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The amelioration of experimental chronic hypertension by vitamin E Rixon, Raymond Harwood 1950

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II So  THE AMELIORATION OF EXPERIMENTAL CHRONIC HYPERTENSION BY YITAMIN E.  BY RAYMOND -HARWOOD RECON  Submitted as P a r t i a l Fulfilment In a Major In Biology and Botany f o r the Degree of Master of Arts In the U n i v e r s i t y of B r i t i s h Columbia.  The U n i v e r s i t y of B r i t i s h Columbia *T0  A p r i l 1950.  ABSTRACT Chronic hypertension was induced i n female albino rats.  Amelioration by means of d a i l y feeding of h i s t i d i n e  and ascorbic a c i d , h i s t i d i n e and vitamin E, h i s t i d i n e and urease, vitamin E, urease and ammonium chloride was attempted.  Blood pressures were determined under sodium  pentathol anesthetic by the i n d i r e c t method using the foot.  Chronic hypertension was produced by two methods,  (1) Injections of DCA. inconsistent r e s u l t s .  This method was found to give Several modifications of t h i s  procedure were t r i e d unsuccessfully. C2) The use of a choline deficient d i e t .  This method proved to give  consistent r e s u l t s i n producing chronic hypertension. Vitamin E was the only substance found u s e f u l i n ameliorating the experimental  chronic hypertension.  This  amelioration r e s u l t e d only i n the presence of excess vitamin IT.  This f a c t was thought t;o give further evidence  for the v a s o d i l a t o r properties of vitamin E. An hypothesis was advanced that DCA may i n h i b i t the sympathetic nervous system, to sensitize the vascular responsiveness  to pressor and depressor  substances.  ACKN01LEDGEMENTS  \T wish to give acknowledgment to Dr. A. H. Hutchinson, Head of the Department of Biology and Botany, under patronage t h i s thesis was written. To Dr. J . Allardyce, under whose capable guidance t h i s project was undertaken and d i r e c t e d . To Mr. J . S a l t e r , co-worker i n the problem, f o r h i s unstinting help and collaboration* To Miss L. Gowie, Mr. E. Fung, Mr. ¥. Rivers, Mr. G. Morrison, Mr. P. Jones, fellow research workers, who were a l l very h e l p f u l I n Innumerable ways during the actual compiling of the data.  TABLE OF CONTENTS  I.  INTRODUCTION  A. THE PATHOGENESIS OF HYPERTENSION 1. Role of the Kidney In Hypertension  1.  2. 2.  (a) Renin - Angiotonin Pressor System  3..  Weaknesses, of the Renin Theory  4.  (b) E f f e c t s of Nephrectomy  6.  (i) U n i l a t e r a l Nephrectomy  6.  Cil) B i l a t e r a l Nephrectomy  8.  (c) Hepato-Renal Vasotroplc Factors  9.  2. Role of the Adrenals  10.  5. Neurogenic Significance In Hypertension  13.•  B. STATEMENT OF THE PROBLEM OF THIS THESIS  15.  1* Methods used i n the Production of Experimental Chronic Hypertension  15.  2, Methods of Ameliorating Experimental Chronic Hypertension 3. General Delineation of t h i s Thesis  17. 19.  IX  APPARATUS  A. DESCRIPTION OF THE APPARATUS  Ill  20.  20.  1. Lighting  20.  2. Microscope  20.  3. Cuff  21.  4. Cuff Pressure Source  21.  METHODS A. THE PROCEDURE OF MEASURING BLOOD PRESSURE  22.. 22.  1. Anesthesia  22.  2. Blood Pressure Determination  24.  B. METHODS- IN EXPERIMENTAL CHRONIC HYPERTENSION.  IT  ¥  RESULTS  DISCUSSION OF RESULTS  25.  29.  32.  A. METHODS _IN PRODUCING EXPERIMENTAL HYPERTENSION  32.  1. Desoxycortlcosterone  32.  2. Choline Deficiency  36.  B. AMELIORATION OF HYPERTENSION VXTAMIN E  38.  C. CORRELATION INADEQUACIES BETWEEN THE DATA OF ACUTE AND CHRONIC HYPERTENSION  40.  D. NEGATIVE RESULTS OBTAINED WITH UREASE AND AMMONIUM CHLORIDE E. SUGGESTIONS FOR FURTHER RESEARCH  41. 42 .  VI  CONCLUSIONS  44.  Yir  SUMMARY  45.  LITERATURE CITED  47.  ABSTRACT  55.  THE AMELIORATION Off EXPERIMENT AX CHRONIC HYPERTENTION BY ¥ITAMIN E  I INTRODUCTION One of the most controversial issues of present day medical research i s hypertension.  The enigma of  t h i s problem has kept some of our keenest medical minds i n constant research since the year 1934 when Goldblatt showed It was experimentally possible to Induce a hypertensive state.  This i n i t s e l f was a major step  forward because i t made f e a s i b l e the f i r s t controllable experiments on hypertension under c a r e f u l l y supervised laboratory condit ions. Previous to t h i s time the amount of work done on t h i s problem, q u a l i t a t i v e l y and quantitatively, was from a co-ordinated viewpoint, n e g l i g i b l e .  There were various  men l i k e Bright, who p r e c i p i t a t e d the problem of hypertension which, even now,  i s only p a r t i a l l y resolved.  But on the whole i n v e s t i g a t i o n Into the problem was  the  exception rather than the r u l e . Hypertension was at one time considered a hemodynamic response to aging o f the blood vessels - a f i n a l e f f o r t on the part of the body to maintain perfusion of blood through narrowed v e s s e l s .  But t h i s  view has long since been superceded and to-day we believe that elevation of blood pressure i s only a  firmly  symptom of some preceding disorder and, as such, has numerous causes. This change i n thought coupled with the a b i l i t y to a r t i f i c i a l l y create hypertension has been undoubtedly responsible f o r the recent acceleration of research. The various ramifications of the problem of hypertension are now approached from a number of bases.  The  f i e l d s of Investigation are usually c l a s s i f i e d as (1) the renal o r i g i n of hypertension (£.) the humoral pressor mechanisms C3) the neurogenic origins and C4) endocrine o r i g i n s of hypertension.  These c l a s s i f i c a t i o n s are f o r  convenience only and must not be mistaken for separate and non-overlapping research.  But even with t h i s category  s i m p l i f i c a t i o n and corresponding research human hypertensive disease remains a b a f f l i n g and mystifying disorder. The more time, thought, work and e f f o r t that i s devoted to the problem itfc <R*W£ we discover the complexity of the andproblem^of i t s ultimate e t i o l o g y . A.  THE PATHOGENESIS OF HYPERTENSION  1. ROLE OF THE KIDNEY IN HYPERTENSION There i s no reasonable doubt that some cases of human hypertension are of renal o r i g i n .  The unsolved  problem i s whether many or most of those s t i l l referred to as  n  e s s e n t i a l " are also of renal o r i g i n CEO).  3.  Essential hypertension has u s u a l l y been defined as the persistent elevation of s y s t o l i c and d i a s t o l i c pressures without accompanying r e n a l disease, and has therefore excluded the r e n a l o r i g i n of hypertension by d e f i n i t i o n . However, numerous mechanisms have arisen which centre about the kidney as the possible I n i t i a t o r of hypertension.  (a) RENIN - ANGIQT.ONIN PRESSOR SYSTEM. The publications of Richard Bright (6) (1827-1836) were the f i r s t to l i n k the r o l e of the kidney and hypertension, but i t was Tigerstedt and Bergmann In 1898(83), who  f i r s t demonstrated a blood pressure r a i s i n g p r i n c i p l e  from a saline extract of r e n a l tissue which they c a l l e d "'renin *. 1  However, i t was not u n t i l such investigators as  Houssay, P l e n t l , TaguinI, Fasciolo, Braun - Merendez, Page, Munoz, L e l o i r , Kohlstaedt and Helmer (1957 (9,  1941)  37, 38, 39, 47, 48, 61,. 62) that the pressor response  was found due to a substance they c a l l e d "angiotonln" or "hypertensln".  Angiotonln proved to be the r e s u l t of a  chemical reaction between a pseudaglobulin of the plasma and the substance "renin" found by Tigerstedt and Bergmann. Investigations by the above mentioned authors have revealed a fundamental scheme f o r the renal pressor mechanism.  Renin i s produced by the kidney cozttex, of  which the exact s i t e i s unknown, but i t has been associated with the juxtaglomerular apparatus and the macula  4.  densa of the kidney.  Renin has been found to have the  property of a p r o t e o l y l i c enzyme (9, 58} and a protein. Renin i s p h y s i o l o g i c a l l y i n e r t , but possesses the a b i l i t y to break down a substrate compound known preferably as "renin - substrate" (12) or as hypertensinogen, into an active vasopressor material "angiotonin" (or hypertensin). Renin - substrate i s a protein produced by the l i v e r and i s found i n the alpha - 2 - globulins of the blood. Reninsubstrate has a r e l a t i v e l y large molecule, which under the influence of renin i s decomposed to a smaller polypeptide, "angiotonin" Angiotonin i s decomposed by the action of another enzyme "anglotonase" (or hypertensinase). Anglotonase i s found in'various tissues namely, kidney, plasma, erythrocytes, and i n t e s t i n a l wall.  I t i s probable that  angiotonin i s destroyed by a number of other enzymes, such as, proteinases of renal and i n t e s t i n a l o r i g i n , by amino polypeptidases found In kidney extracts and i n blood plasma, by tyrosinase, by carboxylpolypeptidase as well as by oxidizing systems (15).  WEAKNESSES OF THE RESIN THEORY.  Using the most sensitive methods of detection, some renin has been found during the acute phase of hypertension i n experimental animals (30) (Haynes and Dexter 1947),  5.  and also i n some patients with acute hypertension due to glomerulonephritis and toxemia of pregnancy.  