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The amelioration of experimental hypertension by histidine and ascorbic acid Sample, Robert Evans 1948

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Z £ 3 5 7 The Amelioration of Experimental Hypertension hy Histidine and Ascorbic Acid by Robert Semple Submitted as Partial Fulfilment of Credit i n a Major in Biology and Botany for the Degree of MASTER OF ARTS i n the University of British Columbia. The University of British Columbia A p r i l , 19W A cknowledg ement s The Author takes this opportunity to express his sincerest thanks to: Dr. A.H. Hutchinson, Head of the Department of Biology and Botany, under whose authority this investigation was carried on, and without whose personal interest and cooperation the studies could not have been undertaken. Dr. John Allardyce, under whose personal direction the investigation was carried out, and whose constantly available help and advice made any progress in this work possible. Members of the Staff and Assistants of the Department of Biology and Botany for cheerful assistance in handling the experimental animals, and especially to Miss L i l i a n Cowie for additional technical assistance. The CIBA Company of Montreal, for considerable donations of materials. Table of Contents I Introduction 1 A. . Classifications of Hypertension and Review of Literature 1 1. Renal Origin 2 2. Nervous Origin h 3. Vascular Origin 6 k. Hormonal Origin 6 B. The Approach to the Problem in This Investigation 8 1. Previous Report From This Laboratory 8 C. Statement of the Problem of This Thesis 10 II Apparatus and Methods 11 A. Apparatus 11 B. Methods 11 1. Preliminary Work 11 2. Routine Procedure 15 3. Methods in Experimental Hypertension 19 III Results 2k A . Normal Systolic Blood Pressures 2k B. Results From the Use of DCA, Histidine and Ascorbic Acid, and Antistine 2k IV Discussion of the Results 29 A. The Validity of the Results 29 1. Consistency of the Results 29 2. Validity of Determinations of Normal Pressures 30 3. Effect of Variable Factors 31 B. The Hypertension Resulting From DCA Injection, and Its Amelioration With Histidine and Ascorbic Acid 3*+ 1 . The Pressor Effect of DCA 3h 2. Amelioration With Histidine and Ascorbic Acid 36 3. The Effect of Antistine 37 C. Suggestions for Further Research *+0 1. Further Investigation of the Histamine Theory ^0 2. The Action of Histamine ^1 3. Effect of Progesterone h-2 V Conclusions **3 VI Summary Literature Cited *+6 Abstract 50 I Introduction Although hypertension has received a great deal of attention from many investigators in recent years, and a l -though several different experimental approaches have been made to the problem, the etiology of most forms of the disease i n man remain uncertain. The unusual problems facing the experimental worker in this f i e l d have had a lot to do with the slow progress that has been made. One of these problems consists of the inability , up to the present, of the worker to induce in an experimental animal, a state that is truly representative of hypertension i n man. However, in spite of this and other obstacles, some progress has been made. A. Classifications of Hypertension and Review of Literature There have been a number of suggested classifications for hypertensive diseases, the most recent of which has been pre-sented by the Russian investigator Kogan-Yasny (2h). This classification i s based on: a) local tissue humeral changes; b) circulating pressor substances in the blood; and, c) changes in the vascular walls. Best and Taylor (2) recognise only two forms: the f i r s t of these classes results from, or i s secondary to, renal disease, while the second is essential, or primary, hypertension. The etiology of the latter form, which i s also the more common form, i s not yet clear. Malig-nant hypertension i s also included under essential 2. hypertension, being considered a severe form of this type. Experimentally, the problem has been approached from a number of angles. Fitch (11) reporting in 19^7 the early work done on hypertension in this laboratory, gave a very detailed review of these approaches and the theories resulting there-from. Consequently the account given here w i l l not repeat his review but w i l l place emphasis on reports published during the past year. Among the more important experimental approaches to hypertension, the author would enumerate the following: 1. Renal Origin. This method was f i r s t used in 1931*- by Goldblatt and his co-workers (15). Hypertension was induced by means of uni-lat e r a l nephrectomy in combination with partial occlusion of the renal artery above the remaining kidney. Page (27) achieved a similar result by encasing the kidney in a cello-phane capsule to produce nephritis. An Improvement on this latter method has been recently suggested by Abramms (1). This consists of using latex for the capsule, and i t i s re-ported to be a relatively safe and simple procedure to attain renal constriction. Bilateral application of these capsules resulted i n rises in the systolic blood pressure of white rats of up to 100 mm. Hg. over normal. As a result of investigations along these lines, the reninangiotonin theory to explain renal hypertension was ad-vanced. Essentially this theory postulates that the kidney elaborates renin, a proteolytic enzyme inert in i t s e l f but 3. possessed of the a b i l i t y to catalyse the breakdown of the substrate, hypertensinogen. This substrate, also hyperten-sively inert, is elaborated in the l i v e r . The breakdown of hypertensinogen, however, results in the liberation of angio-tonin (hypertensin), the active pressor substance. Angio-tonin, in turn, i s destroyed by the enzyme angiotonase (hypertensinase)'. The latter i s found in kidney, erythrocyte, and other tissues. Goldblatt (1*+) has recently summarized the evidence sup-porting this theory, and the concept of a renal origin for the essential hypertension in man. He concludes that i t would be very surprising, in view of this evidence, i f eventually hypertension did not prove to have a renal origin. At the same time he concedes a possible secondary role to the hor-mones of the adrenal cortex. The theory of a renal origin has been supported by some c l i n i c a l evidence. For example, Yuile (hQ) reports several cases of hypertension accompanied by obstructive lesions in one or more renal arteries. Renal hypertension i t s e l f i s claimed to be established by means of a humeral mechanism. Ogden et a l ( 2 6 ) feel that this has been established. Recently these workers have re-ported that the hypertension that follows the application of a clamp to the renal artery disappears i f the clamp be re-moved within 10 days. The hypertension becomes chronic i f the clamp i s applied for longer periods. One of their con-clusions from this work i s that the nervous system plays no part in the establishment of renal hypertension, but may have a role at a later stage of the condition. The renal theory has not gone unchallenged, however, and one of the strongest arguments against i t has-been the pheno-menon of tachyphylaxis. (The progressively diminishing pressor responses to intravenous injections of renin.) Page and Taylor (290 have, found that the administration of tetra-ethylammonium ion overcame this phenomenon. Thus the action of angiotonin, i t s e l f musculotropic in function, was affected by a substance that acts upon the nervous system by blocking the sympathetic ganglia. These latest investigations, then, have raised some interesting questions, principal amongst which is- the problem of why the action of a musculotropic substance should be affected by the use of a neural drug. This work with tetra-ethylammonium also raises doubts as to the validity of the conclusions drawn by Ogden and his co-workers (26), in regard to the role of the nervous system. 2. Nervous Origin. The concept of nervous influences playing a major role i n the etiology of hypertension has existed for some time. It has been pointed out that the strain of l i v i n g under modern ci v i l i z e d conditions could bring on such a condition. Best and Taylor (3)> however, show that Life Insurance st a t i s t i c s , on comparing urban and rural people, f a i l to substantiate such an argument. A good deal of work has nevertheless been done along 5. this l i n e . Schafer (32) and Thomas (36) have reported achieving hypertension by the complete section of the aortic depressor and carotid sinus nerves. In opposition i t i s pointed out by Wiggers (38) that the overall pathological picture in such a neurogenic hypertension is very different from that of essential hypertension. In the former case peripheral resistance remains practically unaltered and the hypertension induced i s the result of cardiac acceleration, with a resultant increase in cardiac output. The reverse i s true of essential hypertension. Holt et a l (21) found that stimulation of the carotid sinus nerve results in the lowering of the systolic blood pressure by This i s accompanied by a decreased cardiac output as well as decreased peripheral resistance. The action of the sympatholytic drug, pentaquine, has been investigated c l i n i c a l l y by Fries (13). It i s said to exhibit a pronounced depressor effect; a dose of 120 mg./day lowering, i n 10 days, the systolic blood pressure of a typical hypertensive patient from 220 to 150 mm. Hg. The drug induced hypotension i n patients with normal blood pressures. Pen-taquine was not recommended, however, for c l i n i c a l use because of i t s toxic effects. What would seem the most convincing evidence favouring a neural genesis of hypertension comes from Medhoff (25) and Farris (9). These workers have exposed rats, from weaning onwards, to noise blasts of 10 minutes duration daily. Hyper-tension developed with age. This work would support Selye(33) 6 who has referred to hypertension as one of the possible "diseases of adaptation", i n connection with the general-adaptation-syndrome. 