrosclerosis and cardiac hypertrophy in chicks by overdosage with the adrenal cortical hormone desoxycorticosterone. Henal lesions included cloudy swelling of the tubules and hy-pertrophy and hyperplasia of both parietal and visceral layers of Bowman's capsule. The blood vessels appeared intact and blood pressure changes were not significant. Darrow and Miller (12) in 194? observed that DCA overdosage in rats produced necrosis of the cardiac musculature and hypertrophy of the renal tubules. Selye et al (47) in 1943 produced experimen-t a l malignant hypertension in rats receiving excess dietary salt 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 cold. Hypertrophy of the adrenal was a characteristic feature of this treatment. Corcoran (9) in 1948 pointed out the fact that patients manifesting "Cushing's Syndrome" are generally hypertensive and show functional levels 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 arteriosclerotic lesions similar to those produced by administration of large amounts of desoxycorticosterone acetate were observed following daily treatment of mice with adrenotrbphic horm-one for a period of weeks. The tendency of Addisonians to develop hyper-tension after replacement therapy with desoxycorticosterone acetate (DCA) has long been recognized (49). General reports also indicate that the ACTH used for arthritic therapy frequently produces hypertension. Nephritis and hypertension is 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 ad-renal gland, as previously mentioned, is not known. How-ever, the evidence that has accumulated in recent years indicates that i t is undoubtedly involved in the chain of events that terminates in hypertension* (3) Nervous Origin. The possibility that psychogenic renal vasocon-str i c t i o n may be a factor in the etiology of human essen-t i a l hypertension has been recognized by various workers, and a consideration of the psychological factors in essen-t i a l hypertension i s given by Weiss (67). Nevertheless there is considerable difference in opinion as to whether the nervous system i s of etiological importance in this condition. Garai (22) found that shipwrecked sailors 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 test). He sugg-ested that the reflex constriction of the vessels of the kidney, known to be caused by exposure to cold, had played a part in producing hypertension. Medoff and Bongiovanni (39) and Farris, Yeakel and Medoff (19) found that they were able to produce hypertension in rats by stimulating repeatedly with intense noise. Heymana (33) and Grimson, Bouckaert and Heymans (29) record the production of sus-tained hypertension in 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 Circulation. Trueta, Barclay, Daniel, Franklin and Prichard (31) in 194-7 made an important contribution to the physio-logy of the kidney and to the study of the nervous elem-ent involved in essential hypertension. They discovered that the blood reaching the kidney has two potential routes through that organ and, according to the circum-stances, 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 arterioles of the juxtamedullary glomeruli leave the interlobular arteries. One route, the medullary, continues through the juxtamedullary glomeruli, the efferent vessels of -these glomeruli and their derivative vasa recta, to the inter-lobular veins. The other route, the cortical, continues through the interlobular arteries, to the afferent arter-ioles of the remaining glomeruli, these glomeruli them-selves, their efferent vessels and the cortical inter-tubular capillary 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 is poorly supplied with blood and the cortical circulation predominates. However, under certain conditions the medullary circulation pred-ominates while circulation through the cortex a l l but ceases. 8 . The evidence ia aa follows The outer layers of the cortex of the kidney-can he blanched by stimulating the peripheral end of the cut splanchnic nerve, by stimulating the nerve plexus surrounding the renal artery, by injecting adrenaline, pit-u i t r i n or pitressin and reflexly, by stimulating the central end of the cut sciatic nerve, or placing a tourn-iquet round the thigh for some hours. Sectioning of the splanchnic nerve causes a flushing of the cortex and ab-olishes reflex effects. It is d i f f i c u l t to evaluate the significance of this work. - It is pertinent however that in the kidneys of elderly human subjects, and those suffering from hyper-tension, many of the juxtamedullary glomeruli were of a degenerate type. It seems as i f one particular capillary channel in a glomerulus can become wider and wider ow-ing, i t is suggested, to the strain of repeated diversion of blood through this part of the kidney, ^  until the glomerulus is no longer a functioning mechanism. A true short circuit of this kind is presumed to be vir 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 cortical circulation. It is sugg-ested by Trueta et a l . that this discovery points the way to a rational explanation of the way in which psycholog-i c a l factors contribute to the induction of essential hypertension. So far as experimental hypertension i s concerned, i t is suggested that cortical ischaemia in the intact an-imal, brought about by stimuli of intense reflex or emot-ional origin, or more easily in susceptible subjects, is equivalent to the Goldblatt clamp, and that conversely, the latter acts in virtue of the jschaemia which i t suppos-edly induces in the cortex. (4) The Nature of the Renal Pressor Mechanism. Investigators seem to be agreed that hypertension of renal origin is due to some humoral pressor substance formed in the kidney, but i t has not been definitely est-ablished where in the kidney this substance is produced. Opinion favors the renal cortex as the source of pressor substance. Goormaghtigh ( 2 6 , 27) has described granular, a f i b r i l l a r cells in the walls of the arterioles of the renal cortex and in the juxtaglomerular apparatus, and as he found that these cells were larger and more numerous in experimental animals with renal ischaemia, he suggested they secreted and liberated a pressor substance. Goormaghtigh (27) also observed the enlargement of these cells in the fatal crush syndrome. Eaufmann (34) found hypertrophy of these cells in the kidneys of patients with hypertension. Friedman and Kaplan (21) believe, on the 10 other hand, that the pressor substance is formed in the cells of the proximal convoluted tubules. It has long been known that a substance called renin, elaborated by the kidney, will,, causec a rise in blood pressure. This substance is apparently an enzyme that acts on a plasma globulin ( d ^ globulin) to produce a pressor substance called hypertensin. The role renin plays in essential hypertension i s not clear. Repeated injectipns of i t e l i c i t a progressively decreasing resp-onse (tachyphylaxis) and i t cannot be regularly found in the blood of chronic hypertensives (45). Wakerlin et a l . (66) conclude that there i s no correlation between the renal renin concentration and the level of experimental renal hypertension, either chronic or malignant. Work in recent years has indicated that other vasodepressor and vasoexcitor principles may be in-volved in hypertension but the nature of these principles and their mode of action i s , as yet, obscure (32, 45, 53, 66, 76) 1 1 . APPARATUS AND METHODS USED IN DETERMINING THE SYSTOLIC PRESSURE IN RATS. : A. Apparatus. The blood pressures of the rats were measured indirectly by observing the pressure required on the thigh of the anaesthetized animal -ftee-e-e-ea*^ - to stop the blood flow in the capillaries of an interdigital web. The method is described by G r i f f i t h and Farris 128), and modifications found useful in this laboratory have been reported by Fitch ( 2 0 ) and Semple ( 5 2 ) . Photographs of the apparatus are shown in Plate I. B. Methods. a( Anaesthesia. Fitch ( 2 0 ) and Semple ( 5 2 ) satisfactorily stan-dardized 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 encountered when applying the technique. The rats were anaesthetized by giving them intraperitoneal injections of a solution of sodium pen-tothal. It was found that 0 . 3 5 nil* of a freshly prepared solution of 2 5 mgm. sodium pentothal dissolved in 1 . 