In dogs with  chronic hypertension of three months to four years duration, no renin has been detected, nor i n the systemic blood of patients with chronic hypertension (12) (Corcoran 1948). Renin i s no more commonly present i n the renal venous blood of patients with e s s e n t i a l hypertension than i t i s i n others with no hypertension (Haynes et a l 1947)  (31).  F a i l u r e to demonstrate the presence of renin i n hypertension might be due to the lack of s e n s i t i v i t y of the methods (12).  I f t h i s were the case, L e l o i r (41) raised  the question as to how  such a small concentration of renin  i n the blood could lead to such marked hypertension, as i t has been shown that the methods are adequate to show i t s presence when i n concentrations s u f f i c i e n t to increase a r t e r i a l pressure i n normal animals (12).  But Page (51)  has found a greater s e n s i t i v i t y to renin injections i n hypertensive animals. Maegraith  Verny and Yogt (84), and Brown and  (8) have also found a greater s e n s i t i v i t y of  hypertensive animals to pressor substances such as adrenalin and tyramine. (.55,  59).  The phenomena of renin tachyphylaxis i s another weakness i n the renin - angiotonln theory.  It is, well  recognized that i t i s d i f f i c u l t or impossible to maintain increased pressure by i n f u s i o n of renin for periods of more than a few hours (33, 52, 82).  This tachyphylaxis  6 to renin was thought to be due to a disappearance of blood hypertensinogen or renin - substrate.  Page (51)  has found however, that i n j e c t i o n of renin - substrate does not restore the response to renin and has shown that exhaustion of the substrate i s only part of the phenomena of tachyphylaxis  (57, 53, 54). (See "Neurogenic  Significance"). (b)  THE EFFECTS OF NEPHRECTOMY  The view that chronic hypertension  as observed i n  the experimental animal, r e s u l t s from the elaboration of a c i r c u l a t i n g pressor substance has been rather generally accepted.  However the experimental data of Grollman and  co-workers cited i n the following sections, not only are contrary to t h i s view, but present  d e f i n i t e evidence  against i t . XI) UNILATERAL NEPHRECTOMY It has been generally assumed that u n i l a t e r a l nephrectomy has no e f f e c t on normal animals (23). Although t h i s i s usually true, a certain percentage of animals develope a moderate but d e f i n i t e increase i n blood pressure which i s evident some weeks following removal of one kidney (28, 25).  Similar r e s u l t s have  been shown to occur with u n i l a t e r a l operations on the kidney by application of a cloth capsule,figure-of-eight  7  etc.  This r i s e may,  however, not be evident f o r weeks or  even months following the operation (Grollman et a l (28,35) ) However, Halpert and Grollman (29), have recently shown that the induction of hypertension as a r e s u l t of u n i l a t e r a l nephrectomy and u n i l a t e r a l operations i s apparently dependent  upon the existance of some l e s i o n i n the  contralateral kidney.  A study of kidneys of rats with  chronic hypertension revealed the presence of l o c a l lesions not only In the kidneys to which a figure-of-eight had been applied but also s i m i l a r lesions i n the c o n t r a l a t e r a l unoperated kidney.  This f i n d i n g i s c i t e d as evidence  that u n i l a t e r a l i n j u r y induces hypertension only i n the presence of some anatomical l e s i o n In the contralateral kidney.  Otherwise, application of the figure-of-eight  and removal of the remaining kidney i s necessary to induce chronic hypertension.  Grollman (26) has c i t e d  these experiments as incompatable with the view that hypertension i s due to the elaboration of a pressor substance by the injured kidney.  They are better ex-  plained by assuming that c o n s t r i c t i o n of the kidney Interferes with a normal function of t h i s organ essential for the maintenance of normal blood pressure. Grollman (25,28), Patton and associates (60) have found that i f the blood pressure of experimental animals i s elevated to hypertensive l e v e l s by the application of a figure-of-eight, cellophane wrapping, etc., to one  8  »  kidney, the subsequent removal of t h i s kidney f a i l s to restore the blood pressure to normal l e v e l s .  Also,  following the removal of the single remaining kidney i n a hypertensive, u n i l a t e r a l l y nephrectomized  animal, the  blood pressure remains elevated for several days, u n t i l a few hours before death of the animal.  They state that  were the injured kidney responsible for the l i b e r a t i o n of a pressor substance, i t s removal should obviously result, in. a return of blood pressure to normal l e v e l s . (11) BILATERAL NEPHRECTOMY. The e f f e c t s of b i l a t e r a l nephrectomy on the blood pressure i s d i f f i c u l t to determine,  since animals deprived  of a l l renal tissue succumb from uremia before any effect of the deficiency of renal tissue on the blood pressure can manifest i t s e l f (26).  Following the removal of the  remaining kidney from a hypertensive animal Grollman (28,25) has found that the blood pressure remains at i t s elevated l e v e l , declining only as uremia sets i n during the l a s t days before death.  However, the I n s u f f i c i e n t time offered  by complete nephrectomy has somewhat been overcome by Grollman and Rule (27) by u t i l i z a t i o n of the parabiotic preparation.  When one of the parabions was b i l a t e r a l l y  nephrectomized, t h i s animal became hypertensive, while the blood pressure of the parabiont with intact kidneys remained at a normal l e v e l .  More recently (Grollman (23)  9  has shown that b i l a t e r a l l y nephrectomized  dogs, maintained  by an a r t i f i c i a l kidney, show an elevation of blood pressure to hypertensive l e v e l s .  These experiments have  been stated as evidence for the absence of renal tissue rather than the presence of an abnormal kidney that i s responsible for the developement of hypertension. According to Grollman  (24) a l l the experiments c i t e d  above are consistent In showing the p o s s i b i l i t y of inducing hypertension by methods which reduce the t o t a l amount of renal tissue and the p o s s i b i l i t y of the existence of hypertension In the absence of any renal tissue i n the organism.  Grollman's alternative hypothesis to explain  the role of the kidney In the pathogenesis of hypertension i s to assume that t h i s organ elaborates a humoral agent e s s e n t i a l f o r the well-being of the organism, In the absence of which hypertension r e s u l t s . (c)  HEPATO-RENAL VAGOTROPIC FACTORS  A pressor-antipressor system has been described by Shorr & Zweifach (79) and other workers (11,86,81,80). Their experiments have shown the regular p a r t i c i p a t i o n i n the hypertensive syndrome i n man and animals of a p a i r of vagotropic p r i n c i p l e s of hepatic and renal o r i g i n , whose opposite action on the vascular bed are of'"'such a nature that they are said to constitute a c i r c u l a t o r y homeostatic system. (VEM)  This system consists of a vasoexcitor substance  released from the kidney under stress, and which i s  10.  apparently neither renin or angiotonln, and a vasodepressor substance  (VDM)  formed i n the l i v e r .  The vasoexcitor  apparently acts by increasing the vasomotion of the metaarterloles, and enhancing these vessels to epinephrine. The vasodepressor exerts an opposite e f f e c t .  VEM has been  shown present i n the blood of animals during acute experimental renal hypertension, and both VEM and VDM are present In high, n e u t r a l i z i n g concentrations In the chronic stage of experimental renal hypertension.  Derangements i n the  balance of these factors have been postulated as a possible mechanism i n the pathogenesis of hypertension.  2.  ROLE OF THE ADRENALS IN HYPERTENSION  The only endocrine organ which may possibly play a s i g n i f i c a n t part In hypertension, even i f only a secondary one i s the adrenal system.  According to GoldbLatt (20),  Best and Taylor (4), there i s no evidence that the adrenal medulla plays a part In hypertension, but recently ffiylon and Heller (46) 1948, have found that "angiotonin" apparently needs minute quantities of epinephrine, tyrosine and other tissue products to make i t e f f e c t i v e .  However,  there are more d e f i n i t e indications that the adrenal cortex plays a r o l e i n high blood pressure, as i t s secretions have been found essential to the experimental and maintenance of hypertension (56j34).  establishment  11  Goldblatt (20) has found that the e x c i s i o n of both adrenals i n dogs i n t e r f e r e s with the developement of hypertension due to the c o n s t r i c t i o n of the main renal artery; and unless supportative therapy i s given high blood pressure i s not established. Ogden and associates (49) and Anderson et a l (3) 1944, have shown that excision of the anterior p i t u i t a r y i n hypertensive rats r e s u l t s i n a f a l l of blood pressure, but becomes normal only i f hypertension i s of l e s s than one month duration. d e f i n i t e effect (20) .  Other workers have found no  Also Houssayband Bexter (34) and  Munozetal (47) have shown that b i l a t e r a l adrenalectomy, although I t has no immediate e f f e c t , Is followed by a progressive decrease i n the response to intravenous i n j e c t i o n s of r e n i n .  