3. Vascular Origin. The suggestion has been made that the a r t e r i o s c l e r o s i s of hypertension may be the cause, rather than the e f f e c t , of the disease. A c t u a l l y there i s l i t t l e evidence for t h i s b e l i e f to date, although King (22) has shown that there i s a d e f i n i t e thinning out of the elastomeric constituents of the a o r t i c wall and an accumulation of collagenous f i b r e s and other deposits with age. Freedman (12) suggests that a hyaluronidase deficiency, i f long sustained, might a c t u a l l y change the vessel walls to such an extent that a compensatory increase i n blood pressure takes place i n order to maintain the normal tissue-blood f l u i d exchange. *»•'. Hormonal Origin. In spite of the fact that a u t h o r i t i e s l i k e Best and Taylor (3) discard the p o s s i b i l i t y of an endocrine o r i g i n for hypertension, and others a l l o t such a mechanism only a pos-s i b l e secondary r o l e , Goldblatt (1*0, there remains a certain amount of evidence to be explained before such a decision can be made with certainty. Knowlton et a l (23) at Columbia Uni v e r s i t y have confirmed previous r e s u l t s that overdosage of rats with desoxycortico-sterone acetate (DCA) resulted i n renal and cardiac hyper-trophy, atrophic changes i n the subcapsular zone of the 7. adrenal cortex, and hypertension. Such rats received normal amounts of NaCl. If, however, the intake of N aCl was drasti-cally reduced, the effects of the steroid were abolished or reduced to a minimum. Grollman (20) has had considerable c l i n i c a l success in ameliorating hypertension in man by means of drastically reducing the NaCl intake. Although the prac-t i c a l value of such treatment was questioned because of the d i f f i c u l t y in establishing the restrictions necessary, never-theless the possible connection between these two investi-gations i s of the greatest interest. The work of Soto (3*0, i n Mexico, i s of interest in this connection. He reports that overdosing mice with such sub-stances as DCA failed to produce the typical pathological symptoms (renal lesions, etc.) that have been repeatedly con-firmed with rats. Further evidence involving the adrenal cortex has come from Victor (37) who obtained immediate and sustained hyper-tension in dogs by a unilateral partial ligation of the peri-adrenal blood vessels and tissues. Such treatment produced elevations in the systolic blood pressure within three days. Six months later, the systolic blood pressures of the animals operated on were reported to average 125 mm. Hg over normal. Goldblatt et a l (16) reported that they were unable to induce hypertension by repeating this procedure. However, that adrenal cortex function and blood pressure are interrelated i s indicated by Cawadias (5). He reports the case of a man suffering from hypotension and other "classic 8. symptoms of adrenal insufficiency". A. post-mortem on this case revealed advanced carcinoma of both adrenals, with metas-tases in one kidney. Selye's "general-adaptation-syndrome" (33) suggests that hypertension may be endocrine as well as neural in origin. (See neural origin.) He states that the disease may "...rep-resent the by-products of the endocrine reactions that are at play in the general-adaptation-syndrome." On the basis of this evidence alone, i t would seem too early to write off the possibility of an endocrine origin for essential hypertension. B. The Approach to the Problem i n This Investigation The success achieved by Wirtschafter and Widman (39) i n ameliorating peripheral vascular disease by injections of histamine and sodium ascorbate, together with the well-known vasodilatory action of histamine, Best and Taylor (*+), point-ed the way to the investigation of the action of histamine in experimental hypertension. 1. Previous Report From This Laboratory. Fitch (11) has shown that hypertension can be induced, i n the albino rat, by a single small intramuscular injection of DCA. Such hypertension was subsequently ameliorated by the feeding of excess histidine and ascorbic acidj moreover, i f such feeding was started at the same time as, or before, the DCA injection, no hypertension resulted. If either the histidine, or the ascorbic acid were omitted, hypertension 9 . developed. The amelioration described above resulted, i t was thought, from the action of excess histamine. ' Fieser (10) and other authors have confirmed the fact that the decarboxylation of histidine can be accomplished in the intestine by several strains of B. c o l i . Normally such histamine would be dest-royed by the oxidative enzyme histaminase. However, this could be prevented by the presence of ascorbic acid, a potent reducing agent, in excess. Reports recently published by Ellinger (7) (8) were of interest in the light of the results obtained by Fitch ( 1 1 ) . Mice, irradiated with lethal doses of X-rays, developed characteristic pathological conditions including fatty degene-ration 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 of DCA showed a protective action against the l i v e r degeneration, and brought about a reduction in the mortality rate. These two effects were correlated, and, within limits, their mag-nitude was proportional to the dose of DCA. It seemed pos-sible that the phenomenon reported above was the reverse of that under observation in this laboratory. In work reported by Ellinger (7) (8) the effects of an excess of histamine were ameliorated by daily dosing with DCA, whereas in the work previously reported from this laboratory the effects of excess DCA were ameliorated by making excess histamine 10. available. C. Statement of the Problem of This Thesis Inasmuch as this work was initiated in association with Fitch (11), the factors that author took into consideration i n the formulation of an objective for his work apply equally to this investigation. Time and experience, as i s usual with a thesis of this nature, were limited. Accordingly i t was necessary to focus attention on a very limited phase of hyper-tensive work. The phase chosen was the possibility of affecting blood pressure by the oral feeding of amino acids, through the pressor or depressor action of their respective amines. The author also shared the problem of developing, and learning to use efficiently, a suitable apparatus for measu-ring blood pressure in the albino rat. Taking the above facts into consideration, a statement of the problem was formulated as follows: 1. To develop a suitable method of measuring the arter-i a l blood pressure of the albino rat, and 2. To confirm the report that the oral feeding of excess histidine and ascorbic acid ameliorated the hypertension i n -duced by a small injection of DCA, and 3. To investigate the mechanism of such amelioration i f confirmed. 11. I I Apparatus and Methods A. Apparatus I t was decided to measure the blood pressure of the rats by the i n d i r e c t method using the foot. The basis f o r t h i s method i s described by G r i f f i t h and F a r r i s (17)» and the modi-f i c a t i o n s found useful i n t h i s laboratory have been reported by F i t c h (11). E s s e n t i a l l y the apparatus was designed to allow the v i s u a l observation of the blood flow i n the c a p i l l a r i e s of one of the i n t e r d i g i t a l webs. This flow was blocked by means of an i n f l a t a b l e cuff which encircled the thigh of the leg under observation. The pressure i n the cuff could be adjus-ted coarsely with an ordinary syringe, or f i n e l y by means of a mercury column. The stoppage of blood flow so induced was observed under the low power magnification (x 100) of the microscope. The s y s t o l i c blood pressure thus obtained was read d i r e c t l y from an anaeroid manometer. The assembly of the apparatus used by the author i s pictured i n F i g . 