0 ml. of d i s t i l l e d water injected intraperitoneal ly was sufficient to anaesthetize a rat weighing 1 5 0 gm. This 12. dose was increased 0.05 ml» for every increase in weight of 50 8m» The action of the anesthetic was more reliable when the animals were l e f t without food for 2 hours before anaesthetization. It was also observed that i f the i n i t -i a l injection did not produce a profound enough anaesthes-ia that an extra 0.1 ml. of pentothal could be adminis-tered with no apparent deleterious effect on the animal. PLATE I. The photograph on the right illustrates the apparatus used in determining the systolic blood pressure of rats (see text) The photograph on the right is a vertical view of the microscope stage showing the toes of the hind leg of an anesthetized rat pinned out (with plasticene) for observat-ion of the interdigital 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 Fitch (20) working in this laboratory found that one intramuscular injection of 1.0 mgm. of DCA sufficed to produce a transient hyper-tension in Wistar rats. The following investigation was undertaken in order to confirm their results and to note the effect of dietary salt 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 in o i l . The systolic blood press-ures of these animals and 8 control animals were det-ermined daily for 10 days. Tr i a l 2. Six male Wistar rats were each given daily for 6 days, intramuscular injections of 1.0 mgm. of desoxycorticosterone acetate in 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 injection of 1.0 mgm. of desoxycortico-sterone every day for 14 days. Four days "before the experimental treatment 1% salt was added to the drink-ing water of the animals and supplementary salt was given throughout the course of injections. The systol-ic pressures were determined throughout a period of 3° days. (2) Results. T r i a l 1. The results are presented graphically in Fig. 1. No pertinent changes in blood pressure were observed with the exception of an i n i t i a l drop in sys-to l i c pressure averaging 14 mm/Hg. Several repetitions of the above procedure produced negative results. T r i a l 2. The results are presented graphically in Fig. 2. It is notable that the systolic pressure reached an average value of 165 mm/Hg. in 12 days and had ret-urned to a normal value in 16 days. Tr i a l The results are presented graphically in Fig. 2. The blood pressure of these animals was observed to rise steadily after the third injection of DCA to an average value of 17^ mm./Hg. 3 days after the last r hormone injections The average s y s t o l i c value had dropped to ' 1 7 ^ mm./Hg. on the twentieth day and tended to s t a b i l i z e at t h i s point. H i s t o l o g i c a l examination of the kidneys, heart, l i v e r , and adrenals of 3 of the above animals by Logan (37) revealed no signs of pathological change. Systolic Blood Pressure mm/H^ FlR« 1 The sold l i n e represents the average s y s t o l i c blood pressure variations in 8 male rats, each receiving 1.0 mgm. of DCA intramuscularly on day 0. The broken l i n e represents the average s y s t o l i c blood pressure changes i n 8 control animals receiving no tre ment. 2 The solid line represents the average systolic blood pressure changes of 6 rats, each receiving 1 .0 mgm. i n j -ections of DCX daily from day 0 to 5 inclusive. The broken line represents the average systolic pressure change in 8 male rats receiving excess dietary salt and 1.0 mgm. injections daily of BC'A from days 0 to 13 inclus-ive . 18. (3) Discussion. Semple (52) and F i t c h (20) found that one i n j e c t i o n of 1.0 mgm. of DOA produced a transient hyper-tension l a s t i n g from 7 to 8 days• Despite the fac t that the r e s u l t s of this i n v e s t i g a t i o n are contradictory to the re s u l t s obtained by F i t c h and Semple, i t does not tend to invalidate their work i n t h i s author's mind. It was puzzling to f i n d that Rixon (6l) simultaneously found that female Wistar rats (some of which were littermates to themales used i n t h i s inves-t i g a t i o n ) developed a severe and chronic hypertension when injected intramuscularly with 1.0 mgm. of DCA. Rixon, on repeating the procedure at a l a t e r date, ob-tained no response. It i s not l i k e l y that errors i n blood pressure determinations were involved, as the pressure values taken by each investigator c l o s e l y agreed when they were made on the same animals. (4) Conclusions. Chronic overdosage with desoxycorticosterone w i l l produce hypertension i n r a t s when excess s a l t i s added to the d i e t . (5) Summary. Male Wistar rats were divided into three ex-per M e n t a l groups. 19. The animals of the f i r s t group each received 1 intramuscular injection of 1.0 mgm. of DCA. They showed no apparent pressor response over a 10 day period. Those of the second group each received in-tramuscular injection 5 of 1.0 mgm. ^ DCA daily for 6 days. There was a moderate transient pressor response observed. The animals of the third group, whose drinking water contained 2% salt, each received X intramuscular injection 5 of 1.0 mgm. v£ DCA daily for 14 days. The systolic 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 effect of estrogens in mammals has been a subject of considerable debate. It is claimed (30) that i n rats, hypertrophy of the kidneys, an elevation in blood pressure and salt and water retention follow the daily injection 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 in producing the common phenomenon of pre-menstrual edema (62). It is also common know-ledge in medical fields that in women suffering from chronic nephritis re-occurrence of the grosser symptons (extensive pitting edema, increase in blood pressure, re-appearance of albumin in the urine (?)) is associated with the onset of mensis. Selye (50) does not agree with the statements above and states that the claim that fo l l i c u l o i d s in-crease the blood pressure in the rat has not been sub-stantiated and that women with menopausal hypertension often show a decrease in blood pressure. Folliculoids 2-1. exert a vasodilator effect which is readily verifiable by direct inspection (e.g., in the rabbit ear). The vessels of the nasal mucosa, and those of the accessory sex organs are particularly sensitive to this effect. It has been assumed that the action i s due to a periph-eral 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 rats. (l) Apparatus and Methods. Apparatus and methods used for blood pressure determination as previously described. Tria l 1. Five pressure determinations were made over a 7 day period on each of 6 male Wistar rats and the av-erage of the readings made on each individual animal was considered to be the animal's normal systolic blood press-ure . Starting on day 0, each rat received subcut-aneously 0.5 mgm. of diovocylin. (Ciba's brand, of est-radiol dipropionate) dissolved in 1.0 ml. of o i l . The injections were repeated daily, for 5 days. The systolic pressure of each animal was determined on days 3, 6, 8, 22 13, 2 0 , and 3 0 . T r i a l 2 . Five male Wistar rats castrated eight weeks previously were treated identically as those in 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 estradiol in o i l (diovocylin). Their individual systolic pressures were determined daily for the f i r s t five days then on days 7, 10 and 14. b) . Six male rats, 3 castrates and 3 intact anim-als, were each given two subcutaneous injections of ^ 0 . 5 mgm. diovocylin, one injection on each of two consecut-ive d ays • (2) Results. T r i a l 1. One day after the third injection of estrogen (day 3) i t w a s found that there had been an average in-crease in blood pressure of 26 mm./Hg. Determinations made one day after the last injection of estrogen rev-ealed the average blood pressure of the six rats to be 225 mm./Hg. Two days later (day 8) the average systolic pressure was observed to have fa l l e n back to a value of approximately 190 mm./Hg. Subsequent determinations showed that the systolic pressure rose steadily until day 2 0 , where i t tended to stabilize at a value of 230mm./Hg. (see Fig. 