These i n h i b i t i n g effects of adrenal i n s u f f i c i e n c y  are possibly due to a decreased concentration of r e n i n substrate, since Lewis and Goldblatt, (42) have shown that the l e v e l of renin-substrate i s reduced i n adrenalectomy.  The  adrenal secretions are postulated as necessary for the production of the substrate. Recently Zweifach and associates (85) 1947, have found that the kidneys of adrenaleetomized rats,.eats and dogs progressively l o s t the capacity to produce the vasoexcitor p r i n c i p a l (VEM)  which appeared i n the blood of  hypertensive animals (See "Role of Kidney").  The  adminis-  t r a t i o n of desoxycortlcosterone acetate (DCA) restored the capacity of the kidney to produce VEM.  They state that the  12.  question remains as to whether the withdrawal  of the  adrenal hormones fromnthe c i r c u l a t i o n produces a s p e c i f i c l e s i o n i n the kidney VEM mechanism, or, whether the generalized c e l l u l a r dysfunction, characteristic  of adrenal  i n s u f f i c i e n c y , i s the factor responsible f o r the decline i n the blood pressure of both normal and hypertensive i n d i v i d uals. Selye (69,70) has postulated on the basis of h i s work on the "adaptation syndrome", the hypersecretion o f mineralo-corticold hormones of the adrenals as a possible cause of hypertension.  Experimentally i t has been demon-  strated that chronic exposure to non-specific damaging agents produces adrenal c o r t i c a l enlargement with an overproduction of c o r t i c a l hormones and simultaneous nephrosc l e r o s i s with hypertension i n the r a t . At present though, there i s no direct evidence i n d i c a t i n g that hypersecretion of the animal s own cortex leads to the developement of r  high blood pressure (70).  However, hypertension has been  produced experimentally by Selye and co-workers (68,71,72, 75„?4,75,?6) and others (40,7) by the administration of large amounts of desoxycortieosterone acetate (DCA) p a r t i c u l a r l y when combined with a high s a l t diet and u n i l a t e r a l nephrectomy, with pathological changes simulating renal hypertension.  Recently Selye (701 has found that  doses as small as 1 mgm. of DCA per day are s u f f i c i e n t to produce the same r e s u l t s .  But l i t t l e evidence exists that  13.  i n j e c t i o n s of c o r t i c a l extracts or the administration of adrenocorticotropic hormone (ACTH), which mediates I t s e f f e c t s through the adrenal cortex, w i l l produce hypertension (16).  However, both adrenal c o r t i c a l extracts and  ACTH have been found by Dougherty (16) to exert s i m i l a r effects on the a l t e r a t i o n of the juxtaglomerular with the s i m i l a r e f f e c t s ascribed to DCA,  apparatus  although DCA  was  found more e f f e c t i v e .  3.  NEUROGENIC SIGNIFICANCE IN HYPERTENSION.  There have always been suspicions that nervous factors were important In the genesis of hypertension, but c r u c i a l experimental evidence was lacking, and for a time i t seemed decisive that hypertension was due to a humoral mechanism.  However, as w i l l be seen below, a number of  investigators'have thrown doubt upon the purely chemical nature of experimental hypertension. Dock. (17) has shown that p i t h i n g a hypertensive rabbit r e s u l t s In a drop In.blood pressure.  The blood  pressure of the pithed rabbit, however, s t i l l by the administration of r e n i n .  I t was  Increased  concluded that the  mechanism responsible f o r the maintenance of high blood pressure i s not dependant upon c i r c u l a t i n g r e n i n and angiotonin, and suggested the p a r t i c i p a t i o n of the nervous system i n the mechanism of renal hypertension.  14. Similar experiments have been carried out by Page (57) i n which he found sectioning of the brain at various l e v e l s , widespread d i r e c t i n j u r y to the central nervous system, and severe shock;, abolished the pressor response of angiotonln. Even more r e c e n t l y Page and Taylor (57) have shown a further connection between the central nervous and the renal pressor systems.  They found that previous administration  of t e t r a e t h y l ammonium chloride (TEA), an agent which blocks the transmission of impulses through autonomic ganglia, overcame the phenomena of r e n i n tachyphylaxis and augmented the response to angiotonln.  TEA augmented the effects of  both pressor and depressor substances.  Corcoran (IS) has  taken t h i s action of TEA to mean some central influence which l i m i t s vascular responsiveness.  He has postulated  two states of tachyphylaxis, the f i r s t r e s u l t i n g from the exhaustion of renin-substrate as seen i n hepatectomized animals, and the other caused by some autonomic influence which I n h i b i t s the action of r e n i n . Evidence has been obtained by Ogden and associates (50), showing that a neurogenic mechanism may be involved i n chronic hypertension.  From studies on the s e n s i t i v i t y  of experimentally hypertensive animals to  sympathoparalytic  agents such as phenobarbital, yohimbine* and F 933.  They  considered i t l i k e l y that renal hypertension proceeds i n two phases. (1) The f i r s t phase i s of humoral o r i g i n dependant on excess l i b e r a t i o n of renin. to depressors.  This phase i s r e s i s t a n t  (2) The second phase i s assumed to be  one  15.  i n which neurogenic influences predominate.  In t h i s phase  the blood pressure i s depressed more by agents which a f f e c t the central nervous or sympathetic a c t i v i t y .  These e f f e c t s  have been confirmed by. other workers (63, 65). More recently Corcoran and associates (13,14)1948, have demonstrated the dependance of c l i n i c a l and experimental r e n a l hypertension on central nervous a c t i v i t y . They found functional denervation (high s p i n a l and caudal anaesthesia) of the renal vascular system w i l l lower the blood pressure of most hypertensives to normal l e v e l s . This response was thought to arise from renal v a s o d i l a t i o n .  B.  STATFJVIENT OF THE PROBLEM OF THIS THESIS.  The problem of t h i s t h e s i s consists b a s i c a l l y of three parts ( l ) to learn the e f f i c i e n t use of the  apparatus  u t i l i z e d by the previous workers of t h i s laboratory f o r the determination of r a t blood pressures, namely, the i n d i r e c t method using the f o o t . (2) To f i n d a suitable method for the establishment of chronic hypertension i n female rats and (3) to f i n d an agent f o r amelioration of t h i s high blood pressure.  1. METHODS USED IN THE PRODUCTION OF EXPERIMENTAL CHRONIC HYPERTENSION. Success by Semple (77) and F i t c h (19) of t h i s  16  laboratory i n producing an acute, t r a n s i t o r y hypertension by a 1 mgm  i n j e c t i o n of desorycortlcosterone acetate  (DCA)  led to the method of producing chronic high blood pressure i n r a t s by repeated administration of DCA.  However, other  methods, including modifications i n the use of DCA, decided upon.  were  These were (1) a starvation diet and sub-  sequent Injectionswith DCA,  (2) Injections of epinephrine  and DCA given simultaneously, followed by d a i l y i n j e c t i o n s of epinephrine. (3) The use of a choline d e f i c i e n t d i e t , with the possible acceleration of i t s e f f e c t s by a DCA injection. The f i r s t modification, namely, the use of a starvation d i e t was i n i t i a t e d by Samuels (66) work on estrogens. He observed that obese women frequently showed i r r e g u l a r menstrual cycles and found evidence that estrogens when i n high concentrations i n the c i r c u l a t i n g f l u i d s , were absorbed by the f a t t y tissue, and diffused out when i n low concentrat i o n i n the c i r c u l a t i n g f l u i d s .  A similar effect was postu-  lated for desoxycorticosterone, because of i t s s i m i l a r i t i e s i n chemical properties. This action would minimize i t s e f f e c t s to produce hypertension. The second modification was the administration of epinephrine with DCA.  This method of r a i s i n g the blood  pressure was thought possible because of the recently d i s covered importance of epinephrine i n the vasotropic factors of Zweifaeh and Shorr, and In the r e n a l pressor system (See "Role of the Kidney" and "Adrenals"  p.9,10  )  17 The l a s t procedure decided upon f o r the production of chronic hypertension was the use of a choline d e f i c i e n t diet.  Best and Hartroft (5) discovered that hypertension  developed i n weanling rats approximately 4 to 7 months a f t e r the I n i t i a t i o n of a 5 to 6 day choline deficient diet.  H i s t o l o g i c a l sectioning of l i v e r s and kidneys of  the above r a t s showed i r r e v e r s i b l e damage.  The kidneys  had widespread tubular lesions, which were thought s i b l e f o r the elevation of blood pressure.  respon-  Because of the  l i m i t e d time at our disposal, DCA was administered along with the diet with hope that i t would accelerate the inchoate hypertension.  2.  METHODS OF AMELIORATING . EXPERIMENTAL CHRONIC. HYPERTENSION.  Success by the previous workers of t h i s laboratory (1) In ameliorating acute hypertension with the administrat i o n of h i s t i d i n e and ascorbic acid, l e d the way to further investigation i n the use of t h i s amino acid.  Since the  e f f e c t s of h i s t i d i n e were studied only on an acute,temporary stage of hypertension, i t was decided to investigate i t s depressor e f f e c t s on chronic high blood pressure.  