2a. B. Methods 1. Preliminary Work. The work done during the early stages of t h i s i n v e s t i -gation was concerned almost i n i t s entirety with two problems. The f i r s t of these was the problem of finding a safe and 12. efficient means of anaesthesia, the second concerned the mastery of the technique involved i n obtaining accurate blood pressure readings, in reasonable time, with the apparatus described above. Anaesthesia: The lack of success with the several anaesthetics f i r s t tried, and the success f i n a l l y achieved with Pentathol Sodium (Abbott), as well as the reasons for these results, have been reported i n detail by Fitch (11). It w i l l suffice here to l i s t those tried, over a period of three months, with l i t t l e or no success (from a point of view of consistent day to day work): a) An i n i t i a l t r i a l of sodium ethyl (1-methylbutyl) thiobarbiturate. (Pentathol Sodium) (Abbott). b) Ethyl ether. c) Sodium propylmethylcarbinylallylbarbiturate. (Seconal). d) Carbritol (Parke Davis). e) Sodium phenylethylbarbiturate (Luminal Sodium) (Winthrop). f) Paraldehyde. As mentioned previously, success was f i n a l l y achieved with Pentathol Sodium. The measure of this success can be judged by the fact that during the early attempts with the anaesthetics enumerated above, one in every three attempted anaesthesias resulted in the death of the rat, and the majo-r i t y of the remainder were ineffective. However, during the four hypertensive runs to be described, there were 280 13. satisfactory (as defined below) anaesthesias, for a total of seven f a t a l i t i e s . Pressure Readings: Early blood pressure readings were also unsatisfactory. Systolic pressures obtained varied from 50 to 1^ 0 mm. Hg., but were generally low (50 to 85 mm. Hg.). Then too, these early readings were inconsistent. A range of 20 to 30 mm. Hg. for two separate determinations on an individual rat was not unusual. Both the low values for normal pressure, and the inconsistency of the readings, were eliminated when the errors induced by the three faults outlined below were cor-rected. a) Faulty Capillary Observation: Because they were conspicuous, and because blood move-ment in them was rather more obvious, the larger capillaries were observed almost exclusively at f i r s t . When attention was turned to the finer vessels, more satisfactory results were obtained. The ideal objective was found to be several small vessels (approximately 8^ in diameter) in which the corpuscles could be seen streaming rapidly in typical eryth-rocyte chains. Although at f i r s t d i f f i c u l t to locate, they were found to give very consistent results. The problem of locating such vessels was solved by practise. Actually i t was found later that with experience on the part' of the operator, the larger vessels could give equally constant re-sults, and that such results do not differ from those ob-tained from the observation of smaller vessels. However, constant and careful focus adjustments were necessary. The flow of the corpuscles near the vessel walls was arrested be-fore that of those in mid-stream. This was the source of the early low values. b) Visual Fatigue: In the author's opinion, the inconsistency of the early readings were mainly a result of visual fatigue. During this period a great deal of time was spent attempting to obtain a single pressure reading. The long searching of the webs by the untrained eye inevitably resulted in eye-strain. This problem, too, was solved by experience. Practise made the. detection of movement in the very fine vessels' readily discernible, with the result that several readings could be taken before any strain was f e l t . c) Improper Lighting: Lighting was found to be of great importance inasmuch as i t affected directly the two factors f i r s t mentioned. The web under observation had to be well, but not  intensely, l i t from beneath. The best results were obtained if^such light was reduced by means of the sub-stage diaphragm of the microscope u n t i l i t affected only the specific area of the web under examination. A l l other lights i n the room were cut to a minimum, and whenever possible the shades were drawn over the windows during daylight. Having observed these precautions, the author found the following rules a help in obtaining satisfactory results: i) Determinations should be made when the observer i s 15. fresh, and avoided when he i s fatigued, and avoided particu-l a r l y when suffering from any eye-strain from other work. i i ) Lights should be adjusted carefully before undertaking any observation. i i i ) When observing the web, the operator should search quickly for suitable vessels and i f such are not noted im-mediately, the eye should be rested and another portion of the web, or another web, examined. 2. Routine Procedure. After preliminary exploration of possible techniques, a set procedure was adopted. The routine followed i s set forth below: a) Records: Each rat, on selection for experimental work, had a serial number allotted to i t which was tattooed on the ear, males on the l e f t ear, females on the right. At the same time a f i l i n g card was prepared, on which the s t a t i s t i c a l data concerning the animal was noted (age, sex, weight, etc.). Subsequently this card was used as a record of the time and nature of any treatment, the results of such treatment, as well as any unusual condition noted in the animal. The card record for one of the rats of Run IV i s shown i n Fig. 1. b) Anaesthesia: Pentathol Sodium was received i n powder form, put up i n vials containing 0 . 5 gm. This powder was made up to 2 1/2$ aqueous solution. Such a solution had to be prepared within three hours of use, any longer period in solution rendering 16. the anaesthetic ineffective. For convenience and economy, therefore, these 0.5 gm. lots were subdivided into 0..125; gm. samples, and these smaller amounts were placed i n vials f i t t e d with rubber stoppers especially prepared for hypodermic use. o The vials thus prepared were stored at ? C. When they were required 5 cc. of water were added to make a 2 1/2$ solution. This amount was found convenient when working with six to twelve rats. It was found very early in the work that the therapeutic dose of Pentathol Sodium varied considerably from one animal to another. Furthermore, there was no definite correlation between this dose and the variable factors that would seem to be indicated, factors such as age, sex or body weight. (Table 1). As a result, the therapeutic dose for each animal had to be established before experimental work could begin. . This "therapeutic dose" for the purposes of this Investigation was defined as: that volume of 2 1/2$ Pentathol Sodium that was required to completely anaesthetise the rat for a period lasting over 30 minutes, but not longer than one hour. This dose was established by starting with a minimum dose (usually. 0.35 ml.) and i f this was found to be ineffective, i t was raised by 0.05 ml. daily u n t i l the required effect was ob-tained. Whenever an animal failed to succumb to a specific dose, i t was replaced in i t s cage and given no further treat-ment on that day. The actual administration of the anaesthetic was straightforward. An assistant was required to hold the rat, 17. TABLE 1. This t a b l e shows the t h e r a p e u t i c dose i n ml. of 2 1/2% P e n t a t h o l Sodium r e q u i r e d to induce 30 to 60 minute anaesthesia i n s i x t y p i c a l r a t s . Rat S e r i a l Weight Sex Dose Number (gms) (ml) I I I L 3 200 M 0.60 I I I L 5 200 M 0.1+0 I I L 5 270 M 0.55 I I I R 5 176 F 0.50 I I I R 1 180 F O.lfO IV R 8 170 F 0.35 18. ventral surface up, and the operator passed the hypodermic needle through the body wall into the peritoneal cavity. It was important to be sure of actual penetration, otherwise a subcutaneous injection resulted. Such an injection caused the animal considerable distress and furthermore was never effec- < tive as an anaesthetic. The correct dose, properly adminis-tered, caused the animal to succumb in three to five minutes, and remain under the influence of the anaesthetic for 30 min-utes to one hour. There were, however, day to day variations i n the response of a given animal to a specific dose of Pentathol Sodium. These variations resulted in the loss of a number of readings, for where an animal failed to start to recover from anaesthesia within one hour, any readings that had been taken on i t were discarded. Although this loss of occasional readings was a definite disadvantage, the method used offered the requisite amount of control over the depth of anaesthesia induced. c) Pressure Determinations: The animal was l e f t undisturbed for about five minutes after the anaesthetic had taken effect. It was then removed from the cage to the apparatus and l a i d , belly down, in front of the microscope. The inflatable cuff was wrapped about the thigh of the hind leg, care being taken not to bind i t tight-l y enough to impair circulation, or loosely enough to allow subsequent cuff inflation to be ineffective. The animal was then placed, again belly down, on the platform of the micro-scope and the foot placed in position. The web to be examined was spread, then stretched slightly, the toes on either side being held in place by strips of plasticene. This mounting 19. i s shown in Fig. 2 b . (The tube of the microscope was removed for this picture to permit a clearer view of the animal's position.) After the rat was i n position under the microscope, the instrument was focused and the web searched quickly for small vessels showing rapid blood movement (see above). When these were detected, the cuff was inflated by means of the syringe u n t i l a pressure of about 90 to 100 mm. Hg was reached. The pressure was then adjusted upwards by raising the head of mercury u n t i l blood flow i n the vessels ceased. The manometer was read at this point and the pressure in the cuff immedi-ately released. A minute or two was allowed to elapse before the cuff was inflated again and a second reading taken. If these two readings differed by more than 10 mm. Hg a third reading was taken. A maximum of four on a rat at one time was set. Where more than two readings were taken, the average of the two highest was accepted as the determination for that day. This procedure was in accordance with the procedure adopted by G r i f f i t h and Farris (18) and other workers (11) (35). 