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 similar to effects i t produced in intact males. However, i t is evident 'from the graph that the pressor response occurs more rapidly in the gonadectomized animal, although the elevation in pressure is no greater in the castrate than the intact animal (see Fig.3) T r i a l 3. a) . As shown in Fig. 4, the administration of 0.5 mgm. of estrogen to 4 male rats produced no marked change in blood pressure. There was a slight indication of a transitory f a l l in systolic pressure. b) . The administration of 1.0 mgm. of estrogen (0.5 mgm. on 2 consecutive days) produced, as indicated in Fig. 4, a definite pressor response. The intact males showed an i n i t i a l drop in pressure averaging 8 mm./Hg. The smallest decrease was 4 mm/Hg., the greatest 14 mm/Hg« Immediately following this slight depression the pressures rose by the end of day 2 to an average value of 25 mm/Hg. above normal. The pressures dropped steadily after the second day and were found to be at normal levels by day 14. The graph (Fig. 4) of the pressor response to 1.0 mgm. of estrogen in castrate males i s incomplete, as in 2 of the 3 experimental animals a sustained pressor 2 4 . response was obtained. 'fhe elevated pressure of the r third animal dropped to normal levels in 14- days. It is notable that in the castrate animals no i n i t i a l f a l l in pressure was detected. The systolic pressures of the 2 animals showing the sustained elevat-ion were found to be 165 and 190 mm/Hg. at the end of 14 days. Further Note: An error in the anaesthetization of two rats (not included in the previous discuss ion j that had each received three injections of 1.0 mgm. estrogen through three days resulted in their death. Immediate autopsy of these animals revealed a marked hyperemia of the l i v e r , and hemorrhagic adrenals and kidneys. The right ureter of one of these animals was markedly enlarged. 25. INTACT CASTRATES Table I. TABLE I. -; • HT.WT. Rat. No. Bid. Press. % Body Wt. 1 226 0.44 2 240 0.52 3 232 0.44 4 216 0.35 5 210 0.39 6 228 0.42 1 215 0.34 2 248 0.56 3 220 0.39 4 225 0.48 5 236 0.5 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 is 0.28% of body weight as determined by Best et a l . (l) ) Systolic Blood P r e s s u r e mm] The s o l i d l i n e represents the average increase i n syst-o l i c blood pressure of 6 male rats, each injected with 0.5 mgm. e s t r a d i o l dipropionate at times indicated by the arrows (I ). The broken l i n e represents the average increase i n blood pressure of 5 male castrate rats injected with 0.5 mgm. e s t r a d i o l dipropionate at times indicated 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 solid line represents the average systolic pressure changes occurring in 4 male rats after 1 subcutaneous injection of 0.5 mgm. of estradiol dipropionate on day 0. The broken line represents the average pressure change in 3 male rats, each receiving a subcutaneous injection of 0.5 mgm. of estradiol dipropionate on days 0 and 1. The broken and dotted line represents the average sys-t o l i c pressure changes of 3 castrate male rats, each receiving 0.5 mgm. of estradiol dipropionate subcutan-eously on days 0 and 1. V. 28. Retraction of the testes occurred in a l l anim-als that received 2.5 mgm. of estrogen (in 0.5 mgm. doses) and autopsy revealed the livers to be abnormally small. (3) Discussion. The results of these experiments indicate that estradiol dipropionate has sustained pressor effect in male Wistar rats. The i n i t i a l decrease in blood pressure found to occur after administration of this hormone is not marked enough to be considered significant. Further investigation of this depressor effect would be of interest. ( 4 ) Conclusions. 1) Sustained hypertension can be initiated in in-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) Estradiol overdosage causes a decrease in the size of the l i v e r . ( 5) Summary. The administration of 0.5 mgm. estradiol dipro-pionate daily for 5 days to each of 6 intact and 6 cas-trate male rats produced an average increase in their systolic blood pressures of 100 mm./Hg. The castrate animals were found to be more sensitive to the pressor effects of estrogen than were the intact males. The induced hypertension was sustained and 16 days after treatment there was no sign of the induced condition abating. The heart weight made 4-0 days after treatment indicated that the hypertension was chronic. The administration of 0.5 mgm. of estradiol dipropionate daily for 2 days produced a transient i n -crease in the systolic blood pressure of three male Wistar rats. The castrate animals showed a sustained pressor response to similar treatment. No pressor resp-onse was evident in intact males each receiving 1 inject-ion of 0.5 mgm. of estradiol 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 in which hypertension had been previously induced hy renal lesions resulting from nutritional choline deficiency (see choline def-iciency and hypertension) were given•<«•**©-subcutaneous injection of 0.5 mgm. of diovocylin (Ciba's brand of estradiol dipropionate) daily for 4 days. The average systolic 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 in-jection of estradiol were determined daily for 6 days and again on the eighth, tenth and twentieth days. (3) Results. The systolic pressures of a l l 4 animals was 2IQ1 i > i = , . s . 0 I * 3 \ s5 <b T 8 S 10 Days Fig. 5 This graph represents the average change in the blood pressures of 4 hypertensive male rats following the subcutaneous administration of 0.5 mgfiu of estradiol dipropionate to each daily from days I to ^  inclusive. PLATE II. The picture on the right shows a typical skin lesion that occurs in hypertensive rats. (The area around the lesion has "been shaved). This animal suffered hyperten-sion induced by renal lesions and aggravated by estrogen overdosage (The rat was anesthetized for the photo). The picture on the right of the anesthetized animal shows a typical haemorrhage about the eye that occurs in hyper-tensive rats. This animal i s also suffering hypertension secondary to renal lesions and aggravated by estrogen over-dosage. 34-. ©Observed to rise from an average value of 222 mm/Hg. to an average value of 290 mm/Hg. (see Pig. 5) on the f i f t h day. (The pressures ranged from 280 - ^ 00 mm/Hg.) The systolic pressures dropped from day 5 to day 8 to an average value of 262 mm/Hg. Observations made on day 20 revealed no change in the latter value (262 mm/Hg*). Heart weights of these animals are given in Table H i TABLE II. HT.WT. Rat. Ho. Bid. Press. % Body Wt. 1 290 0.61 2 240 0.48 3 265 0.53 4 250 0.5 Table II. 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 indicat-ed a general physical degeneration. There was a marked decrease in weight, hemorrhage about the eye, scabby skin lesions, extensive edema ( in 1 animal), and diu-resis and anorexia. (See PlateII) (4) Conclusions. 1) Hypertension secondary to renal lesions is agg-. i.(The heart weight of normal rats is 0.28% as is shown by Best et al (1)) 8 * ^ ' -35-ravated in male Wistar rats by overdosage with es-tradiol dipropionate. (5 ) Summary. Four male Wistar rats with hypertension sec-ondary to renal lesions induced by nutritional choline deficiency were injected subcutaneously with 0 . 5 mgm. estradiol dipropionate daily for 4 days and were found to respond with a sustained increase in systolic press-ure. 36. THE EFFECT OF DCA ON THE DEVELOPMENT OF HYPERTENSION  SECONDARY TO RENAL DAMAGE INDUCED BY CHOLINE AVITAMINOSIS. A. Introduotion. Beat and Hartroft reported in 194-9 (l) that weanling rats that were fed a diet low in 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. The hypertension was 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 in mature rats and the effect that desoxycorticosterone acetate might have in animals whose renal tissue had been red-uced in such a manner. (l) Methods. Eight mature male albino rats of the Wistar strain were fed a diet (low in choline and i t ' s pre-cursors) identical to that used by Best and Hartroft (l) ( 6 l ) for 5 days and were then returned to normal stock diet. On the sixth day 4 of the 8 rats were given intramuscular injections of 1.0 mgm. each of 37 desoxycorticosterone acetate in o i l . This was repeated on days 7 said 8. The remaining 4 animals received no further treatment. (2) Results. The results are represented graphically in Fig. 6. The animals receiving the 3 injections of DCA showed an immediate increase in systolic pressure. The increase was not marked during the f i r s t 4-§- days, but had risen sharply by the sixth day and continued to rise until day 10 to an average value of 222 mm/Hg• The average systolic pressure of these animals 40 days later was 226 mm/Hg. The animals that were subjected to 5 c l a y s of a choline deficient diet only, showed l i t t l e or no in-crease in systolic blood pressure after 9 days on a normal diet. The pressure showed a slight increase on day 12 and was found on day 20 to be at an average val-ue of 226 mm/Hg. On day 25 the pressure had declined to a value of 212 mm/Hg. and 40 days later was found to be at a value of 222 mm/Hg. Heart weights are presented in Table I I I . 