The  possible ameliorating e f f e c t s of ammonium chloride were also investigated. Histidine was found to have l i t t l e depressor e f f e c t without the simultaneous use of excess ascorbic acid, a  18.  strong reducing agent.  H i s t i d i n e , therefore, was thought  to be converted to histamine i n the body, probably by the action of several strains of B. C o l l i n the intestines; and the depressor a c t i o n of histamine was thought to be protected from the oxidative enzyme, "histamlnase", by the reducing powers of ascorbic a c i d . i n mind, the replacement  With t h i s p r i n c i p l e  of ascorbic a c i d by some other  agent was deemed possible. Two other substances were decided upon, namely:  Vitamin E and urease.  Vitamin E (tocopherol) has been found e s s e n t i a l for numerous phases of metabolism (32) (45).  The action of  vitamin E i n many of these biochemical systems seems to be g r e a t l y dependant upon I t s powerful antioxidant a c t i o n . Tocopherol, therefore, was thought to be a suitable r e placement for ascorbic a c i d .  The apparent  c l i n i c a l success  of Shute and associates (78) In vitamin E therapy of many cardiovascular diseases was s u f f i c i e n t to assume that vitamin E may play an Independent r o l e In the amelioration of hypertension. , I t has been reported that urease was h e l p f u l i n the hypertensive stage during pregnancy (2).  Because of the  possible reducing e f f e c t of urease by the-production of ammonia from urea, urease was postulated as a possible agent i n replacing ascorbic a c i d . I t i s well established that an overdosage of desoxycortlcosterone acetate produces nephrosclerosis and hypertension.  Biochemical studies of changes p r e c i p i t a t e d  19.  by DCA overdosage i n animals revealed s t r i k i n g disturbances i n the e l e c t r o l y t i c metabolism and p a r t i c u l a r l y a marked r i s e i n the serum Na/ €L r a t i o (70,73).  The Na/d  ratio  could be p a r t i a l l y restored to i t ' s normal by the administ r a t i o n of  ammonium chloride which at the same time  prevents the production of nephrosclerosis and hypertension. I t was decided to confirm further t h i s action of ammonium chloride.  3..  THE GENERAL DELINEATION OF THIS THESIS.  In l i g h t of the foregoing considerations, a formal summary of our problem can be stated as follows: (1) To become p r o f i c i e n t i n determining blood pressures of albino rats by the i n d i r e c t method of using, the f o o t . (£) To t r y to induce chronic hypertension by repeated injections of DCA,  and to t r y numerous modifica-  tions of t h i s procedure, namely;  the administration of  DCA with a s t a r v a t i o n d i e t , d a i l y Injections of epinephrine, and a choline d e f i c i e n t d i e t . (3) To discover the ameliorating a c t i o n of h i s t i d i n e and ascorbic acid, h i s t i d i n e and vitamin E, h i s t i d i n e and urease, Vitamin E, urease, and ammonium chloride on chronic high blood pressure.  II  APPARATUS  The apparatus used f o r determining the blood pressure of rats i n t h i s investigation u t i l i z e d the i n d i r e c t foot method.  The basis f o r this, method i s  described by G r i f f i t h and F a r r i s and the numerous modifications used have been reported by Allardyce, Semple and F i t c h ( I ) , previously of this laboratory. A. DESCRIPTION OF THE APPARATUS.  The apparatus has been f u l l y reported by F i t c h (1.9), therefore the following sections on the apparatus w i l l be dealt with b r i e f l y , and w i l l Include a few modifications decided upon to improve the accuracy of the pressure determinations.  A photograph of the apparatus i s shown  i n figure I . 1; LIGHTING The source of l i g h t used was from a 100 watt diaphram s p o t l i g h t .  The l i g h t was passed through the  microscope condenser to the web of the foot under consideration.  The f i e l d was found to be well and r e g u l a r l y  illuminated, p a r t i c u l a r l y i f the condenser was regulated to give the most diffuse l i g h t . a. MICROSCOPE The microscope was f i t t e d with a mechanical stage  21.  onto which a wooden platform was attached f o r supporting the r a t .  There i s an aperature i n the platform coinciding  with the passage of l i g h t .  T h i s aper&ture i s surrounded  by p l a s t i c i n e onto which the web of the foot i s spread and f i x e d to v i s u a l i z e the c a p i l l a r y movement.  Because  of the supporting arrangement f o r the web, i t i s only possible to use a low power objective. However, f o r more accurate observation and l e s s s t r a i n on the eyes, the use of a 15 X eye-piece (magnification 150X) was found helpful. 3. CUFF. The making of the cuff i s adequately described by F i t c h (19).  In t h i s i n v e s t i g a t i o n the cuff was made longer  than previously reported to ensure complete e n c i r c l i n g of the r a t thigh.  This procedure was found to give more  d e f i n i t i o n i n determining the s y s t o l i c pressure, and thus more accuracy. 4. CUFF PRESSURE SOURCE. B r i e f l y , the pressure i n the cuff i s obtained through the use of a mercury column.  The mercury tube i s  attached to the cuff, a pressure guage (aneroid manometer) and a syringe, f o r aiding the i n i t i a l pressure to the c u f f . The mercury column i s so assembled as to be used f o r f i n e adjustment•  22  III  METHODS  The previous work done In t h i s laboratory Investigated and established two very important problems, namely, f i n d i n g a safe and e f f e c t i v e means of anesthesia and the mastery of the microscopic technique Involved In determining accurate blood pressures.  The establishment of  these r e s u l t s aided g r e a t l y i n the development of our own technique.  The solution to these two problems i s adequately  described by both Semple (77) and F i t c h Cl9). •A. THE PROCEDURE FOR MEASURING BLOOD PRESSURE. 1* ANESTHESIA. The anesthesia found most safe and e f f e c t i v e by the previous investigators was sodium pentathol (monosodium s a l t of 5 - ethyl - 5 - (1 - methylbutyl) t h l o b a r b i t u r l e a c i d ) , and was the anesthetic used throughout our entire experimental research. Sodium Pentathol i s obtained In ampoules containing .5 gms. Since i t i s necessary to have a fresh s o l u t i o n of pentathol d a i l y f o r blood pressure determinations, with a 2.5$  solution as the most r e l i a b l e , i t was found  convenient  to subdivide the .5gms i n t o f i v e groups of 100 mg., and store i t I n a r e f r i g e r a t o r i n dry, s t e r i l e bottles e s p e c i a l l y f i t t e d with hypodermic rubber stoppers.  When  required, 4 ec. of water were added to make up the 2.5%  23  solution, an amount s u f f i c i e n t to do 8 - 10 r a t s . From the previous work of Semple (77) and F i t c h (19) and our own  observations,  the therapeutic dose f o r most  WisfcfcfrSk was established.  Contrary to F i t c h and Semple,  who  did not f i n d the administered  dose influenced by such  f a c t o r s as body weight, we d i d f i n d the dose of sodium pentathol was most dependant upon the factor of body weight. Other factors such as recent meals also e f f e c t s the dose. The value of the therapeutic dose was well defined by Semple;  n  that volume of 2±5% sodium pentathol that i s  required to completely anesthetize the r a t f o r a period l a s t i n g over 30 minutes but not longer than one hour." However, with the development of a more rapid technique, i t was possible to lower the period of anesthesia from 20 - 40 minutes, thus lowering the possible e f f e c t of an overdose.  Table I shows the therapeutic dose found f o r  most aiHwiasts..  I f the r a t f a i l s to succumb to the regular  dose, i t i s permissable to give only .1 cc more of the anesthetic at that time.  I f more than .1 cc of sodium  pentathol i s given, the rat usually succumbs to r e s p i r a t o r y failure. Sodium pentathol i s injected i n t e r p e r i t o n e a l l y . Care must be taken that the needle of the hypodermic i s i n the peritoneal cavity and not i n the abdominal wall or some v i s c e r a l t i s s u e .  The administration of the anesthetic  was previously <|tf«*;«^iii&&Wpan assistant to hold the r a t ,  24.  and an operator for tho Injootiono, but with practice an adequate method can be developed fo:ie>k\ch 'ri&  \n<§lff ««3f£cjoi|recJ  indivi(?rr-"., 2.  BLOOD PRESSURE DETERMINATIONS.  A r a t i s anesthetized and l e f t for about 5 - 1Q minutes.  After the anaesthetic has taken e f f e c t , the  animal i s l a i d face down, and the thigh of the l e f t l e g (found most convenient) Is wrapped somewhat f i r m l y with the cuff.  Holding the cuff In p o s i t i o n , the rat i s l i f t e d onto  the adjustable platform and placed In p o s i t i o n , namely, with the web to be examined (preferably between d i g i t s 4 & 5) spread over the l i g h t aperature on the stage and f i x e d In place with p l a s t i c i n e .  The web Is searched under low  power f o r a suitable f i e l d of c a p i l l a r i e s with a rapid flow of corpuscles.  When the most s a t i s f a c t o r y f i e l d has been  located, the pressure i n the cuff i s raised by means; of the syringe to approximately 110 - 115 mm.  of Hg.  The pressure  i s then raised by the use of the syringe and by allo?jing mercury to run into the U-tube, u n t i l the blood flow and movements have been arrested. The pressure i s released, and a second pressure reading i s recorded.  