3* Methods in Experimental Hypertension, a) Normal Pressures: The establishment of the normal blood pressures of the animals was given careful consideration. It was realised that a number of factors, normally variable, might conceivably influence such blood pressure and, as a result, be a source of error in the subsequent hypertensive work. Such factors included age, sex (and the sex cycle in the female), time of 20. feeding, time of day, and anaesthesia. The last named, while not a factor affecting "normal" pressure as such, nevertheless had obviously to be considered as affecting normal pressures for the purposes of this investigation. Two possible methods were considered for investigating the effect of these factors. The better method would have been to make experimental runs against each individual factor. Such a procedure alone would have taken more time than was at the disposal of the author for the whole problem, and so had to be ruled out of the question. It was decided, therefore, to establish as far as possible, the effect of these variables in conjunction with the main experimental runs. Before an animal was subjected to any procedure that was l i k e l y to i n -duce abnormal pressure, at least four readings were taken on i t to establish i t s normal systolic blood pressure. Such readings were recorded along with a l l relevant data, (Fig. 1) and at the conclusion of the four experimental runs a l l the normal values of the 29 rats used were checked in an effort to establish a correlation between any of the variables under discussion and systolic blood pressure, b) The Injection of DCA: It was decided f i r s t of a l l to confirm the characteristic pattern of the pressor response to a single injection of DCA as reported by Fitch (11). For Run I. therefore, three males and three females were selected, and their normal blood pressures established in the manner indicated above. A l l rats were then injected 21 . intramuscularly with 1 mgm. DCA in sesame o i l (Ciba). The day on which this injection took place was termed Day ' 0 ' in re-lation to the period during which observations were taken. This terminology was retained throughout subsequent runs. With the exception of Days 2 and 5» two blood pressure readings per day were taken on each rat up to and including Day ' 9 ' . c) The Use of Histidine and Ascorbic Acid and the Injections  of Antistlne; Bun II: Eight rats were selected, four of each sex, and their normal systolic blood pressures determined. A l l then received injections of DCA (1 mgm.) and the resultant pressures determined daily as described for Run I. On Day 5, six of the eight animals were found to be hypertensive (systolic pres-sures 20 mm. Hg or more over normal) but readings were not obtained on the other two. The run was then divided into three groups as follows: Group 'a'. consisting of one male and one female, received no further treatment. Group 'b1. one male and one female, were fed 20 mgm. h i s t i -dine and 70 mgm. ascorbic acid daily. These amounts were of-fered each morning mixed with a l i t t l e Fox Chow (Purina MillsX When this mixture had been consumed the animals were given additional Fox Chow ad libitum, but any food remaining by late afternoon or evening was removed and the animals required to fast overnight to ensure consumption of the histidine mixture on the following morning. Such feeding was carried on from 22. Day 5 to Day 10 inclusive. Group 'c'. two rats of each sex, were fed as were those in Group 1b', and in addition received a total of four intramus-cular injections each of the anti-histamine, antistine (2-phenylbenzylaminomethylimidazoline) (Ciba), in aqueous solution. The f i r s t two injections were 0.05 mgm. doses ad-ministered following the pressure determinations on Days 5 and 7 respectively. The two f i n a l doses were smaller (0.0125 mgm. each), and were injected h to 6 hours before the pressure determinations of Days 10 and 11 respectively. Run III: This run involved ten rats, five of each sex, and was carried out over a period of five weeks. The normal pressures and DCA injections were carried out as for the previous runs, and on Day 5 the animals were again subdivided into three groups: Group 'a'. one male and two females, received no further treatment. Group 'b', two males and one female, were fed histidine and ascorbic acid i n the manner described for Run II and this feeding was continued over a period of 16 days (Day 5 to Day 20 inclusive). Group r c'. two animals of each sex, were fed as were Group ' b 1 and i n addition received a total of nine 0.0125 mgm. intramuscular injections of antistine each. The days on which these injections were administered, and their timing i n rela-tion to the daily determinations of blood pressure, are shown by Fig. 6. During Run III, determinations were taken daily 23. up to and including Day 8. Subsequent readings were taken as shown by Table h and Fig. 6. The run was discontinued on Day 26. Run IV; Three rats of each sex were used for this run, which was carried out as a control run on the effect of antistine. After normal pressures had been determined, each rat received a total of five 0.0125 mgm. intramuscular i n -jections of antistine each. These injections were timed to correlate with the f i r s t five antistine injections (also 0.0125 mgm.) given Group 'c' of Run III. For example, the f i r s t injections in both runs were given immediately following pressure determinations of the day, the second l o t were given 26 hours later, (2 hours after the pressure determinations of the following day). Thus these procedures allowed for a study of the effect of DCA i n raising normal systolic blood pressures, the effect of histidine and ascorbic acid in lowering this experimental hypertension, and f i n a l l y the effect of antistine on rats which had received histidine and ascorbic acid treatment. 2h. I l l Results A. Normal Systolic Blood Pressures The systolic blood pressures of the 29 rats under obser-vation ranged from 106 to 1^ 5 mm. Hg, with 2k of the 29 coming within the 120 to lhO mm. Hg range. Two animals showed systo-l i c blood pressures of less than 120 mm. Hg, while three were over l^tO mm. Hg. B. Results From the Use of DCA. Histidine and Ascorbic Acid,  and Antistine. Results are given i n detail by Tables 2 to 5 inclusive, and are shown graphically by Figs, h to 7 inclusive. These graphs show the deviation from normal systolic blood pressure i n mm. Hg. Each point represents the average of the two daily readings taken on an individual rat. Day '0 ' on a l l graphs and tables represents the day on which the f i r s t i n -jection was given. In Runs I, II, and III this f i r s t injec-tion was DCA, in Run IV i t was antistine. In reference to Figs. 6 and 7, the period of feeding (see methods) is denoted by the heavy black line at the base. Pressure determination times are denoted by vertical lines below, and injections of antistine are shown by arrows above the heavy line. TABLE 2. The Results of Run I. The variation in the systolic blood pressures, in mm. of Hg, of each of five rats. Two readings per day are: given covering a period of two weeks. Each rat received, on Day ' 0 ' , an intramuscular injection of 1 mgm. DCA. See also Fig. h. Rat Sex • -k -3 -2 -1 Time in Days 0 1 3 ^ 6 7 8 9 L . l M 126 • 131 * 128 126 128 130 M B 19 132 13^ - 116 120 1 * - 170 170 160 155 L.k M • - 127 125 125 130 H • 125 125 97 100 - 16k 158 150 160 2*+0 233 170 172 R.2 F 127 133 128 133 130 133 - b e_i. (1 O 126 128 12*f 122 18k 176 118 123 # R.3 F 126 13^ l*+0 13>+ 135 125 139 H -O 3 - 100 100 - - 156 165 170 165 1^ 0 lh2 R.5 p - - 128 130 13^ 13^ O 13^ 136 118 123 135 1M+ l M f 150 152 160 160 129 128 Note: ( - ) anaesthesia either ineffective or too long in duration. ( # ) died in anaesthesia. TABLE 3. The Results of Run II. The variations in systolic blood pressures of eight rats over a period of sixteen days. A l l rats were Injected on Day '0* with 1 mgm. DCA. Group 'a' received no further treatment, Group 'b' were fed 70 mgm. ascorbic acid and 20 mgm. histidine daily from Day '5 ' to Day '10 inclusive. Group 'c' receivej. the same treatment as did Group 'b1 and in addition received four intramuscular 0.0125 mgm-. injections of antistine. For the times and spacing of these injections see Fig. 5. Rat Sex • Gp.