38. TABLE I I I . HT.WT. Rat No. Bid. Press. % Body Wt". 1 232 0.45 2 218 O.39 3 220 0.40 4 240 0.53 5 216 0.35 6 228 0.38 7 222 0.33 8 220 0.41 Table I I I . The above data represents the heart weights expressed as % of body weight for male rats 45 days after term-inating 5 days on choline deficient diet. Rats 1 to 4 received DCA the f i r s t 3 days after term-inating the nutritional deficiency. (The heart weight of normal rats is 0.28% as is shown by Best et al (l ) ) (e« fe°dy weight) 1 S)/5tollC Blood PrtSSUTfc mm/H<y J F i g . 6 / The solid line shows the average changes in blood press-ure 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 average increase in press-ure of 4 male rats that each received 1^0 mgm. a day of DCA for 3 days following their^return from a choline deficient to a normal diet. ( 4 2 . (3) Discussion. Best and Hartroft claim (1) that they cannot consistently produce renal lesions by feeding mature rats a choline deficient diet. The rats used in this investigation were of the same strain as those used by Best et a l . , the diet was prepared according to their formula and the animals were maintained on the deficient diet for similar, or shorter periods of time. It was found both by Rixon (6l) and rde that choline deficiency produced renal lesions in a l l the animals histologically examined. The renal pathology i s shown in Plates II and III. Hypertension was invariably produced and dev-eloped within 3 weeks in the mature animals. Best found that in weanlings hypertension did not generally devel-op for several monther. Such features (as seen by Best) as hyalinizat-ion of the glomerular loops and thickening of Bowman's capsule are, in the opinion of Best (I), most l i k e l y the result of high levels of intravascular pressure, and parenchymal loss is probably attributable to the acute dietary deficiency. However, a clear picture of the pathogenesis of these renal lesions has not been given. The influence of DCA in accelerating the 4-3. development of hypertension i s not known. Dean and Oleson (15) have shown that there is hypertrophy of the adrenal cortex in weanling rats which exhibit the syn-drome of hemorrhagic kidney. Best ( l ) suggests that this hypertrophy may contribute in some manner to the develop-ment of hypertension. Adrenal hypertrophy may, in this case, occur as a direct response to the stress. ( 4 ) Conclusions. 1) A period of choline deficiency, followed by a normal diet, w i l l produce hypertension in male Wis-tar rats within 3 weeks. 2) The administration of desoxycorticosterone w i l l accelerate the production of hypertension in rats that have survived a period of choline deficiency. (5) Summary. Eight male Wistar rats were maintained 5 days on a choline deficient diet. The animals were returned to a normal diet and 4 of the 8 rats were given DCA in-jections intramuscularly. The animals receiving the DCA developed hypertension in 1/3 to 1/2 the time re-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 Shelesnyak (2) Biskind and Bisk-ind (3), Singher et al (55) Shipley and Gyorgy (54) claim to have shown that vitamin B complex factors are necessary for the inactivation of estrogen and that the site of this catabolic process is. in the l i v e r . There is considerable evidence to indicate that prog-esterone and desoxycorticosterone are also inactivated in the l i v e r through similar catabolic processes ( 43 ) . The conclusions drawn on the relationship between estrogen metabolism and B complex factors has been questioned by D r i l l and Pfeiffer (44). They point out that in the foregoing work paired inanition con-trols were not used and that when paired inanition con-trols (animals which were receiving the same amount of food but receiving the B vitamin) were used in their work, the controls showed the same response to estrogen as did the experimental animals. The authors conclude therefore that the effect of B complex deficiency is the result of concomitant inanition. With this is mind i t was decided upon to observe the blood pressure eff-ects produced by administration ef DCA to rats in a 45. state of general inanition, (1) Methods. Nine male ?/istar rats, 7 to 10 months old, were given no food (water ad l i b . ) for. three days. F o l l -owing this they were placed on a diet consisting of 7«0 gms. of fox chow each (£) per day for 21 days. Starting on day 8 of the enforced fast 5 animals each received an intramuscular, .injection of 1.0 mgm. desoxycortico-sterone acetate daily for 5 days, (The remaining 4 anim-als 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 30). Attempts to make systolic pressure determinat-ions during the period of starvation were discouraged by the distressing effects the anaesthetic had on the undernourished animals. The systolic pressures were read on days 31, 33» 36, and 40. (*)....The normal weight of fox chow consumed by one rat in a day is approximately 20 gms. (2) Results. Ten days after the last injection of DCA the blood pressures of the animals receiving the DCA were s t i l l normal and no change in systolic pressure was 46 evident in the paired inanition controls. At this time the results 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. n It was surprising to the author to find that on re-checking these animals after the 60 day period, the blood pressures of both the experimental animals and the controls had reached hypertensive levels. The data is presented in the table below. It i s to be noted that the heart weights verify these findings. TABLE IV. Ht.Wt. Rat Mb'.' Bid .Press. % Body Wt. 1 230 0.53 2 210 0.42 3 165 O.35 4 220 0.51 5 210 0.40 6 218 O.39 7 165 O.30 8 215 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 sacrificed. U ) A...(the heart weight of normal rats is 0.28^ of body weight as shown by Best et a l ( l ) ) 4? At the time of writing histological sections of the organs have not been completed. However, there is gross evidence of fatty i n f i l t r a t i o n in the liver j accompanied by hemorrhagic lesions and small areas of focal necrosis. There is also gross evidence of renal lesions and possibly enlargement of the adrenal gland. (3) Discussion. It is pertinent in this experiment that both the undernourished animals receiving desoxycorticoster-one acetate and the paired inanition controls developed hypertension. Thus the exogenous cortical hormone was not apparently responsible for the pressure changes. It is also of interest to note that Rixon (6l) found no such pressure changes in female Wistar rats 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 irreversible pathological changes, resulting from a general avitaminosis. In the light of recent findings of Best and Hartroft (1) and the apparent gross path-ology of the liver 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 inan-i t i o n . ( 4 ) Conclusions. 1) A prolonged period of inanition w i l l produce hypertension in male Wistar rats. 2) Desoxycorticosterone does not markedly i n f l u -ence the development or intensity of the hyperten-sion thus produced. (5) Summary. Nine male Wistar rats were placed on a sub-minimal diet for 30 days. Five animals received intra-muscular injections of DCA for 5 days during the period of inanition and for 5 days immediately following i t . Four animals received no hormonal treatment. Both the control and experimental animals were found to be hyper-tensive 60 days after their return from a subminimal to a normal diet. 49. THE EFFECTS OF ANTIHISTAMINES ON THE BLOOD PRESSURE  OF MALE WISTAR RATS. A. Introduction. Observations on parabiotic twins led Grollman (30) in 1946 to the conclusion that the role of the kidney in hypertension is not one of actively 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 disbal-ance of this mechanism might account for either hypo-tension or hypertension. Histamine is a very potent material producing marked pharmacologic effects. Upon intravenous in-jection 0 ( y suffices to produce a marked f a l l in blood pressure in ether-anaesthetized c a t s . l y produces sev-ere hypotension even in humans. It is not therefore, extravagant to postulate that this substance may func-tion in normal animals as a factor: involved in a system that controls vascular activity; nor is i t too imagin-ative to assume that the loss of histamine from the circulating blood may allow vasoconstriction to occur with a subsequent increase in blood pressure. 