The average of  these two values i s taken as the s y s t o l i c pressure.  It i s  necessary that several groups of vessels be observed simultaneously to make sure that the blood flow has ceased throughout the  web.  25.  B. METHODS IN EXPMIMENTAL CHRONIC HYPERTENSION.  RUN I:  For the f i r s t run, 11 female rats were chosen,  and t h e i r normal blood pressures established f o r 5 consecut i v e days.  Of the 11 r a t s , two were set aside as normal  controls, the other 9 were then injected intramuscularly with 1 mgm. of desoxycorticosterone  (DCA).  DCA i n j e c t i o n s were termed day V .  The day of  Subsequent  s t a r t i n g from dayo'* were taken up to day 25. n  desired chronic hypertension  readings, Since the  was obtained by one i n j e c t i o n  of DCA, the r a t s were divided as follows: GROUP (a) Two r a t s set aside at the start of the run f o r normal controls.  They received no treatment.  GROUP (b) Two r a t s which received 1 mgm. of DCA, and received no further treatment. GROUP (o) One r a t , which received 20 mgm. of h i s t i d i n e and 70 mgm. of ascorbic acid d a l l y i n powdered fox chow (Purina M i l l s ) This was; prepared as follows: A quantity of s p e c i a l d i e t i n the form of a mixture consisting of 140  of powdered fox chow, 140 mgm  of h i s t i d i n e , and 490 mgm of ascorbic acid was prepared for a seven day period and was divided into 7 equal portions. GROUP (d)  One r a t , which received 20 mgm of h i s t i d i n e i n powdered fox chow, and 10 mgm of vitamin E i n o i l (alpha-tocopherol,  B r i t i s h Drug Houses)  26  were added d a i l y .  The h i s t i d i n e and powdered fox chow  were mixed as described above. GROUP (e)  One r a t , which was given 10 mgm. of vitamin E d a i l y on powdered fox chow;  GROUP (f)  One r a t , which received 20 mgm of h i s t i d i n e and 25 mgm of urease d a i l y i n powdered fox chow.  A mixture of powdered chow, 140 mgm  of h i s t i d i n e and 175 mgm of urease was prepared as f o r group (c) GROUP (g)  One r a t , given 25 mgm of urease d a i l y i n powdered fox chow as described i n group ( c ) . One r a t , which received 2$ ammonium chloride  GROUP (h)  (NH4 CI ) d a i l y i n powdered fox chow. Ammonium chloride was prepared with powdered fox chow as described f o r group ( c ) . A l l special diets were started on day 27. Pressure readings of these groups were taken up to day 48, when the special diets of groups (c) to (h) were stopped.  A reading  of a l l - r a t s was again taken on day 62, and the diets of only groups (d) and (e) were resumed.  Subsequent readings  on these two groups were taken on days 71 and 78. The r e s u l t s of t h i s run are shown i n table 2, and figures 3-6. RUN I I ;  Eor t h i s run 12 female rats were selected and  t h e i r normal blood pressures established as i n the previous experiment.  Two rats were kept as normal controls and  received no treatment.  The remaining 10 rats were injected  27*  with 1 mgm of DCA on day "o". F a i l u r e to produce high blood pressure resulted i n further i n j e c t i o n s of DCA (Imgm.) on days 11 and 16. u n t i l day 38.  The pressure readings were continued  The r e s u l t s are shown i n table 3 and figure  7. RUN. I I I ;  10 female r a t s were chosen and t h e i r normal  blood pressure determined as before. were injected with 1 mgm of DCA.  On day "o" a l l r a t s  F a i l u r e to obtain  hypertension resulted i n a second i n j e c t i o n of 1 mgm of DCA on day 12.  Pressure readings were taken up to day 32.  The r e s u l t s are shown i n table 4 and figure 7. RUN IV:  The procedure f o r t h i s run was the same as  for runs I I and I I I . DCA (Imgm) i n j e c t i o n s were given to 12 female r a t s on days "o", "9", "29f and "52". pressure readings were established up to day 66.  Blood The  r e s u l t s are shown i n table 5 and figure 7. RUN V:  Failure of runs I I , I I I and IV i n e s t a b l i s h i n g  hypertension by repeated injections of DCA, resulted i n a modification  of i t s use (See introduction p.15^. In t h i s  run 8 female rats were chosen and t h e i r normal blood pressures established f o r 2 days.  Two of these r a t s were  kept f o r normal controls and received no treatment.  The  6 remaining rats were placed on a "starvation d i e t " consisting of 12 gms of the regular diet (fox chow), an amount found adequate i n reducing the weight.  This diet  was continued f o r 17 days with intermittent blood pressure  28.  readings. "The r a t s were found to lose an average of 35 gms In t h i s 17 day period.  On day 17, the s i x r a t s were  Injected with limgm of DCA. up to day 33.  Subsequent readings were taken  The r e s u l t s are shown i n table 6 and  figure 8. RUN VI:  This run consists of a further modification i n  the use of DCA i n producing high blood pressure.  For t h i s  run 5 female r a t s were obtained and t h e i r normal pressures recorded.  Two r a t s were set aside as normal controls and  were given no treatment.  The remaining 3 rats were i n -  jected with '1 mgm. of DCA and .002 mgm. of epinephrine on day o .  The adrenalin injections were given d a i l y up to  day 24.  Nine pressure readings were established up to  day 24.  The r e s u l t s are shown i n table 7 and figure 9.  RUN VTI:  Unsuccessful attempts to obtain hypertension  M  n  since run I, culminated i n using a choline deficient d i e t . Five female rats were used.  After t h e i r normal pressures  were established, they were placed on a prepared choline deficient diet (see figure 2) f o r 9 days s t a r t i n g on day "o",  On day 9, 4 of the 5 r a t s were injected with 1 mgm  of DCA.  Readings were taken of a l l r a t s up to day 29.  Results of t h i s run are shown i n table 8 and figure 10. RUN VIII:  This run was composed of 12 female r a t s .  The  normal blood pressure of each r a t was established f o r two days.  On day o n  n  a l l rats were placed on a 7 day choline  deficient diet (figure 2 ) . Chronic hypertension was established i n a l l r a t s by day 20, and were then divided  •  Sucrose Gelatin Oaesin Fibrin  67.5% 7.0% 5.0% 1.0%  *Salta Celluflour "Vitamin mix Cystine  * Salts (N.S.O. salt mix No.2) NaCl 4.55% Mgso^ 15.70% NaH2P04 8.72% KzPO^ 25.98% Ga(H P84) 15.58% Ferric Citrate 2.97% Calcium Lactate52.70%  5.0% 2.0% 1.0% . 0.5%  Beef f a t 12.0% Cod l i v e r o i l 1.0%  * Vitamin powder/100 gm. Thiamin 500 mg Riboflavin 250 mg Pyridoxine 200 rag Ca Pantothenate 1 gm. Nicotinic acid 1 gm.  2  -added to 997.05 gm of powdered.sugar.  |]g$|bj£V Showing the constituents of the choline deficient diet used for the production of chronic high blood pressure.  29.  into the following groups. GROUP (a) Two r a t s used as hypertensive controls and received no further treatment. GROUP (b)- Four rats, which were given 20 mgm of h i s t i d i n e and 70 mgm. of ascorbic acid d a l l y / r a t . i n powdered fox chow. The mixture was given as described i n Run I , group ( e ) . GROUP Cc) S i x rats, which received 40 mgm of vitamin E i n o i l added d a i l y / r a t . to powdered fox chow. Both supplemented diets were continued f o r 13 days. On day 33 the special diets were stopped. continued f o r 39 days.  The test  The r e s u l t s are shown i n table  9 and figure 11.  17 RESULTS  The r e s u l t s of t h i s investigation are l i s t e d i n tabular and graphic form. Figures 3 - 6 (table 3, Run I ) show a r i s e of blood pressure of ten female r a t s injected with 1 mgm of DCA on day o " . n  The blood pressure rose i n four days, 170 mm of  Hg above normal, to s y s t o l i c pressures of over 300 mm of Hg.  Pressures over 300 mm of Hg could not be recorded  by the aneroid manometer.  Figure (3) shows the amelior-  ative effect of h i s t i d i n e and vitamin E and vitamin E  30  supplement.  The pressures dropped to an average of 232 mm  of Hg with both d i e t s .  These diets were stopped i n 21  days, after which the hypertensive l e v e l s returned to their previous state. 62 f o r 18 days. of 215 mm of Hg.  The diets were r e i n s t i t u t e d on day  The pressures again lowered to an average Figures 4, 5 and 6 show the negative  r e s u l t s of h i s t i d i n e and ascorbic, urease, and ammonium chloride  h i s t i d i n e and urease,  respectively.  Figure 7 (tables -3 - 5) shows the negative response of Runs I I , I I I and IT to 1 mgm i n j e c t i o n s of DCA.  The  rats showed no response to DCA injections with the exception of Run IV, i n which a temporary r i s e of 25 mm of Hg was observed. Figure 8 shows the negative response of 6 rats to a 17 day starvation diet followed by  1 mgm injections of  DCA to r a i s e the blood pressure. Figure 9 shows the negative e f f e c t s on the blood pressure of 3: female r a t s a f t e r 24 d a i l y injections of adrenalin with an i n i t i a l 1 mgm i n j e c t i o n of DCA on day o " . M  Figure 10 shows the r i s e i n s y s t o l i c pressure of 5 r a t s placed on a choline d e f i c i e n t d i e t f o r nine days s t a r t i n g on day " o . M  4 r a t s were injected on day 9 and  t h e i r s y s t o l i c blood pressure rose to an average o f 210 mm of Hg on the 14th. day. l e v e l u n t i l day 20.  These 4 rats remained at t h i s  On day 20 the uninfected DCA r a t had  a pressure of 200mm of Hg.  