- Time in Days -5 -if -3 -2 0 1 2 3 1+ 5 7 8 9 10 11 L.7 M a - 237 1^ 3 125 125 130 ll+0 125 120 105 105 116 120 nr 186 18*+ - 190 190 - 158 162 li+8 11+8 R.7 F a 130 135 l*+0 130 135 li+5 11+8 0 - 115 115 Ikk 130 nr 175 175 170 170 # L .9 M b - 130 130 - llh 120 = ^ — 0 100 106 - - 12*+ 115 176 160 170 136 iko 120 120 110 116 ll+O ll+O R.9 F b - 110 110 130 115 120 115 •i ct-H* , n 100 112 10*+ 100 125 133 - - 11+0 ll+O 11+0 100 100 125 135 11+8 152 L.6 M e 120 130 105 106 118 120 M C + n> - - 118 118 - 155 1^+6 - 108 112 120 126 120 120 ll+O ll+O L..8 M c - 107 108 ii>* 110 100 100 0 ct 9 105 101 - - 110 130 130 126 115 110 120 120 130 130 ll+O 11+6 # R.6 F c - l*+0 150 130 126 - - 120 130 110 10*+ 120 120 - - # R.8 F c 130 130 120 12** - - - 97 100 121 115 - li+l 155 11+1+ 137 130 130 100 106 180 176 130 138 Note: ( - ) anaesthesia either ineffective or too long i n duration. ( # ) died i n anaesthesia, (nr.) no reading. ( @ ) the f i r s t two of the four injections were 0.05 mgm. TABLE *+. Results of Run III. The variations in systolic blood pressures of ten rats over a period of 5 weeks. A l l were injected on Day '0* with 1 mgm. DCA. Group 'a' received no further treatment, Group 'b1 were fed 70 mgm. ascorbic acid and 20 mgm. histidine from Day '5* to Day ^O 1 inclusive. Group 'c 1 received the same treatment as did Group 'b', and in addition received nine 0.0125 mgm. injections of antistine intramuscularly, the f i r s t being given on Day ' 5 ' . For the times and spacing of subsequent antistine injections see Fig. 6. • Rat X V CO -8 -7 -6 Time in Days -5 -k -1 0 1 2 3 5 6 7 8 9 ' 10 12 13 ll+ 16 20 21 26 L< I 118 -126 — 135 nr nr 136 l>+0 10k - 15*+ 16k 180 158 - 120 IkO li+0 IhO 10k 158 180 180 161 116 nr nr 128 128 - 13^ 96 128 102 3 R2 F 126 136" - 130 126 100 lk6 116 150 " 1 3 0 " 12l+ 1 0 8 150 120 " 158 " 128 l*+0 118 lk6 nr nr - IkO IkO 102 101+ F 120 " 12k - . 116 n _ ^112 10k 110 108 150 156 158 120 Q118 96 108 110 150 168 162 " 108 118 " nr nr 100 132 100 136 120 128 LI M - 138 135 l h 0 nr nr fl - - 1 2 1 1 6 0 - 136 150 n r  l k 6 g ^ U q ^ ^ r 110 n r 110 150 160 nr 118 123 nr $ •* b L2 M - - - ikO lk2 n_ "g 112 160 168 190 198 150 IkO n r 110 l$k 173 180 210 ~ 1 0 2 nr 102 n r 150 140 nr 100 110 nr Rl F 120 " 120 - 130 150 I315 120 120 Ihk- # IkO 156 135 " 120 120 " l*+3 L3 H - - I*f0 150 155 ik8 niko 116 IkO lk6 16k 120 IkO 138 n r Blk6 118 " Ikk- 15k 17k 125 n r 120 12k nr 166 176 nr nr 130 115 130 101+ M - IkO lk8 lk5 1*+0H130 116 160 166 220 170 155 l*+6 l»f0 120 168 17!+ 225 17*+ 128 lk8 131+ 150 nr nr nr 110 19+ 110 158 R3 F - - - . 130 ike . 130 156 116 ikk 168 . n r lk2 136 132 156 120 ll+8 162 Ikk ikk 150 li+2 nr 11+0 IkO nr nr 166 # 166 & F « mm l*+0 1»*6 . 130 n _ 130 126 165 li+8 _ iko 136 n r 130 130 1 58 1 50 l*+0 n r 110 Ikk 106 150 nr - nr nr 150 17k ifk 180 Note: ( - ) anaesthesia either ineffective or too long in duration. ( # ) died in anaesthesia, (nr.) no reading. TABLE 5. Results of Run IV. The systolic blood pressures of six rats taken twice daily over a two-week period. These rats received a total of five 0.0125 mgm. intramuscular injections of antistine, the f i r s t injection being on Day '0 ' (immediately after readings). Subsequent injections were timed to correspond with identical injections given Group 1 c 1 of Run III. See also Figs. 6 and 7. Rat Sex -9 -7 -6 -*+ Time -3 -2 in Days 0 1 2 3 5 7 L.7 M - - - 136 138 120 122 136 138 120 120 - 116 116 105 Ilk 128 13^ 125 129 L.8 M 132 123 120 123 - 120 112 - -128 138 111+ 108 108 118 100 102 90 92 100 100 L.9 M - 116 118 - 120 110 106 106 - 128 122 13*+ 128 108 118 - 100 100 R.6 F l*+0 132 138 ikO ±9+ 158 132 l*+0 120 122 nr - 110 108 - - 100 Ilk 100 98 R.7 F 1 130 132 136 l*+0 118 12k 126 118 116 120 nr - 8k 92 122 128 118 120 120 122 106 108 R.8 F - 130 138 12h 128 128 128 nr nr - 13k . 138 90 90 107 110 96 92 96 96 Note: ( - ) anaesthesia either ineffective or too long in duration, (nr.) no reading. PLATE I MP F i g . 2a: A p p a r a t u s A s s e m b l y ( a b o v e ) . F i g . 2b: P o s i t i o n o f R a t f o r P r e s s u r e R e a d i n g . P L A T E E F i t . 3.-o n o f Nonnal Blood Pressure mrith Time o Day, i 4-P.M. i n c . 8c. Cottlto*fer0*e £<cctotc. Eo*-*» Wet:ed °* Ny To*. -JoL Fig.4. Retultf of Run I i — = * — = 1 — A - •* i > f rcr I n j e c t i o n P L A T E LH • 2 O E • 6 8 10 Days P l « . 5. R e s u l t s of R u n I I An m i s i n j e c t e d i n I ram u > c u / « t / y w i t h \mim deto x y c o r f l co sferone aceta te on J a y ' o ' . l a ) : . . . . . . n o f u r f h e * t r e a t m e n t , i v ) . Ib)i , 7o in»m a icoibic acltl < to mam h i i t l d i n e d a i l y in f o o d d u n n . 8 p e i i o i l i f l g r k K i i ( l a * , 1 8 ) (ik_ . . . us in(b) p lu s i n l i u m u b c u l u r i n j e c t i o n s of .os m<m (1) or .ousm»m(!) 6c. 4C. CQ ^ OL cc-20 -40 A l l rofs i n j e c t e d i n r t a "» uscuic .• i t w i t h i msm desoxycort ('cs t e r o n e a c e t a f e o n d a / " o -. no f u r f h e r t r e a t m e n t (itr. z O (b) , io msm ascorbic acid i-zomgn h i s T i d i n e in f o o d d u r i n g penod marked-- U<r, l ?) ic)-/, as in 'b' p /«s intnrrmsulat i n j e c t i o n s of a n f i s t i n e at t i m e s s h o w n by arrow$i a t) 8 12 16 20 -8 - 4 0 Time in Days aftet Injection of J>esoxycotticosfe rone Fl s. 6. Results of RUN LU 24 28 P L A T E Y Fig. 7. Results of RunlVI (a) Showing Ite Effect of .cizi ;ngm I n t i Q f n u s c u l a f I n j e c t i o n s | o f / A n t i s f i r t e at t i m e s shown by W) Compared with (b) S i m i l a r I n j e c t i o n s of Anfistjne on Rats ia Group'c'of HuaM. (Fi&.6). Fi>it Antistine Injection on Day'o'in Both Ca ses ~ "-Fig. 8 . : The In, I t/c rice of Se x on the Expen'menfol Hyper-tension Induced by Injection of I m g m I)esoxy-c © M i c o s t e rone onJ)ay 'o'. M o / e s _ _a f e m a l e s * •I 1 »U S A mates io n \l d a y s PLATE 21 8ol Fis. 9. Tti Combined R« iut t i of Runt I.Hartdflli (ti) Injected with lagm \T)tioxycottico$ttronc (Pay Kg lb) A* in fa) plus daily feed of Histidine andAitobtc Acid during period mathtdm^mnm sect 16 Days -RalO-Ut) Effect of l e u Injecllenl ot DcsoAycofMcoiTe tone on Day V (7 f « f i ) (fa) Daily Fading of Hist-idine and Ascorbic Acid Stcrtintf with Injection as !4 Da*s. 29. IV Discussion of the Results A. The Validity of the Results In evaluating the validity of the results obtained, the author has taken into consideration several factors which might effect systolic pressure. As far as possible these fac-tors w i l l be discussed separately in order to decide which of them can be disregarded, and which, i f any, must be considered as significant sources of error. 1. Consistency of the Results. Theoretically, the two readings that were taken daily on the same rat at the same time should agree perfectly. This was seldom the case. These deviations must be considered as errors. In this regard, Run II (Table 3.) can be taken as typical and i s analysed below to il l u s t r a t e the extent of this error. Of 73 pairs of readings, two pairs showed a deviation of more than 10 mm. Hg, and six others showed deviations of exactly 10 mm. Hg. The average deviation was h mm. Hg, or 3% of the average systolic pressure (127 mm. Hg). Such a devi-ation i s small i n relation to the elevation in blood pressure of hS to 60 mm. Hg (38 - h7% increase) brought about by DCA. Further analysis shows that the average deviation for normal pressures was similar to the deviation observed when the rats had been treated. Thus these deviations have no sig-nificant bearing on the hypertensive results obtained. 30. 2. Validity of Determinations of Normal Pressures. The average normal systolic pressure of the 29 rats (1^ males and 15 females) was 127 mm. Hg, with individual normals ranging from 106 to l*+5 mm. Hg. In assessing the accuracy of these figures the author has turned for confirmation to the results of other workers. Prado et a l (30) have given a s t a t i s t i c a l l y derived figure for mean blood pressure of the albino rat, a figure re-ported by them to include 95$ of any group of rats of statis-t i c a l size. This figure was 108±lh mm. Hg. Converting to systolic pressure, a range of 115 to l*+5 mm. Hg i s obtained. Only one of 29 rats used in the experiments under discussion exhibited a normal systolic pressure outside of this range. Sulkin and Brizzee (35) report that anaesthesia lowers the blood pressure of experimental animals, and "normal" pres-sures taken under such conditions do not, in fact, represent true normal pressures. These workers report ah average sys-t o l i c pressure of 12^.8 mm. Hg for the unanaesthetised rat, and lower values for anaesthetised animals. They report dep-ressions ranging from 7 mm. Hg with light ether, to 6l.5 mm. Hg with morphine. They do not report on pentathol sodium, but other barbiturates, nembutal and amytal which are similar i n action to pentathol, gave depressions of 20.7 and 21.3 mnu Hg respectively. However, i t w i l l be noted that the normal pres-sures as established in the investigation reported here agree not with the pressures of their rats under the influence of 31. barbiturates, but rather with the figures they give for un-anaesthetised animals. Some figures for normal systolic blood pressure in the albino rat as reported by a number of workers are given below: Abramms (1) reports a mean of 125.7 mm. Hg for three anaesthetised rats, by the indirect method using the t a i l (and plethysmograph), and 129.2 for three unanaesthetised rats by a direct method with a manometer reading directly from the femoral artery. Page and Reed (28), with five rats, report a range of 105 to 125 mm. Hg. Fitch (11) after work with 26 rats reports an average value of 120 mm. Hg. Pratt et a l (31) after c l i n i c a l studies of the action of pentathol sodium, report that blood pressure usually f a l l s the moment after a dose of pentathol sodium has been injected, and that after a small dose the return of the blood pressure to i t s previous level occurs quickly. As a result of the consistency of the readings obtained in this investigation and as a result of checking the reports mentioned above, the author i s satisfied that the normal sys-t o l i c blood pressures as established were correct and that the anaesthesia, as administered in this experiment, played no significant part in subsequent pressure changes. 