50. It is also notable that histamine has been used successfully to cause peripheral vasodilatation in the treatment of certain vascular diseases (70). With the information above in mind, i t was decided to investigate the pressor changes that might occur in rats after the administration of some of the commercial antihistamic compounds. (l) Apparatus and Methods. The apparatus and methods used in determin-ing blood pressures have been previously described in this paper (see *• apparatus and methods-Introduction) Tria l 1. a) The normal pressures of white male Wistar rats numbered 1 to 10 were determined daily over a 4 day per-iod. The average value of the 4 readings taken on each rat was accepted as the approximate normal systolic pressure of the animal. On day 0, rats 1 to 5 received intraperitoneal in-jections of 1 cc. physiological saline and were thus considered as controls. Rats 6 to 10 received intra-peritoneal injections of 1.0 mgm. of the antihistamine, antistine (Ciba's brand of phenylbenzylaminomethyl-imid-azoline hydrochloride). This procedure was repeated every second day (The antistine solution was freshly 51. prepared before each injection) until 5 injections had been given each animal. b) The procedure followed was identical to that of part a above, with the exception that 0.2 mgm. injections of antistine were given rather than 1.0 mgm. T r a i l 2. a) The normal systolic pressure of 5 male Wistar rats was determined as in T r i a l 1. Each animal was then given one injection intraperitoneally of 1.0 mgm. of antistine dissolved in 1 ml. of physiological normal saline. The systolic pressure of each rat was determ-ined 1-J- hours after the .antistine injection 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 rats, us-ing -0.5 mgm. of pyribenzaraine dissolved in 1.0 ml. of physiological saline, in place of antistine. c) Procedure a was repeated on 2 male Wistar rats with the antistine injected subeutaneously, instead of intra-peritoneal l y . T r i a l 3. Four male Wistar rats were anaesthetized and their normal systolic pressure determined. Each rat then 52. received an intraperitoneal injection of 1.0 mgm. of antiatine dissolved in physiologically normal saline. Blood pressure determinations were made on each animal 5 minutes after receiving the antistine, again at 10 minutes, and thereafter every 10 minutes throughout the period of an hour. A fin 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 injection each of 0.1 mgm. of antistine dissolved in 0«1 nil. of water. Pressure determinations were made 2, 18, 34, and 5° hours after the i n i t i a l injection. A final reading was made on each animal 7 days later. b) Procedure a was repeated using intramuscular i n j -ections of 0.01 mgm. of antistine. Pressure determinat-ions were made on each of the 3 rats 2, 10, 24, 32 and 48 hours after they received the antistine. 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 for each individual by taking five pressure determinations at 2 hour intervals throughout a day in which they remained relatively quiet and spent most of 53 their time s i t t i n g at a desk. On a day that their activities were similar to those previously described, each student was given or ally one tablet of 100 mgm. antistine at 9 AM, at which time their blood pressure was again recorded. Blood pressure values for 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 results (as represented graphically in Pig. 7) show that after the injection of 1.0 mgm. of antistine, the blood pressures of the experimental animals had risen in 24 hours to an average value of 220 mm./Hg;. from an average value of 132 mm./Hg. The greatest increase in pressure was 100 mm./Hg. shown in 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. The smallest increase in press-ure was 55 mm./Hg. (135-190 mm./Hg.). It was found that with further injections of antistine, blood press-ure variations decrease and the pressures tended to stabilize at an average value of approximately 200 mm/Hg. (see Pig»7 ) Porty-eight hours after the last injection of antistine the average systolic pressure dropped from a 5*. value of 200 mm./Hg. to 185 mm./Hg. and rose slowly ^ throughout a period of 6 days to stabilize i t s e l f at an average value of 200 mm./Hg. The highest individual 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 in place of 1.0 ml. of a l^ O^^ mgm. solution of antistine, showed no sig- vJL-c nificant change In blood pressure over a period of 20 days. The greatest average variation in the systolic pressures of these animals was 6 mm./Hg. The greatest individual variation was 10 mm./Hg., which occurred twice in 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 dif f e r app-reciably from those obtained in part a. Tr i a l 2. (results) a) It was observed (see Fig 7) that one intra-peritoneal injection of 1.0 mgm. antistine apparently produced i t ' s maximum pressure response in Wistar rats 1-jjt- to 2 hours after injection, at which time the average systolic 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 rapidity 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 stabilize. The pressures of the animals at the end of 20 days ranged from values of 180 - 220 mm./Hg. with the great-est number of values concentrated between values of 185 - 195 mml/Hg. It is pertinent that one injection of 1.0 mgm. antistine w i l l apparently produce an irreversible hypertension in male Wistar rats (see also T r i a l 3 results). b) It was found that antihistaminic substance pyribenzamine produces blood pressure changes identical to those produced by antistine. <2) Antistine injected subcutaneously is as effec-tive in raising the blood pressure as it is after intra-peritoneal administration. Trial 3 (results) Observations showed (see Fig 8) that immed-iately following an intraperitoneal injection of 1.0 mgm. antistine the blood pressure of a male Wistar rat 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. in 10 minutes after which time they rose steadily for 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 partial confirmation of Tri 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. T r i a l 4 .(results) a) An intramuscular injection of 0.1 mgm. of antistine caused an average elevation of systolic blood pressure in male Wistar rats of 29 mmi/Hgi The systolic 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 later revealed that the systolic pressure of one of the animals had returned to normal, one remained -10 points above normal, and the third was apparently hypertensive, (systolic pressure - 170 mm./Hg.) (see Fig. 9) b) It was observed that 2 hours after an intra-muscular injection of 0.01 mgm. antistine there was an average decrease in blood pressure of 14 mm./Hg. The systolic 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 systolic pressures of the 3 animals had returned to normal (See Fig. 9). 57. TABLE V. Ht. Wt. Rat No. Bid. Press. % Body Wt, 6 220 0.40 7 210 O.36 8 205 O.36 9 195 0.37 10 185 0.35 11 200 O.36 12 190 O.39 Table V. The data above represents the heart weights expressed as % of body weight of sone of the experimental anim-als treated with antihistamine. (The heart weight of normal rats is 0.28^ of body weight as shown by Best et al ( l ) ) 58 T r a i l 5» (results) The oral administration of 100 mgm. antistine apparently caused a decrease in blood pressure of 6 humans averaging 15 mm./Hg. The drop in pressure was evident at the end of three hours after which time i t rose steadily and was found to be normal 26 hours after the drug was administered (See Fig. 9) It is remarkable that a seventh student (not included in the above t r i a l ) consistantly showed an increase in blood pressure of 20 mm./Hg. after taking 100 mgm. antistine orally. (3) Discussion. The pressor effects of antihistamine are most simply explained as occurring through the loss of the vasodepressor, histamine. The exact nature of anti-histamic action i s not known, although i t is 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 is not generally accepted that i t w i l l e l i c i t press-or response. Drug manufacturers claim that with a few exceptions* blood pressure changes have not been evid-ent in 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 the average s y s t o l i c p r essure changes of 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 with 1.0 mgm. of a n t i s t i n e at time s i g n i f i e d by the arrows (^). [See t r i a l l a j 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 of 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 of 1.0 mgm. of a n t i s t i n e on day O.lsee t r i a l 2a) F i g . 