From day 20 to 26 the s y s t o l i c  31  blood pressure of a l l r a t s rose to 300 mm of Eg. Figure 11 shows the e f f e c t s of h i s t i d i n e and ascorbic acid and vitamin E on chronic hypertension produced by a 7 day choline d e f i c i e n t d i e t .  Most of the  rats had s y s t o l i c pressures of over 300 mm of Hg. 2:0 days a f t e r the start of the choline d e f i c i e n t d i e t s . ¥itamin E i s shown e f f e c t i v e i n lowering the blood pressure to an average of 205 mm of Hg.  Time i n Days  •S  3  a  126  a  129  9  c  108  8  25  27  30  35  38  41  155 134  132 152  -  1361 154  150 153  15^ 154  156 152  133 135  138 140  -  136  i4o 230 300  300 300  300 300  500 300  300 500  -  300 300  500 300  5001300 I 300 300  500 300 300 500  300 500  500 500  124  151 130  20  134 132  2  126 122  16  134  13l| 13 * 132 126  13  *  145  300  109  108  119 173 212  300 300  300 300  300 500  116  114  144 210 300  300 300  300 300  500  300 300 300  £  154 133  155 134  152  260 242  117  156 275 500  500 500  500 300  e  125  128  128  148 227 255  300  f  116  118  120  I56 215 288  500 300  300 300  g  120  122  124  154 297 300  500 300  300 300  116  118  148 190 260  300 300  300 300  #  500  1  S.  78  500 o-" 280  215  HI 15  280 265  254  255 235  300 500  300 300  500 500  300 300 500 300  500 300  300 300 500  71  48  246 250 \o  — — —  116  44  |T3  \ t  ST? 300 ST? 284  £  300 300  300 300  500 500  300  300 500  300 |500 1500(500 1500 .BOO  Table 2. Showing the r e s u l t s of the d a i l y feeding of h i e t i d i n e and ascorbic acid(groupo),histidine and vitamin S (group d), vitamin S (group e), h i s t i d i n e and urease (group f ) , urease (group g.), and ammonium chloride (group h) on the chronic hypertension of female rats (Run I) produced by a 1 mgm. i n j e c t i o n of desoxycorticosterone acetate (DCA) on day ' 0 ' . (see figures 5-6) * not properly anesthetized. - no reading. # died under anesthetic.  i '  ;  220  Time i n Days 5  11 I 11  2  !  145  144 145  £  146  150] 140 146  2  145  140 I38 «3 o  140  1*  3  144  145  150  4  145 14^  •  140  140 144  1*5  8  158 142  7  145 145  140 »  158 155  15* 156  158  15*  1361  »  150 13A  132 13*  156  140 160 130  o  125  126  135 140  158 142  140  130 150  150 152  0  150  132  *3 o 1 t  136 146  145 142  143 • ' . . . 144 146  130 125  144 135  130  130 156  140 140  150 135  5 o •  125 JL35  o 3  125  130 134  I  12ojl25  I  122  125 140 ~ ^ ~ ^ >  "  120 115  *  152 L50  %  1*°  »' r+  144 140 142 , ,  _  155 155  4  155152_  1  8. 150 152  155  9  145  o 140 £ £ § 3  10  155 1>6  150 126  136 155  11  142 140  140 150  130130  12  1>4 I32  138 126  128 126  •  J  22 26 _5p_J^___28_  125  (0  6  138  20  J kjo  155 135  • 1  5  16  | 1A | 16  *  140  155 142.  £  132  1  4  6  " a  128  .  y  # 132 156  138 142  13^ 128  138  150 132  146 140 140 • '  150 125  13A 150  131  H5i50_  130 l g  13* 132  136 138  130 122  128 13A 13*  *  &  8  138  152  15*  136 155  irtjectione of desoxycorticoaterone acetate Table 3 . Showing the reeulte of 1 mgm. (Run II ). (see figure 7)» (DCA) on the blood preesure of female rata * not properly"anesthetized. # died under anestetic.  nam  Time i n days  §  3  »  1  2 :  ^^  1 = = =  8  0  ______ , i •„.  1 26 130 130  130  125  12  5 4  126 13* 128  128 150  * 154  o o 132 £ O 126 £  a a> *t *i  5  130  132  6  132  134 138  7 7 8  134 134 155  3  134 § 15*  S  152  C*128 B >  132  128  156  • 134 13* i  o  138  140  136 O 136  10 125  152  128  3  52  19  134  130  152 130 126  130  132  126 127  128  131 134  152 150  126  g ft  158 132  128 128  132  §  129 132  13*  B  132  27  <?  132  1 2 8  130  126  130 134  5 135 132 126 I52 150  1 2  S  «<! o 3. H*  a  134  132  I36 130  <B  136  154 134  152 136  130  126 126 *  134 128  II150  34  154 128  136 130  c+  9  24  16  152 1 34  CD  2  12  g  130 136  130 134  CDCD C^-  130  133 136  152 154  152  «|  134 155  I30 13*  138  13* 138  138 140  155  125 128  122 130  128  £ £  0  40  138  142  156; £  128  126  I30 132  Showing the results of 1 mgm. injections of desoxycorticosterone ( DCA ) on the blood pressure of female rats (Run III) (see figure 7 ) . not properly anesthetized.  3  1D 2  Time in days  0  138 §" CO  9  130  124  134  S? s?  o  155 *& h-  29  128 122 145  160  <?  36  40  132  128 128  I65  150 145  140  135 138  45  o  o  #  <+  2  56  60  66  126  124 125  <?  158  140 134  *S o  145  142 158  132  J *1 o  156  130 128  134 §  158  £  136 120  I38 140 122 125  140  130 128  126  g  1  O  o  118 £ 1 o  125  170  120  140  125  160  o I o §  150 130  145 135  155 140  150 125  128  £ •1 o  S  ® p  140  I55 132  160  152 135  g"  135  150 132  135  132 154  3  130  128 128  a  3  140  130 130  126  160  120  130  155  128 130  122  125 124  152  170  150  124 128  152  125 120  g c+  120 §  52  01  134 %  o  120 •  25  o  o  110  20  §  «*  Showing the r e s u l t s of 1 mgm, injections of desoxycorticoacetate (DCA) on the blood pressure of female rats (Run IV) (see f i g . 7)  11  0  17  17  23  BE  150 128  129  128 129  130  130 155  126  129 132  >  155  134  128 130  3  134  124  128 130  ctior  D  Time i n Days  158  155  155 156  15*  152  151 126  128  129 124  152  a  127  a  126 128  132  128 128  155  158  158  152  154  150  155  155  152  126  142  140  158  156  159  140  125  *•*  > a  ctior  125  CD  tarveit ion  150  •  B n B  Table 6. Showing the results of a starvation diet (group b ) with subsequent 1 mgm. injections of DCA on the blood pressure of female rats (Run V). (seefigure 8) no reading.  Time i n days  2  1  o  2  -  142  152 130  5  6  13  15  20  24  140 143  143 142  144  l4o  142  135  158 159  156 135  136  135  134  145 142  146  142 140  158 145  142 145  156  142 142  145  144 141  144 138  140 159  136  136 158  159  142 140  157 138  138 142  135  145 145  10  Table 7. Showing the results of a 1 mgm. injection of desoxycorticosterone acetate (DCA) on day ' 0 ' , with with d a i l y injections of JKBflBfl of epinephrine(adrenalin) (group b) on female rats(Run VI). (see figure 9)  9 a  1J4  I  132  g  ;  «.  - , -b b  I  I36  13€  140  14c  0  J  I  150 135  9  I 14  16  20  24  27  I 29  -  140 1^0  205 210  5OO  300  185 185  180 190  300  5OO  1 ; 195 225  300  500  142  150  g  142  144  js  180 200  §• o  205 210  205 215 :  296  298  250 235  245 260  300  300  *  9  » o  155  136  138  142  Table 8. Showing the results of a 9-day choline deficient diet (group a) with a lrngm, injection of DOA on the blood pressure of female rate (Run VII) . (see figure 10). •  no reading.  I I  Time i n Days 8 a  125  124  -  126  a  1?6  140  -  138  142  140  145  o D 142 £  152  150 g>  e  144 J  16  20  20  27  300 J 300 300 293  138  £  -  500  -  296  300 300  300  300 300  293  290 296  l : 2 215  300  300 300  £  300  142 220  240  220 210  "  230  14C 130 280  220  215 200  285  II 205 300 156  240  225 215  295  146  154  I  300  I?? 200 300  r  33  500  1 CB ft-  500  1  294  P.  Hj  156  29  a  c  135  c  123  126  0  144  142  c  140  144  145  134  21S300  245  255 220  270  125  125  138  153 i ? o 295  215  200 190  236  13S  140  141 144  210 300  220  210 200  290  c  «< 125  Table 9. Shoving the e f f e c t s of histamine and ascorbic acid (group b), and vitamin E (group c) on the chronic blood pressure of female rats produced by a choline deficient diet(Run V I I I ) . (see figure 11)  3^  *0  30 f  of  floi  40  (-meeting of-  «.ti9io<  r&te  cwej-aije o f  -2r\»is ,  inje<Je<J TiormaJ  i)i>^<Jinc ob>iH»  cortfcvl  fco  5o o t i J  V»/Qtn«T> (L  ^  J>€5o«^cor^cosfcrcme 0  <jroup(j) l r a l '  and  ?o  7o  tfi/amin  £  trrt  ace/ate. ^]m^tn| o n </a»j /  huhJi-nt  |joT*l<)^)  *o'  a r » J V i f e w r x * F (tO-m^r^  daily  ¥.  A,  DISCUSSION OF RESULTS«  METHODS IN PRODUCING EXPERIMENTAL HYPERTENSION.  1. DESOXYCORTICOSTERONE.  The use of desoxycortieosterone acetate has shown extremely varied r e s u l t s In the production of chronic hypertension.  In the introduction, i t was postulated on  the basis of previous work, that repeated Injections of deoxycorticosterone acetate (DCA) would be necessary f o r the production of chronic high blood pressure.  But, as  shown by the r e s u l t s of Run I (figures 3 — 6), a very marked hypertension occurred i n a l l r a t s with a single, i n j e c t i o n (lmgm) of DCA. were recorded.  Values of 300 mm of Hg and over  Aside from the ameliorating of blood  pressures i n two r a t s with vitamin E therapy, a l l r a t s remained chronically hypertensive f o r the remainder of the t e s t which lasted 68 days.  Two r a t s from t h i s run that  were h i s t o l o g i c a l l y sectioned by Logan (43) were s t i l l chronically hypertensive eight months after administration of DCA.  These r e s u l t s d i f f e r from F i t c h (19) and Semple  (77), who obtained only acute, t r a n s i t o r y hypertension by the same i n j e c t i o n of DCA. Runs I I , I I I , and HT (figure 7) showed even more  33.  divergence than the preceding run.  No s i g n i f i c a n t r i s e  i n blood pressure occurred with single or repeated i n j e c t i o n s (1 mgm) of DCA.  These l a t t e r r e s u l t s were the  ones obtained by S a l t e r (64) of t h i s laboratory, who worked p r i m a r i l y with male r a t s .  The negative r e s u l t s of  these experiments, however, were more i n keeping with the l i t e r a t u r e , whichii^fi«k»Jthat very large repeated i n j e c t i o n s , or implants of DCA are required, with a diet supplement of sodium chloride (see introduction p. 12 ). Although some workers are f i n d i n g that lower amounts of DCA w i l l produce the same e f f e c t s , these amounts are s t i l l much higher than the dosage used In t h i s  experiment.  