3. Effect of Variable Factors. a) Age: In general there was a very rough correlation between 32. age and systolic blood pressure, the older and heavier rats tending to have higher normal pressures than the younger, lighter rats. Inasmuch as rats were selected with a view to uniformity, the range of age and weight was small. Eight male rats used weighed less than 225 gms. and these showed an average systolic pressure of 128 mm. Hg; whereas the other six males investigated, a l l of which weighed more than 225 gms., had an average pressure of 135 mm. Hg. G r i f f i t h and Farris (19) state that there i s a slight but definite rise in blood pressure with age. Medhoff and Bongiovanni (25) concur. The latter give figures on this rise i n terms of the percentage of rats of a given age group, that are found to be i n certain arbitrary pressure groups. The rise indicated i s , however, so slow that i t is neglible for the periods over which the rats in this investigation were observed. b) Sex: There was no appreciable difference between the two sexes i n regard to systolic blood pressure. Further, the females failed to show any day to day, or rythmic pressure changes, indicating that the sex cycle was not a factor to be consider-ed. Medhoff and Bongiovanni (25) are in agreement on these points. c) Time of Day: The normal pressures obtained for a l l rats used are plotted against time of day of determinations in Fig. 3« The pressures tend to be a l i t t l e low in the morning, rise at 33. noon, drop again in the afternoon and rise a l i t t l e more defi-nitely in the evening. A l l these variations, however, are very small (Fig. 3)• It w i l l he noted that only h of hQ determi-nations show a deviation from normal of over 10 mm. Hg. The general diurnal variation as shown by Fig. 3 i s , therefore, negligible from the standpoint of induced hypertension. It i s possible that the slight rise about noon was correlated with feeding (which was carried out between 8.30 and 10.00 A.M.) and the rise in the evening with the natural nocturnal activ-i t y of these animals, d) S t a t i s t i c a l and Human Factors: Although the more obvious variables have been shown to have l i t t l e or no effect on the results of the experiment, two further factors must be considered. These are the s t a t i s t i c a l value of the results, and the human error involved i n the determination of blood pressures. The number of rats used in each run was admittedly small. This was necessary because of the limited time available. When this work was f i r s t started, two to three hours a day were required to carry through a run in which four animals were involved. Practise reduced this time, but nevertheless two or three hours were s t i l l required at the end to handle a run of ten rats. The author i s of the opinion that this small sampling is the weakest point of the investigation. The human factor i s rather d i f f i c u l t to evaluate, as there are openings for error in the procedure. Mention has 3*K already been made of the possibility of error from faulty capillary observation. Localized vascular spasms could be mistaken for true stoppage of blood flow, and fatigue on the part of the observer was always a potential source of error. However, i f the consistency of the results obtained, and their agreement with other workers can be used as a yardstick, then these sources of error can have l i t t l e significance In the f i n a l results of the investigation. B. The Hypertension Resulting From DCA Injection, and Its  Amelioration With Histidine and Ascorbic Acid 1. The Pressor Effect of DCA. The effect of a 1 mg. intramuscular injection of DCA on systolic blood pressure i s summarized in Fig. 9 for a l l rats so treated. The general shape of the graph agrees with that reported by Fitch (11), as shown by Fig. 10a. It w i l l be noted that in both cases the systolic blood pressure rises rapidly to reach a pronounced peak about the 7th or 8th day after an injection of DCA, (although the author found that there was an i n i t i a l lowering of pressure immediately f o l l o -wing the injection, whereas Fitch (11) reports an immediate ri s e ) . In degree of hypertension achieved, however, the re-ports disagree. Fitch reports systolic blood pressures averaging IhO mm. Hg over normal on the eight day after i n -jection while the author has found i t to average 50 mm. Hg. It i s d i f f i c u l t to find confirmation in the literature for these values. Prado et a l (30) achieved hypertensive 35 levels of a degree similar to that reported by Fitch (11), (150 to 160 mm. Hg above normal), but as a result of massive dosing (*4-0.0 mg. pellets subcutaneously implanted). Other workers, a l l using similar large doses, show rough agreement (23). With the exception of the present work, and that done by Fitch there are no reports known on the effect of small doses of DCA. a) The Influence of Sex on the Effect of DCA: There was found to be a marked difference between the sexes in their response to DCA. This i s shown graphically by Fig. 8. The number of animals represented by this graph varies with time, due to the nature of the experiments. Inas-much as a l l rats in a l l runs except Run IV received the same DCA injections with no further treatment u n t i l Day 5j the graph up to this point represents 9 males and 12 females. At this point several animals of Runs II and III were started on other treatments (see methods), so as a result the number of animals represented drops to *t males and 6 females. Day 12 represents only 3 rats of each sex. Up to and including Day 8 the number of rats available for readings i s sufficient to give a good indication of the influence of sex on this pressor response. It w i l l be noted that the i n i t i a l drop in the systolic blood pressure of the males i s a l i t t l e more pronounced on the average than that of the females, and that the eventual maximum rise, reached about Day 8, i s twice as great on the average in the males as in the females. 36. T h i s f i n d i n g could be e x p l a i n e d ,by t h e f a c t t h a t i n the female t h e r e are found s i g n i f i c a n t amounts o f progesterone, p r e g n a n d i o l , and a l l o p r e g n a n d i o l . These are found o n l y i n v e r y s m a l l amounts i n the male (as measured by u r i n a r y ex-c r e t i o n ) . These hormones, e s p e c i a l l y progesterone, a r e c l o s e -l y r e l a t e d c h e m i c a l l y t o DCA, and the p r o g e s t e r o n e - l i k e a c t i -v i t y of DCA, has been demonstrated (Best and T a y l o r , ( 4 ) ) . Thus i t would seem l o g i c a l t o expect an animal t h a t i s natu-r a l l y " b u f f e r e d " a g a i n s t such substances t o r e a c t l e s s v i o -l e n t l y than one t h a t i s not so " b u f f e r e d " , or a t l e a s t not n e a r l y as w e l l " b u f f e r e d " . 2. A m e l i o r a t i o n With H i s t i d i n e And A s c o r b i c A c i d . A composite p i c t u r e of the a m e l i o r a t i o n o f the DCA-induced h y p e r t e n s i o n t h a t was a c h i e v e d by h i s t i d i n e and a s c o r b i c a c i d f e e d i n g i s g i v e n i n the graphs shown i n F i g . 9« F i g . 10 shows the r e s u l t s o b t a i n e d by F i t c h (11) when t h e f e e d i n g was s t a r t e d on the same day t h a t the DCA was adminis-t e r e d , t h a t i s before any h y p e r t e n s i o n had developed. With such a procedure h y p e r t e n s i o n f a i l e d t o develop. From these r e s u l t s t h e r e seems l i t t l e doubt t h a t t h i s form o f experimental h y p e r t e n s i o n can be a m e l i o r a t e d by the treatment o u t l i n e d . I t has a l r e a d y been suggested by F i t c h t h a t t h i s a m e l i o r a t i o n i s a r e s u l t o f the e l a b o r a t i o n of ex-cess histamine by i n t e s t i n a l b a c t e r i a from the h i s t i d i n e ad-m i n i s t e r e d . T h i s theory w i l l be r e f e r r e d to l a t e r . 37. 