8 The curve represents the average change in systolic 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 represents the average ^change i n s y s t o l i c pressure 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 represents the average pressure changes i n 3 r a t s r e c e i v i n g one intramuscular 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 dotted l i n e repres-ents the average pressure 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 action of cer-tain adrenal cortical factors i t could possibly cause functional changes in the organ (cortex) and work in an insidious and detrimental fashion. It appears that the physiological response to this compound should he further investigated. Recently, antihistamines have been used in the treatment of chronic nephritis because the disease exhibits characteristics typical of an allergy (41). Histological sections of the kidney of animals used in this investigation have not yet been expertly examined. However, from the general results thus far obtained, the use of antihistamines in the treatment of nephritis i s contra-indicated. (4) Conclusions. 1. A single intraperitoneal injection of 1.0 mgm. of antistine or pyribenzamine w i l l produce chronic hypertension in white male Wistar rats. 2. Repeated injections of 1.0 mgm. antistine do not appear to markedly augment the changes induced by a single injection of the same amount. 3 ' The administration of (small) amounts of antistine to both rats and humans causes a slight drop in the systolic blood pressure. 63. 4. The drop that precedes the elevation of blood pressure, when 1.0 mgm. antistine is administered to rats, and the Asustained hypotension that occurs after administration of very small amounts to both rats and humans appears to be due to the intrinsic action of antistine as a vaso-depressor. 5* The elevation in blood pressure induced by an-tistine is presumably due to the loss of histamine, i f this is true, the loss of a vasodepressor mat-er i a l from the blood is as pertinent to the i n i t -iation of hypertension as the increase in c i r c u l -ating vaso»excitor material. 6. Indiscriminate use of antihistaminic compounds may be exceedingly dangerous. 64. Summary, (as stated in Conclusions) 65. THE FACILITATION OF THE TRUETA SHUNT BY DESOXY- CORTICOSTERONE ACETATE AND BY ANTIHISTAMINE A. Introduction. The results of an experiment originally per-formed for academic interest only, led to the following investigations. During the laboratory exercise des-igned to illustrate 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 res-ponse from other animals (rats). The rat 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 possiblity 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 silver tipped electrode connected to a Harvard inductorium 66. which was i n t u r n connected (to give a continuous shock) to one l£ v o l t dry c e l l . The s t i m u l u s used was one t h a t would j u s t e l i c i t s e n s a t i o n when the thumb and index f i n g e r were moistened with s a l i n e and a p p l i e d to the secondary term-i n a l s . When t h i s stimulus had been obtained the sec-ondary c o i l was l e f t i n t a c t throughout a l l the exper-iments. Observations were made by e x t e r i o r i z i n g the l e f t kidney of a l l animals and a p p l y i n g the s t i m u l a t -i n g e l e c t r o d e to the r e n a l a r t e r y about 1/8 of an inch from the kidney. In each case 3 s t i m u l i were gi v e n of approximately one second d u r a t i o n and spaced one sec-ond a p a r t . The animals were a n a e s t h e t i z e d w i t h nembutal. T r a i l 1. a) F i v e i n t a c t male r a t s were t r e a t e d as above and ob-served f o r signs of b l a n c h i n g i n the s u r f a c e of the k i d -ney . These animals were con s i d e r e d as c o n t r o l s e b) F i v e male r a t s t h a t had each r e c e i v e d 0.5 mgm. des-o x y c o r t i c o s t e r o n e i n t r a m u s c u l a r l y each day f o r 4 days preceding the experiment were s t i m u l a t e d and observed f o r r e n a l p a l l o r ^ c) F i v e male r a t s were t r e a t e d as above 3 hours a f t e r 67-they had each received 1 intraperitoneal injection of 0.5 mgm. of antistine dissolved in 0.5 ml. of physio-logical normal saline. (2) Results. T r i a l 1. a) In no case was renal blanching obvious in the intact male rats after stimulation of the splanchnic plexus. b) and c ) In every case where the animals had received desoxy-corticosterone acetate or antistine, marked blanching of the. surface of the kidney was evident after stimul-ation. (3) Discussion. The above experiment has been through necess-ity, crudely performed, and is by no means conclusive. However, i t does appear that on the basis of these res-ults, further investigation into the matter would be of great interest. Trueta (63) states that there i s marked individual variation in the ease with which one can normally obtain this shunt. If the adrenal cortical hormones are involved in such a manner i t would possibly elucidate the relationship that apparently exists be-tween hypertension and the adrenal cortical hormones. 68 (4) Conclusions. Adrenal cortical activity may be associated with the mechanism controlling 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 (of Trueta) than animals receiving neither of these substances. 69. THE EFFECT 0? DESOXYCORTICOSTERONE ACETATE ADMINISTRATION ON THE PRESSOR RESPONSE TO ADRENALINE IN THE RAT. A. Introduction. Adrenalectomy decreases the size 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 particularly to histamine (51a). It has also been observed by Ellinger (16)(17) that mice irradiated with lethal doses of X-rays, dev-eloped characteristic pathological conditions, including fatty degeneration of the l i v e r . These changes, i t was determined, were the result of the elaboration of total body tissue breakdown products, the most important of which was histamine, or a histamine-like substance. The daily administration off DCA exerted a protective action and brought about a decrease in the mortality rate. Fitch (20) and Semple (52) working in this laboratory, reported that the effects of DCA over-dosage could be antagonized by co-incident administrat-ion of histamine. It is 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 lines might aid in throwing some light upon the factors influencing renal vascular activity. (1) Methods. Eight male Wistar rats were each given one intramuscular injection of 1.0 mgm. DCA daily for 4 days. One day after the f i r s t dose ofT DCA each of the 8 rats was anaesthetized and the blood pressure changes deter-mined over aperiod of five minutes immediately follow-ing subcutaneous administration of 0.01 mgm.- of adren-aline per kilogram of body weight. Pressor changes 1 subsequent to adrenaline administration were also ob-served on 6 control rats (not receiving DCA). The ob-servations were repeated 4 and 6 days after the i n i t i a l injection of DCA. (2) Results. The results are shown graphically in Fig. 9* It is to be noted that the animals receiving the DCA showed a greater response to adrenaline than did those receiving no DCA. (3) Discussion. 