H i s t o l o g i c a l Inspection of renal tissue taken from animals subjected to overdosage of DCA has revealed that kidney damage i n the form of nephrosclerosis i s necessary for the production of hypertension.  This explanation may  account f o r the negative r e s u l t s i n Runs I I , I I I , IV" (figure 7) i n which 34 rats f a i l e d to reach hypertensive levels.  However, i t i s inadequate to explain the r e s u l t s  of Run I, since sectioning of kidney tissue from two r a t s i n t h i s Run by Logan (43), f a i l e d to show any kidney damage, even a f t e r hypertension of 8 months duration. I t i s c l e a r l y shown from t h i s evidence that the hypertension produced i n Run I was possibly due to some extrarenal mechanism.  I f i t were possible to repeat the production  of hypertension a f t e r the method of Run I by DCA i n j e c t i o n s , certain experiments  could be carried out to determine any  34. neurogenic influence, namely, the use of sympatholytic drugs.  These have been successfully employed by Ogden  and associates ( see introducion p.14  ) i n showing the  influence of the nervous system i n chronic hypertension. The i n a b i l i t y to produce even a marked r i s e i n blood pressure by the Intramuscular i n j e c t i o n of DCA made i t necessary to modify the technique.  The modifications  were ( l ) , a starvation diet with subsequent injections (1 mgm)  of DCA,  and (2) the i n j e c t i o n of epinephrine and  DCA simultaneously, with subsequent d a i l y Injections of epinephrine (see introduction p. 16).  As can be seen from  figures 8 and 9, 6t>3o& modifications of these  experiments  proved unsuccessful. However certain factors were established. Mr. Salter (64), a co-worker i n these investigations, observed that both the starved r a t s which received DCA i n j e c t i o n s and also those which obtained no treatment with  DCA,  produoed hypertension 3 months a f t e r the i n i t i a l starvation, with average pressures of 195 mm of Hg.  This evidence  points to a possible d i e t a r y deficiency as an i n i t i a t o r of high blood pressure.  Such a p o s s i b i l i t y has been  suggested by various workers.  Calder (10) and Durlacher  and Darrow (18) have shown the production of hypertension by a diet d e f i c i e n t i n the heat-stable f r a c t i o n of the vitamin B complex, which can be reversed by r e s t o r i n g this fraction.  However, the involvement of a choline  deficiency could be evident here, as w i l l be seen i n  •35.  the following sections. The experiments with epinephrine and DCA may show that desoxycorticosterone plays a r o l e i n counteracting the nervous system.  Work: done i n conjunction with Mr;  S a l t e r (64) (reported i n Mr. S a l t e r ' s thesis) has shown that DCA  injections s e n s i t i z e r a t s to the pressor response  of epinephrine.  The r e s u l t s show that r a t s increase t h e i r  s e n s i t i v i t y to the pressor response of epinephrine from 9 to 16 mm of Hg, over a 5 day observational period. But r a t s that were given d a i l y Injections of 1 mgm  of DCA  previous to a small amount of epinephrine showed a higher pressor response Increasing from 16 to 32 mm of Hg. over the same observational period.  These r e s u l t s might  possibly indicate the p a r t i c i p a t i o n of the nervous system i n t h i s pressor response.  Page and Taylor (57) have  recently found that i n j e c t i o n s of t e t r a e t h y l ammonium chloride (TM),  an agent which blocks sympathetic ganglia,  increases the response of both pressor and substances.  depressor  Among these substances they found a manifold  increase In the pressor response to epinephrine and angiotonin and In the depressor response of histamine. Corcoran (12) has taken t h i s action of TEA to mean some central nervous influence which l i m i t s vascular responsiveness to pressor substances.  DCA may have a similar e f f e c t  i n the i n h i b i t i o n of t h i s neurogenic mechanism, thus increasing the response to epinephrine.  However, more  experimental evidence i s needed to j u s t i f y t h i s hypothesis.  36 This w i l l he r e f e r r e d to l a t e r . 2. CHOLINE DEFICIENCY. As can be seen from figures 10 and 11 t h i s method, as found by Best and Hartroft (see introduction p. 17 ), was the only d e f i n i t e means of inducing; experimental hypertension.  Best and Hartroft found that i n a group  of weanling r a t s which had been subjected to a 5 and 6 day choline d e f i c i e n t d i e t , hypertension occurred 4 to 7 months l a t e r , along with i r r e v e r s i b l e l i v e r and kidney damage.  However f i g u r e s 15 and I I show that In the case  of t h i s investigation only a few weeks was necessary to induce hypertension by t h i s  method.  Specifically in  the case of Run VII, 17 days, and Run VIII, 13. days. The mean pressure of the most severe group obtained by Best and Hartroft was 195 mm of Hg, from which we can estimate the severest s y s t o l i c pressure as being 260 mm of Hg, whereas s y s t o l i c pressures i n these  experiments  were consistently above 290 with the majority over 300mm of Hg.  However, several factors could possibly account  for these differences i n r e s u l t s : ( l ) The period of deficiency was longer i n both t r i a l s ; Run VII having a 9 day choline d e f i c i e n t diet and Run VIII a 7 day deficiency. (2) The use of weanling r a t s by Best and Hartroft rather than adult r a t s ( 6 months) as used In t h i s Investigation.  Young r a t s may be more r e s i s t a n t to  such changes. (3) The l a s t factor i s that the choline  37 d e f i c i e n t diet, mixed f o r the purpose was not i d e n t i c a l to that used by Best and H a r t r o f t . A comparison w i l l show a l a c k of "arachin" and "corn o i l " .  However i t does not  seem l i k e l y that the unsaturated and saturated f a t t y a c i d metabolism would enter into the problem f o r such a short deficiency period. Figure 1G represents the f i r s t attempt to obtain hypertension by a choline deficiency supplemented by DCA. As the graph shows the i n j e c t i o n of DCA at the end of the choline d e f i c i e n t d i e t , r a i s e d the blood pressure i n f i v e days to a hypertensive l e v e l .  However, t h i s hypertensive  l e v e l , an average of 205 mm of Hg, remained constant f o r 6 days u n t i l the blood pressure of the control, which received no DCA, rose to meet t h i s l e v e l , at which time the blood pressures of a l l r a t s rose concomitantly beyond readable l e v e l s (300 mm of Hg). The manner i n which these hypertensive l e v e l s were reached r a i s e s a very Interesting point. Is the mechanism which raises the blood pressure i n choline deficient rats the same as i n choline diet deficient DCA injected rats ? We have two possible Interpretations. I f we assume that renal lesions produced by the choline d e f i c i e n t y i n i t i a t e s the renal pressor system as suggested by Best and Hartroft, then two possible mechanisms are involved i n using DCA. (1)  DCA may act on the renal tissue causing an  38. e a r l i e r secretion of renin thereby allowing the reninangiotonin mechanism to come into play more q u i c k l y . (2) DCA may function i n i n h i b i t i n g a neurogenic -tr mechanism as discussed i n a previous section, i n which i t was noted that the i n h i b i t i o n o f t h i s mechanism s e n s i t i z e d the pressor response to angiotonin B.  AMELIORATION OF HYPERTENSION WITH VITAMIN E.  Of the various ameliorating agents used i n t h i s investigation, only vitamin E or alpha-tocopherol seemed to be of value i n chronic hypertension.  In Run I (figure 3)  rats which had been made hypertensive by a 1 mgm DCA i n j e c t i o n , were given vitamin E and vitamin E i n combination with h i s t i d i n e (see Introduction p.17-18).  In both cases  the e f f e c t s were similar In p a r t i a l l y reducing the blood pressure.  The ameliorating effects of the h i s t i d i n e and  vitamin E combination were i n the i n i t i a l stages faster, although somewhat more i r r e g u l a r than vitamin E alone, possibly i n d i c a t i n g the p a r t i c i p a t i o n of histamine*. However the f i n a l ameliorating r e s u l t s of the above procedure was similar to that obtained by vitamin E, and was considered as being p r i m a r i l y caused by vitamin E therapy. In Run VIII (figure 11), r e s u l t s almost i d e n t i c a l with the f i r s t Run were obtained with alpha-tocopherol  treat-  ment on r a t s made hypertensive by a choline deficiency.  39 Although these l a t t e r finds seem more e f f e c t i v e , i t i s explanable on the basis of a higher dosage of alphatocopherol. The cessation of the vitamin E supplement r e established the hypertension to i t s former l e v e l .  This  fact shows very c l e a r l y that the presence of Vitamin E i n excess amounts i s needed for amelioration.  To further  substantiate t h i s fact the special diets of the r a t s i n Run I (figure 3) were r e i n s t l t u t e d with previously noted results.  