3. The Effect of Antistine. If the theory mentioned above is tenable, i t seems l o g i -cal to expect that the administration of an anti-histamine would destroy such histamine, and as a result rats so treated would become hypertensive in spite of the histidine feeding. With this in mind, the results of Runs II and III were examined. (In order to avoid repetition, the three groups of rats treated in these runs w i l l be referred to in this dis-cussion as groups 'a 1, 'b', and 'c'. The reader is referred to the outline of the methods used (page 21) or to the legends to Figs. 5 and 6 for details.) The response of the animals to intramuscular injections of antistine was rather variable. Thus, in Run II, (Fig. 5) . i t w i l l be noted that the pressures of the rats in group 1 c' tended to follow those of group '„b' after the f i r s t two, relatively large, injections of the anti-histamine. At that point i t would seem that the antistine was having no effect. However, inasmuch as the antistine was in aqueous solution, and would therefore, be readily absorbed, i t was f e l t that a different result could be obtained i f the injections were given a few hours before the blood pressures were read, when i t s effect would not have had time to wear off. Actually hQ hours elapsed before a determination was taken after the f i r s t injection of antistine, and 2k hours elapsed after the second. This delay was necessary because the size of dose used proved too large and resulted in considerable distress to the animals concerned. They exhibited a partial temporary 38. paralysis of the leg injected, abnormal excitability and anorexia. Pressure determinations were therefore delayed un-t i l these symptoms had subsided. The third injection of antistine was given when the animals had f u l l y recovered, and i t and the fourth injection were reduced from 0.05 mgm. to 0.0125 mgm. Readings were taken in these cases a few hours after the injections and the result was that the pressures of the antistine rats went up instead of down, and thereafter showed a correlation with the pressures of the rats in group 'a'. In Run III the mistake in regard to dosage (of antistine) was avoided and as a result this run (Fig. 6) shows a better indication of the effect of the antistine. Dosage was again 0.0125 mgm., and these doses were given more frequently. It was noted i n general that the rats of group 'c' tended to give a pressure graph similar in shape to that given by the rats of group 'a'. The effect was s t i l l slight-l y variable, but i t was again noted that whenever pressure readings were taken within 2k hours after an antistine i n -jection, the systolic blood pressures of the rats thus treat-ed tended to approach the hypertensive line represented by the blood pressures of the rats of group ' a 1 . Thus, although the rats of group ' c 1 received the treatment that otherwise brought about amelioration of the experimental hypertension, their pressures nevertheless continued to rise after the start of this treatment, apparently due to administration of antistine, reaching a maximum equal in degree ,. 3 9 . w i t h the pressures of t h e r a t s o f group ' a ' a t the same t i m e . The p r e s s u r e s , on the other hand, o f the r a t s o f group ' b ' , ceased to r i s e s h o r t l y a f t e r a m e l i o r a t i o n treatment was s t a r t -ed and f a i l e d t o show the c h a r a c t e r i s t i c 7 o r 8 day peak of t h e o ther two groups . A f t e r Day 8 the pressures o f group ' c ' f e l l r a p i d l y and tended to f o l l o w those o f group ' b ' as c l o s e l y as they d i d those o f group ' a 1 . I t was c o n s i d e r e d a g a i n t h a t the i n j e c t i o n t i m i n g was o f importance h e r e , f o r , when subsequent-l y the a n t i s t i n e i n j e c t i o n s were g i v e n *f t o 8 hours p r i o r t o p r e s s u r e d e t e r m i n a t i o n s (on Days 12 and l * f ) , the s y s t o l i c b l o o d pressure d e t e r m i n a t i o n s o f the animals so i n j e c t e d r o s e a g a i n . To summarize, t h e a n t i s t i n e d e f i n i t e l y exer ted a p r e s s o r e f f e c t , but t h i s e f f e c t was s h o r t l i v e d and was not apparent i f p r e s s u r e d e t e r m i n a t i o n s were not taken w i t h i n 2*+ hours o f an i n j e c t i o n . The q u e s t i o n now a r o s e , "was t h i s p r e s s o r e f f e c t a r e s u l t o f a b y p l a y w i t h another substance such as h i s t a m i n e , or was t h e r e a pressor a c t i o n i n h e r e n t i n the a n t i s t i n e i t s e l f ? " The answer t o t h i s q u e s t i o n i s found i n the r e s u l t s o f Run I V . A l l an imals i n t h i s r u n r e c e i v e d a n t i s t i n e i n j e c t i o n s to correspond to the i n j e c t i o n s g i v e n group ' c ' o f Run I I I (see methods and F i g . 7). I t was noted ( F i g . 7a) t h a t a n t i s t i n e i n j e c t i o n s a l o n e d i d not r e s u l t i n a r i s e i n b l o o d p r e s s u r e , b u t . r a t h e r the pressures o f t h e r a t s so t r e a t e d dropped s t e a d i l y . T h i s r e s u l t was compared w i t h the r e s u l t s of s i m i -l a r i n j e c t i o n s to r a t s o f group ' c 1 , Run I I I ( F i g . 7), where a d e f i n i t e r i s e i n b lood p r e s s u r e took p l a c e a f t e r s e v e r a l of the injections of antistine. The conclusions drawn from these results are discussed below. C. Suggestions For Further Research As a result of this investigation, suitable subjects for further work along the same lines present themselves. 1. Further Investigation of the Histamine Theory The results discussed above give definite indications that the amelioration of the DCA-induced hypertension was due to the action of histamine, but further work on this i s re-quired. Several lines of approach suggest themselves, including: a) Oral Administration of Antistine: It i s possible that a clearer picture of any histamine-antistine balance could be obtained i f the antistine were administered orally instead of by intramuscular injection. A preparation suitable for such administration i s now avail-able (Ciba). The Injection method was chosen by the author because i t promised more accurate control of dosage. However, in the light of experience, i t would seem that this is more than balanced by the fact that, with injections, the rate of absorption i s erratic. Absorption from the digestive tract, on the other hand, would be relatively constant and the re-sults of such absorption should show definitely the effect of this drug. Oral administration, too, would have the hi. advantage of avoiding the p h y s i c a l l y i r r i t a t i n g effects of intramuscular injections of a n t i s t i n e . b) Histamine Occurance: Proof that body histamine r i s e s a f t e r the o r a l administ-r a t i o n of h i s t i d i n e and ascorbic acid would be important evidence i n the confirming of the r o l e of histamine. For example, the contents of the colon could be analysed for histamine, and an analysis of blood f o r histamine would be i n t e r e s t i n g . Best and Taylor (h) quote Anrep as reporting on the histamine content of the blood, and the method used by t h i s investigator may be applicable to the work under d i s -cussion. 2. The Action of Histamine. a) Vasodilatory Action: I f i t i s conclusively shown that histamine i s responsible for the amelioration of the experimental hypertension as des-cribed above, i t would be in t e r e s t i n g to investigate, i n more d e t a i l , the mechanism through which i t acts. In reporting the formulation of the theory, F i t c h (11) suggested that the amelioration might be due to the vaso-d i l a t o r y action of histamine. In addition to t h i s property, histamine possesses other ph y s i o l o g i c a l (or chemical) proper-t i e s that would make i t a blood pressure reducer under the conditions of these experiments. b) DCA Antagonism: E l l i n g e r ' s work(7) (8) on mice, previously noted, shows that DCA seems to act as an anti-histamine. This e f f e c t , 1+2. therefore, must be considered as a possible mechanism i n the amelioration of any DCA-induced hypertension, c) Effect on Cardiac Output: Best and Taylor (3a) state that histamine increases the cardiac output in man, but recent work, including that of Deyrap and Root (6) seems to establish an opposite effect, at least on some animals. These investigators injected, subcu-taneously, 10 mgm. histamine per Kgm. body weight into un-anaesthetized dogs. The result of such injections was a de-f i n i t e increase in peripheral resistance, with a very marked decrease in cardiac output, and blood pressure. The possibilty thus exists that histamine caused the amelioration of hypertension by decreasing the cardiac output. 3» Effect of Progesterone. In view of the different responses to a DCA injection shown by the two sexes, i t would be instructive to note the effect of progesterone administration on the systolic blood pressure. Because of the chemical and physiological simi-l a r i t i e s between DCA and progesterone, i t might be expected that the latter would cause a similar hypertensive response. The theory that the difference in response to DCA bet-ween the sexes, in the white rat, i s due to the relatively large amounts of progesterone and progesterone-like hormones in the female could be confirmed by administering DCA to ovaryectomized females, and checking the resultant systolic blood pressures against those obtained when DCA i s adminis-tered to complete females and to males. V Conclusions The conclusions drawn from the results of this investi-gation in the light of the problem set out in the introduction are as follows: An indirect method of determining the systolic blood pressure of the rat, which entails the use of the foot, has been found to be satisfactory. Incidental to the conclusions to the assigned problem of this thesis, several minor conclusions of some value have been drawn: 1. Pentathol sodium, when carefully administered, i s a satisfactory anaesthetic for hypertensive work with rats. 2. The normal systolic blood pressure of albino rats be-tween the ages of 10 months and 18 months ranges from 115 to l*+5 mm. Hg, with an average of 127 mm. Hg. There are no significant differences in systolic blood pressure between the sexes. 