4<V /?0 I 1 Day} A I i The blank bar represents the average increase in blood pressure of 6 intact male rats following the subcutan-eous injection of adrenaline. The lined bar represents the average increase in pressure following the subcutaneous injection 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 in most cases the animals' sys-t o l i c pressure rose and dropped to normal levels within 5 minutes. The animals could not he observed for periods over 5 minutes after adrenaline administration, as i t tended to bring them out of the anaesthetic. A very interesting side effect was observed to occur. Pour of the animals receiving the DCA and adrenaline became chronically hypertensive. The systolic pressures ranged from values of'165 to 190 mm./Hg. The heart weight6 taken 45 days after the in i t i a t i o n of this hypertension verify these findings KJey Tably V). lb incidence of hypertension occurred in the 6 control animals and previous work (Effects of DCA on Systolic Pressure of Rats) shows that DCA given in the amounts used in this investigation w i l l not ini t i a t e a sustained hypertension. (4) Conclusions. Desoxycorticosterone acetate administration to male Wistar rats appears to increase the animals' pressor response to adrenaline. (5) Summary. The increase in systolic blood pressure f o l l -owing adrenaline administration was found to be greater 73 in male Wistar rats receiving DCA than i t was in rats not pre-treated with DCA. 74. SYNTHESIS It is interesting to note from this work and from the work of others previously mentioned that l i v e r damage appears more or less as a constant feature In the i n i t i a l stages of hypertension (regardless of i t ' s et-iology). The exact nature of the role played by the liver in the "detoxification" of the steroid hormones is obscure but i t is generally accepted that i t is the site of steroid catabolism (43). Several workers have shown that estrogen, desoxycorticosterone and progesterone are less active when given via the liver and more active in the animal after hepatectomy. It has also been shown that dietary factors influence steroid metabolism and that the action of these hormones is enhanced by general inanition and by certain avitaminoses. It has been observed that estrogen w i l l cause a reduction in the size of the liver (see Est. and Blood Pressure), and that DCA w i l l cause degenerative changes (60) in the liver such as fatty i n f i l t r a t i o n , hyperemia, focal necrosis, and hemorrhagic lesions. Demonstration of a hepatic vasodepressor subs-tance has been claimed in recent years by several inves-tigators (7, 10. 56, 57t 58, 59i 72). 7 5 . In view of the foregoing information, the following chain of events could conceivably occur:-1) A nutritional deficiency renders the liver incapable of metabolising certain steroid hormones. 2") Normal concentrations of these steroids under these circumstances become toxic to the liver (and possibly the kidney) and initiate damage* 3) The damage could constitute a stress that occasions further steroid secretion from the adrenal cortex and aggravates the damage (vicious cycle). 4 ) The damaged l i v e r becomes incapable of elaborating vasodepressor material and subsequent vasoconstriction and hypertension occurs, and/or the failure of the l i v e r to "detoxify" steroid hormones (particularly corticoids) allows them to reach nephro-toxic levels. It would be of interest to know whether or not hypertension is pre-ceded by liver damage or liver dysfunction. There seems to be l i t t l e doubt that the inher-ent action of estrogen i s one of lowering the blood pressure (via vasodilatation) (50). However, the second-ary pressor effect appears to be due to the corticomimet-ic action of this compound (64) (30). The remarkable feature of this hormone is that 7 6 . i t has, in this investigation shown i t s e l f to he more active in raising the "blood pressure than has DCA, and that such pressor effects are not dependent on the salt intake of the experimental animal. If i t causes stim« ulation of the entire adrenal cortex and the secretion of several cortical factors, i t may prove true that one of these factors has a much greater pressor activity than has desoxycorticosterone. In this regard, i t is interesting to note that Selye and others have given no adequate account of why salt is such an important faetor in the production of nephrosclerosis and hypertension through DCA overdosage. An explanation of the influence of salt i s suggested below. The action of desoxycorticosterone is to main-tain the balance of electrolytes in the blood. It affects the retention of sodium and the excretion of potassium (35). Kendall (35) n a s shown that adrenalec-tomized rats can be maintained indefinitely under labor-atory conditions when large salt supplements are added to their diet. It is logical to assume therefore, that the desoxycorticosterone requirements of the organism decrease with an increase in salt intake. If an animal is given large amounts of sodium chloride and simultan-eously overdosed with DCA i t would appear that the horm-one, unless metabolized to some other compound, would induce sodium retention and that the sodium levels in 77* the blood would rise rapidly and violently disturb water and electrolyte balance. The effect upon the organism would be extremely detrimental i f not fat a l (35)» This latter 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 activity* It is the feeling of this author that DCA is not in i t s e l f responsible for the pressor changes that are attributed to i t and that another cortical factor is involved. It has previously been suggested that vascular reactivity may be involved in the etiology of hyperten-sion (see - Facilitation of Trueta Shunt, The Influence of DCA on Pressor Response to Adrenaline). Briefly stated, the theory suggests that a lack of a vasodepressor material (such as histamine) In the blood augments vascular activity and f a c i l i t a t e s vasoconstriction, and that cortical hormones antagonize in some manner the vasodepressor action. It was observed in the course of these investigations, renal c o r t i c a l blanching (vasoconstriction) was more easily stimulated after the administration of DCA to the experimental anim-al and the DCA increased the pressor response to adrenal-ine. 78 There may he more than a casual relationship between these phenomena and the Trueta shunt. If vasoconstrict-ion was augmented by either DCA or a lack of histamine (or similar substance) i t would be expected that vaso-constriction in the cortex of the kidney would occur? more easily and more frequently, thus producing renal ischemia and consequent renal damage. Renin can be detected in the blood during the i n i t i a l stages of hypertension, but cannot be detected during the later phases of hypertension. It has been claimed that pressor agents other than renin can be dem-onstrated in the blood of chronic hypertensives, but the claims are not well substantiated and not at a l l con-vincing. It appears as though renin functions primarily to raise the blood pressure to the levels required to ensure; adequate renal circulation only for the time i t takes for another pressure increasing mechanism (adrenal cortex responding to stress?) to become functional. 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 injection of 1.0 mgm. of desoxycortico-sterone 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 injection of 1.0 mgm. desoxycorticosterone acetate daily for 6 days. A transient increase in the systolic pressure of each rat was observed. The highest pressure level was 165 mm./Hg. and occurred in 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 salt, were each injected intramuscularly with 1.0 mgm. of desoxycorticosterone daily for 14 days. The systolic pressure of the animals reached an average value of 177 mm./Hg. in 17 days, dropped to an average value of 170 mm./Hg. on the twentieth day and tended to remain at this point indefinitely. . a) The administration of 0.5 mgm. of estradiol dipro-pionate daily for 5 days to each of 6 intact and 6 castrate male Wistar rats produced an average increase 8o. i n the systolic blood pressure of 100 mm./Hg. The cas-trate animals were found to he more sensitive to the pressor effects of estrogen than were the intact males. The induced hypertension was sustained without further treatment. b) The administration of 0.5 mgm; of estradiol dipro-pionate daily for 2 days, produced a transient rise in the systolic blood pressure of 3 intact male rats. Castrate male rats treated similarly showed a sustained pressor response. c) One injection of 0.5 mgm. of estradiol dipropionate to each of 4 intact male Wistar rats appeared to produce a slight, transient decrease in blood pressure. Four male Wistar rats withhyertension second-ary to renal lesions induced by a nutritional choline deficiency were injected subcutaneously with 0.5 mgm. of estradiol dipropionate daily for 4 days and were found to respond with a sustained increase in systolic blood pressure. Eight male Wistar rats were maintained 5 days on a choline deficient