This singular e f f e c t of vitamin E indicates i t s  independent action, p a r t i c u l a r l y I f the  hypertension  induced by a choline deficiency and DCA  are assumed to  be d i f f e r e n t . Recently Shute and associates (45) 1949,  have shown  a similar ameliorating effect by vitamin E therapy on hypertensive patients..  They state that a l l t h e i r  indicates vitamin E i s a c a p i l l a r y d i l a t o r . they have found that alpha-tocopherol  evidence  However,  does not always  show ameliorative action, and have come to the conclusion that some hypertensives have c o n s t r i c t i o n higher i n the vascular tree, perhaps at a r t e r i a l a r l e v e l s .  They have  found some evidence that estrogens may act as a r t e r i o l a r dilators.  In t h i s respect, combinations of alpha-toco-  pherol and estrogens have proved u s e f u l . From the r e s u l t s of our experiments t h i s d i l a t o r y action of vitamin E seems quite probable,  Also, the  40; presence of a r t e r i o l a r c o n s t r i c t i o n could very possibly account f o r the p a r t i a l amelioration effects of vitamin E on these chronically hypertensive r a t s .  I t would  therefore be of interest to f i n d the e f f e c t s of combined vitamin E and estrogens.  Mr. Salter (64) of t h i s  laboratory, however has found estrogen i n j e c t i o n s capable of inducing high blood pressure.  Nevertheless McGrath and  Hermann (44) and Kaiser (36) have found prolonged and considerable d i l a t i o n of c a p i l l a r i e s r e s u l t i n g from i n t r a muscular injections of estrogen.  C. CORRELATION INADEQUACIES BETWEEN THE DATA OF ACUTE AND CHRONIC HYPERTENSION.  Attempts to ameliorate chronic hypertensions on the whole, have been unsuccessful.  F i t c h (19) and  Semple (77), who worked exclusively on acute hypertension had d e f i n i t e ameliorative success.  These workers found  that h i s t i d i n e and ascorbic a c i d had a d e f i n i t e effect on lowering the s y s t o l i c pressure of acute hypertension;  In  comparison, these substances were found to be i n e f f e c t i v e i n chronically hypertensive rats (Run I and VIII; figures 3 and 11) of a DCA and choline deficiency o r i g i n .  The  explanation probably l i e s i n the basic d i s s i m i l a r i t i e s between these two forms of hypertension.  41. D. NEGATIVE RESULTS OBTAINED WITH UREASE AND AMMONIUM CHLORIDE. The Individual e f f e c t s of urease and i t s e f f e c t i v e replacement of ascorbic a c i d i n combination with h i s t i d i n e (see introduction p. 18) has been found unsuccessful i n ameliorating DCA - c h r o n i c a l l y hypertensive figure 5 ) .  rats (Run I,  The use of h i s t i d i n e and ascorbic acid was  found i n e f f e c t i v e i n the chronic stage but successful i n ameliorating the acute stage of hypertension;  therefore  the i n a b i l i t y of urease i n replacing the reducing action of ascorbic acid and i t s singular e f f e c t i n ameliorating acute hypertension  i s yet to be determined.  Ammonium chloride was also unsuccessful i n ameliorating chronic hypertension produced by a DCA i n j e c t i o n (Run I , figure 6).  The l i t e r a t u r e f i n d s that a c i d i f y i n g s a l t s , such  as ammonium chloride d i d lower the blood pressure of hypertension produced by larger doses of DCA.  This hyperten-  sion, however, was always accompanied by nephrosclerosis. The e f f e c t s of ammonium chloride are attributed to i t s balancing e f f e c t s on the sodium metabolism (see introduction p.18).  Since the DCA - chronic hyperten-  sion of Run I (figure 6) no such Kidney damage was observed (Logan 43), therefore i t would seem that sodium metabolism was not involved i n t h i s type of experimental hypertension.  E.  SUGGESTIONS FOR FURTHER RESEARCH.  Examination of the r e s u l t s of t h i s i n v e s t i g a t i o n and t h e i r subsequent discussion, fsfeM&es- the following suggestions f o r further research: 1,  The use of vitamin E In ameliorating hypertension needs to be investigated f u r t h e r , fa) Experiments could be conducted to discover the e f f e c t s of vitamin E i n preventing the production of experimental hypertension, and i t s ameliorative e f f e c t s In acute high blood pressure. (b) To discover the maximum ameliorating action of vitamin E by prolonged therapy on hypertension. (c) To discover the e f f e c t i v n e s s of combined estrogens and vitamin E therapy on chronic hypertension. Cd) To discover further the vasodilator action of vitamin E, by t e s t i n g i t s a b i l i t y to lower the blood pressure of normal r a t s .  Such i n -  formation would add further confirmation to this action. 2.  The effect of h i s t i d i n e and ascorbic a c i d has been  found i n e f f e c t i v e i n chronic hypertension and a comparable  43  s i t u a t i o n a r i s e s i n the replacement urease.  of ascorbic a c i d by  However, h i s t i d i n e and ascorbic acid were  successful i n ameliorating acute hypertensive.  An  experiment could then be carried out -to establish the effectiveness of h i s t i d i n e and urease i n acute high blood pressure. 3.  To investigate the p o s s i b i l i t y of a dual mechanism  between acute and chronic hypertension produced by ( l ) a choline deficienty and (2) DCA i n j e c t i o n s .  Such experi-  ments could be c a r r i e d out by the use of sympatholytic drugs such as phenobarbitol and yohimbine.  This procedure  would p o s s i b l y determine the influence of the nervous system on the problem, p a r t i c u l a r l y i n chronic hypertension. 4.  Evidence i n the effect of DCA i n I n h i b i t i n g the  nervous system, as previously discussed, could be obtained i n p a r a l l e l i n g the response of pressor and depressor substances In r a t s s i n g u l a r l y injected with either DCA and TEA  (tetraethyl ammonium).  The pressure  response  of angiotonln and adrenalin, and the depressor action of histamine might be  determined.  VI 1.  CONCLUSIONS.  The production of experimental hypertension by  1 mgm i n j e c t i o n s of desoxycorticosterone acetate has been found to be unreliable i n female albino r a t s . 2.  A choline d e f i c i e n t diet was found dependable  i n producing severe hypertension i n adult female albino rats. 5.  The d a i l y feeding of vitamin E to female r a t s was  shown to be p a r t i a l l y e f f e c t i v e i n ameliorating experimental hypertension caused by both desoxycorticosterone acetate i n j e c t i o n s and a choline deficient d i e t . 4.  The p a r t i a l amelioration of hypertension resulted  only i n the presence of excess vitamin E. This fact was thought to give further evidence to the vasodilator properties of vitamin E. 5.  The feeding of h i s t i d i n e i n combination with  ascorbic a c i d and with urease were i n e f f e c t i v e i n ameliorating chronic hypertension produced by a choline deficiency and DCA i n j e c t i o n s . 6»  The feeding of urease and ammonium chloride  i n d i v i d u a l l y have been shown i n e f f e c t i v e In DCA chronic hypertensive  rats.  The hypothesis was advanced that DCA may I n h i b i t the sympathetic nervous system to explain the Increased pressor response of epinephrine In r a t s Injected with desoxycorticosterone  acetate.  45. SUMMARY This Investigation deals with the p o s s i b i l i t y : of ameliorating c h r o n i c a l l y hypertensive  female r a t s by  means of the d a i l y feeding of h i s t i d i n e and ascorbic acid, h i s t i d i n e and vitamin E, h i s t i d i n e and urease, vitamin E, urease, and ammonium c h l o r i d e . The apparatus used i n determing the blood  pressures  was the i n d i r e c t method using the foot, of G r i f f i t h and F a r r i s , as modified by Allardyce, F i t c h and Semple. Sodium pentathol was used as anesthetic. Two methods were used to Induce chronic Cl) desoxycorticosterone  hypertension  acetate (1 mgm) i n j e c t i o n s .  This method was found to give very diverse r e s u l t s , and was disregarded as unsatisfactory.  Modifications of  t h i s method were used involving a starvation diet and epinephrine  i n j e c t i o n s . Both of these modifications  f a i l e d to produce hypertension. choline deficient d i e t . i n producing  fS) The feeding of a  This method proved consistant  a severe hypertensive  state.  A DGA  i n j e c t i o n was t r i e d with the purpose of I n i t i a t i n g an e a r l i e r hypertensive  state.  Vitamin E was the only substance found useful i n ameliorating the experimental  chronic  hypertension.  This amelioration resulted In the presence of excess vitamin E.  This fact was thought to give further  evidence f o r the vasodilator properties of vitamin E.  An hypothesis was advanced that DCA may  inhibit  the sympathetic nervous system, to s e n s i t i z e the vascular responsiveness to pressor and depressor substances.  47. LIT.ERATPRE CUED. 1.  Allardyce J . , F. F i t c h , R. Semple, 1948 Trans. Royal Soc. Can. 42: 25 - 35.  2.  Allardyce T.» personal communication.  3.  Anderson E., E.W.Page, d H. L i , and E. Ogden, 1944 Am. J . P h y s i o l . 141, 393 - 96.  4;  Best C.H., and N.B. Taylor, 1950 P h y s i o l o g i c a l Basis of P r a c t i c a l Medicine P /Li  5.  Best C.H., and W. S. Hartroft, 1949 Federation Proc. 8: 610-617.  6.  Bright, Richard - cited from conference on Experimental Hypertension,N.Y.Acad S c l , 3. 1^47  7.  B r i s k i n H. L., F.R.Stokes, C. I . Reed and Mrasek, R.G. - Am. J . P h y s i o l . 1943 138: 385 - 90.  8.  Brown G.M., and B.G. 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