diet. The animals were returned to a normal diet and 4 of the 8 rats were each given 1 injection daily, for 3 days, of 1.0 mgm. of desoxycortico-sterone acetate. The animals receiving the hormone 81. developed hypertension in 1/2 to 1/3 the time required for the control animals to develop the syndrome. Nine male Wistar rats were placed on a sub-minimal diet for 30 days. Five animals received intra-muscular injections daily of 1.0 mgm. desoxycorticoster-one acetate for 5 days during the period of inanition and for 5 days immediately following i t . Four animals rec-eived no hormonal treatment. Both the starved animals receiving desoxycorticosterone acetate and the starved controls were found to be hypertensive (0 days after their return from the subminimal to the normal di e t ) . The hormone apparently had no effect. The blood press-ure change was believed to be the result of the renal lesions that were found to be present. a) Five rats each receiving 1 injection of. 1.0 mgm. of the antihistamine, antistine, every second day until 5 injections had been given each animal, showed an immed-iate increase in systolic pressure to an average value of 220 mm./Hg* that wa3 l i t t l e affected by further anti-histamine administration* The blood pressure changeswas sustained indefinitely with no further treatment. b) One intraperitoneal injection of 1.0 mgm. of anti-stine was given each of 5 male Wistar rats. It was obser' ved that the maximum pressure response occurred 1$ to 2 hours after injection, at which time the average systolic 82. pressure of the 5 animals was 225 mm./Hg. Within a period of 20 days the average systolic pressure dec-reased 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 injection of 1.0 mgm. antistine. C/) The blood pressure changes in 4 Wistar rats that occurred immediately following antistine injection were observed periodically throughout 2 hours. It was found that following these injections of antistine the blood pressure dropped immediately to abnormally low levels arti then increased to hypertensive levels within 2 hours. d) An intramuscular injection of 0.1 mgm. of antis-tine to each of 3 rats caused an average elevation in systolic blood pressure of 20 mm./Hg. The pressures returned to normal values within 48 hours. An intra-muscular injection of 0.01 mgm. of antistine to each of 3 male Wistar rats caused a temporary decrease in blood pressure of 14 mm./Hg. The systolic pressures were found to be normal after 40 hours. e) The oral administration of 100 mgm. antistine to 6 humans caused an average decrease in 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 effects 83. as a n t i s t i n e . These compounds were a l s o found to be as a c t i v e when g i v e n subeutaneously as when g i v e n i n t r a -p e r i t o n e a l l y . F i f t e e n male Wistar r a t s were d i v i d e d i n t o 3. groups. One group acted as c o n t r o l s , the second r e c e i v e d i n t r a m u s c u l a r i n j e c t i o n s o f d e s o x y c o r t i c o s t e r o n e a c e t a t e and the t h i r d r e c e i v e d an 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 a n t i h i s t a m i n e . The nerves surrounding the r e n a l a r t e r y o f every animal were st i m u l a t e d with a weak f a r a d i c c u r r e n t and the e x t e r i o r i z e d kidney observed f o r b l a n c h i n g . I t was found t h a t i n both the animals t h a t r e c e i v e d c e s o x y c o r t i c o s t e r o n e a c e t a t e , and the animals ? th 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 b l a n -c h i n g was e v i d e n t . In those animals r e c e i v i n g no prev-ious treatment no r e n a l c o r t i c a l b l a n c h i n g was e v i d e n t . 84. LITERATURE CITED 1. Beat, C.H., and Hartroft, W.S. 1949 Nutrition, renal lesions and hypertension. Eed. P r o c , 8, 610 2. Biskind, M.S., and Shelesnyak, M.C. 1942 The relationship 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 hyperten-sion. Ann. Surg., 106, 826. 5. Bright, R. I836 Reports Med. Gases, London 1827 Guys. Hosp. Rep., 1,.338 6. Castleman, B., arid Smlthwick* R.H. 1943 The relation of vascular disease to the hypertensive state based on the study of renal biopsies from 100 hypertensive pat-ients. 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 in experimentally produced shock.. Proc. Soc. Exptl. B i o l . and Med., 56, 127. 8. Child, C.G. 1938 Observations on pathological changes f o l l -owing experimental hypertension produced by constriction of the renal artery. J. Exptl. Med./ 67, 521. 9. Corcoran, A.C. 1948 The renal pressor system and experimental and c l i n i c a l hypertension. Recent Progress in Hormone Research. 3, 325. 85 1 0 . 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 in normal and in hypertensive human subjects. J. Clin. Investigation, 26, H 7 8 . 11. Cruz-Coke, E. 1946 Mechanism of renal hypertension in Goldring and others, experimental hyper-tension. New York: The New York Academy of Sciences 12. Darrow, D.C., and Miller, H.C. 1942 Production of cardiac lesions by re-peated injection of desoxycorticosterone acetate. J. C l i n . Investigation 21, 601. 1 3 . Dexter, Lewis 1946 Translation of Renal Hypertension: Braun-Mendez, et a l . Review of the relation of the adrenal cortex to the maintenance of the hyper-tensive state. Charles Thomas, Springfield. 219 - 2 2 7 . 14. Dougherty, T.F. 1948 Relation of adrenal cortical stimulation to histological alterations in the kid-neys and cardiovascular tissues of mice, in: Factors regulating blood pressure. Transaction of the Second Conference. New York, N.Y. - Josiah Macy, Jr. Foundation New York, N.Y. 15. Dean. H.W., and Olson, R.E. 1948 Hypertrophy of the adrenal cortex of weanling rats which exhibit the synd-rome of hemorrhagic kidney. Anat. Rec., 100, 2 1 . 1 6 . Ellinger, F. 1946 Protective action of DCA against X-ray induced l i v e r damage. Science 104, 502. 8 6 . 1 7 . ibid. 194-7 1 8 . E l l i s , A 1938 Some effects of DCA on mice irradiated with X-rays. Proc. Soc. Exptl. B i o l . Med. 64, 3 1 . Histological studies on human patients with malignant hypertension. Lancet 1, 977. 1 9 . Farris, E.J., Yeakel, E.H., and Medoff, H. S. 2 0 . 1945 Pitch. 1947 H.F. Development of hypertension in emotion-al gray Norway rats after air blasting. Amer. J. Physiol. 144, 331. The amelioration of experimental hyper* tension by histidine and ascorbic acid, Masters' Thesis, University of British Columbia. 21. Friedman, M., and Kaplan, A. 1943 Studies concerning the rate of renin formation in the kidney IV. The renin content of the mammalian kidney f o l l -owing specific necrosis of the proximal convoluted tubular epithelium. J. Exptl. Med. 77, 6 5 . 2 2 . Garai, 0 . 1945 2 3 . Goldblatt, 1937 Immersion as a factor of hypertension. B r i t . Heart J., 7, 2 0 0 . in the development H. 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 Summer-v i l l e , W.W. 1934 J. Exptl. 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, Librarie R. Fonteyn. 27. ibid 1945 Vascular and circulatory changes in the renal cortex in the anuric crush syndrome Proc. Soc. Exptl. B i o l . N.Y., 59, 303. 28. G r i f f i t h , J.O., and F a r r i 3 , E.J. 1942 The Rat in Laboratory Investigation Lippincott, Philadelphia 274 29* Grimson, K.W., Bouckaert, J.J. and Heymans, C. 1939 Production of a sustained neurogenic hypertension of renal origin. Proc. Soc. Exptl. Biol., N.Y. 42, 225. 30. Grollman, A. 1947 Essentials of Endocrinology. J.B. 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I, p.4^3 and p.602 Academic P r e s s Inc. P u b l i s h e r s , flew ¥ork 44. P f e i f f e r , C.A., and D r i l l , V.A. 194-6 On the r e l a t i o n o f v i t a m i n B complex d e f i c i e n c y and i n a n i t i o n to the i n a c t i v -a t i o n of estrogens i n the l i v e r . E n d o c r i n o l o g y 38, 300. 45. Schroeder, H.A., Olsen, U.S., and Goldman, M.L. 1948 Pressor substances i n human hy 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 p r e s s u r e . T r a n s a c t i o n s of the second conference J o s i a h Macy - J r . Foundation, lew *ork. 118. 46. Selye, 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 over-dosage with DCA J.A.M.A. 47, 515 47. Selye, H., H a l l , C.F., and Rowley, R.M. 1943 Pathology of d e s o x y c o r t i c o s t e r o n e over-dosage In va r i o u s s p e c i e s . A r c h . P a t h . 36, 19. 48. 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