3. The pressor effect of DCA i s more pronounced i n males than in females. Fitch's report that oral feeding of excess histidine and ascorbic acid ameliorates the experimental hypertension brought on by an injection of DCA, has been confirmed. More-over i t has been shown that this amelioration is generally counteracted by the use of an anti-histamine (antistine), which when used on non-DCA treated rats acted as a depressor. Hence this anti-amelioration (a pressor action) : may p r e s u m a b l y b e d u e t o a n i n t e r a c t i o n o f a n t i s t i n e w i t h DCA a n d / o r h i s t i d i n e ( o r t h e i r m e t a b o l i c p r o d u c t s ) . A n t i s t i n e i s a k n o w n a n t i - h i s t a m i n e , a n d h i s t a m i n e h a s a l r e a d y b e e n m e n -t i o n e d a s a l o g i c a l m e t a b o l i c p r o d u c t o f h i s t i d i n e . I n v i e w o f t h i s i t i s l o g i c a l t o c o n c l u d e t h a t t h e a m e l i o r a t i o n e f f e c t o f h i s t i d i n e a n d a s c o r b i c a c i d i s d u e t o t h e p r o d u c t i o n o f h i s t a m i n e i n t h e r a t . V I S u m m a r y T h i s i n v e s t i g a t i o n w a s a n a t t e m p t t o c o n f i r m t h e r e p o r t t h a t o r a l f e e d i n g o f h i s t i d i n e a n d a s c o r b i c a c i d w a s e f f e c t i v e i n t h e a m e l i o r a t i o n o f h y p e r t e n s i o n i n d u c e d b y s m a l l 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 ( D C A ) . I f s u c h a m e l i o -r a t i o n w a s c o n f i r m e d , i t s m e c h a n i s m w a s t o b e i n v e s t i g a t e d . A n i n d i r e c t m e t h o d u s i n g t h e f o o t h a s b e e n d e s c r i b e d f o r m e a s u r i n g s y s t o l i c b l o o d p r e s s u r e i n r a t s l i g h t l y a n a e s t h e -t i z e d w i t h p e n t a t h o l s o d i u m . N o r m a l s y s t o l i c b l o o d p r e s s u r e s w e r e e s t a b l i s h e d f o r a l l r a t s u s e d . S i n g l e s m a l l d o s e s o f DCA w e r e 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 i n t o t h e r a t s t o i n d u c e h y p e r t e n s i o n . S u c h i n j e c t i o n s r e -s u l t e d , o n t h e a v e r a g e , i n a n i n i t i a l d r o p i n s y s t o l i c b l o o d p r e s s u r e , f o l l o w e d b y a s t e a d y r i s e i n p r e s s u r e u n t i l a m a x i -mum o f *+0 t o 60 mm. H g o v e r n o r m a l was r e a c h e d 7 o r 8 d a y s a f t e r t h e i n j e c t i o n o f D C A . W h e n o t h e r r a t s s o i n j e c t e d h a d b e c o m e h y p e r t e n s i v e , b u t >+5. had not reached the peak of hypertension, they were fed 20 mgm. h i s t i d i n e and 70 mgm. ascorbic acid with food. This treatment resulted i n the r i s e i n blood pressure being arres-ted, and on the eighth day after DCA i n j e c t i o n these rats showed blood pressures that were almost normal. When rats injected with DCA, and subsequently fed h i s t i d -ine and ascorbic acid as above,.were treated with intramuscular i n j e c t i o n s of 0.0125 mgm. of the anti-histamine substance " a n t i s t i n e " (the hydrochloride of the methane-sulphonate of 2-phenylbenzylaminomethyl-imidazoline), the r e s u l t , i n general, was to n u l l i f y the ef f e c t of the h i s t i d i n e feeding described above. There were some exceptions to t h i s general e f f e c t . Similar intramuscular in j e c t i o n s of an t i s t i n e alone instead of generally r a i s i n g the blood pressure, effected a steady lowering of the s y s t o l i c blood pressures of s i x rats so injected. if 6 . L i t e r a t u r e C i t e d 1. A b r a m m s , M . a n d S . S . S o b i n 19^7• L a t e x R u b b e r C a p s u l e f o r P r o d u c i n g H y p e r t e n s i o n i n R a t s b y P e r i n e p h r i t i s . P r o c . S o c . E x p t l . B i o l . M e d . 6 4 : ^ 1 2 2 . B e s t , C H . a n d N . B . T a y l o r 191+5. T h e P h y s i o l o g i c a l B a s i s o f M e d i c a l P r a c t i s e . W i l l i a m s a n d W i l k i n s , B a l t i m o r e , p .1 2 9 3 . i b i d . p . 1 3 5 3 a . i b i d . p . 2 2 7 h. i b i d . p.2*f9 a n d p . 6 9 6 5. C a w a d i a s , A . P . 19^6. A d r e n o c o r t i c a l C a n c e r w i t h U n d u l a t i n g F e v e r i n A d d i s o n ' s D i s e a s e -J o u r . C l i n . E n d o c r i n o l . 6 : 5 0 7 6 . D e y r a p , I . J . a n d W . S . R o o t 194-7. T h e E f f e c t o f S u b c u t a n e o u s H i s t a m i n e I n j e c t i o n s On t h e C a r d i a c O u t p u t o f t h e U n a n a e s t h e t i z e d D o g . A m . P h y s i o L l ^ : ^ 7. E l l i n g e r , F . 19^6. P r o t e c t i v e A c t i o n o f DCA a g a i n s t X - r a y I n d u c e d L i v e r D a m a g e . S c i e n c e 10*f:502 8. i b i d . 19^7. Some E f f e c t s o f DCA o n M i c e I r r a d i a t e d W i t h X - r a y s . P r o c . S o c . E x p t l . B i o l . M e d . 6 4 : 3 1 9 . F a r r i s , E . J . , E . H . Y e a k e l a n d H . S . M e d h o f f 191+5« D e v e l o p m e n t o f H y p e r t e n s i o n i n E m o t i o n a l G r a y N o r w a y R a t s A f t e r A i r B l a s t i n g . A m . P h y s i o l . l ¥ f : 3 3 1 1 0 . F e i s e r , L . F . a n d M . F e i s e r 19M+. O r g a n i c C h e m i s t r y . D . C . H e a t h , p . 5 0 4 11. F i t c h , H . F . 19H-7. T h e A m e l i o r a t i o n o f E x p e r i m e n t a l H y p e r t e n s i o n B y H i s t i d i n e a n d A s c o r b i c A c i d . M a s t e r s ' T h e s i s , U n i v e r s i t y o f B r i t i s h C o l u m b i a 47. 12. F r e e d m a n , G . M . a n d C . L . F r e e d m a n 1947. N o n - R e n a l H y p e r t e n s i o n . C a n . M e d . A s s o c . J . 5 6 : 6 5 5 13. F r i e s , E . D . a n d R . W . W i l k i n s 1947 • E f f e c t o f P e n t a q u i n e i n P a t i e n t s W i t h H y p e r t e n s i o n . P r o c . S o c . E x p t l . B i o l . M e d . 64: 455 Ik. G o l d b l a t t , H . 1947. T h e R e n a l O r i g i n o f H y p e r t e n s i o n . P h y s i o l . R e v . 2 7 : 1 2 0 15. G o l d b l a t t , H . , J . L y n c h , R . F . H a n z a l a n d W . W . S o m e r v i l l e 193k. S t u d i e s i n E x p e r i m e n t a l H y p e r t e n s i o n ; t h e P r o d u c t i o n o f P e r s i s t e n t E l e v a t i o n o f S y s t o l i c B l o o d P r e s s u r e b y M e a n s o f R e n a l I s c h e m i a . J . E x p t l . M e d . 5 9 : 3 4 7 16. G o l d b l a t t , H . , E . O g d e n a n d G . E . W a k e r l i n 1947. C o n f e r e n c e o n H y p e r t e n s i o n . N e w Y o r k , N . Y . 17. G r i f f i t h , J . Q . a n d E . J . F a r r i s 1942. T h e R a t i n L a b o r a t o r y I n v e s t i g a t i o n L i p p i n c o t t , P h i l a d e l p h i a . p . 2 . 1 k 18. i b i d . p.279 19. i h i d . p.286 20. G r o i l m a n , A . 194-6. S o d i u m R e s t r i c t i o n a s a D i e t a r y M e a s u r e i n H y p e r t e n s i o n . J o u r . A m e r . D i e t e t i c . A s s o c . 2 2 : 8 6 4 21. H o l t , J . P . , W . J . R a s h k i n d , R . B e r n s t e i n a n d J . C . G r e i s o n 1946. T h e R e g u l a t i o n o f A r t e r i a l B l o o d P r e s s u r e . A m . J . P h y s i o l . 1 4 6 : 4 1 0 22. K i n g , A . L . 1947. E l a s t i c i t y o f t h e A o r t i c W a l l . Sciencel05:127 23. K n o w l t o n , A . I . , E . N . L e o b , H . C . S t o e r k a n d B . C . S e e g a l 1947. D C A . T h e P o t e n t i a t i o n o f I t s A c t i v i t y b y N a C l . J . E x p t l . M e d . 8 5 : 1 8 7 24. K o g a n - Y a s n y y V . M . 1946. A m . R e v . S o v i e t Med.3:66 c i t e d b y W i g g e r s i n A n n . R e v . P h y s i o l . 1 0 : 2 4 2 48. 2 5 . Medhoff, H.S. and A.N. Bongiovanni 1945. Age, Sex, and Species Variations on Blood Pressure in Normal Rats. Am.J.Phys iol.143:300 2 6 . Ogden, E. 1946. The Production of Neurohypertension by the Kidney. Texas Repts.Biol.and Med .4:l4 (Abstract) 27. Page, H.I. 1939• Production of Persistent Hypertension by Cellophane Nephritis. J.Am.Med.Assoc.133:604 2 8 . Page, E.W. and R. Reed 1945. Hypertensive Effect of L-Dopa and Related Compounds in the Rat. Am.J.Physiol.143:122 2 9 . Page, I.H. and R.D. Taylor 1947. The Mechanism of Renin Tachphylaxis, Restoration of Responsiveness by Tetraethyl-ammdnium Ion. Science 105:622 3 0 . Prado, J.L., P.Dontigny and H. Selye 1947. The Influence of Diet upon the Hypertension and Nephrosclerosis Produced by Desoxycorticosterone Acetate Overdosage. Soc.Exptl.Biol.Med.Proc.66:446 31 . Pratt, T.M., A.L. Tatum, H.R. Hathaway and R.M. Waters 1936. Sodium ethyl (l-methylbutyl) thiobarbiturate. Preliminary Experimental and C l i n i c a l Study. Am.J.Surg.31:464 3 2 . Schafer, P.W. 1944. Surg.,Gynecol.Obstet.79:163 cited by Wiggers in Ann.Rev.Physiol.9:289 3 3 . Selye, H. 1947. Textbook of Endocrinology. Acta Endocrinologica, Montreal, p.837 34. Soto, E.V. and R.N. Gertierrez 1943. Effectos del Dietilestilbeostrol sobre l a respuesta vascular renal de l a ratona a l a vasopressin. Biol.Lab.Est.Med.yBiol.2:l4l 49. 35. S u l k i n , N . M . a n d K . R . B r i z z e e 1947. E f f e c t s o f V a r i o u s A n a e s t h e t i c A g e n t s o n t h e B l o o d P r e s s u r e o f t h e W h i t e R a t . P r o c . S o c . E x p t l . B i o l . M e d . 6 4 : 1 2 5 36. T h o m a s , C B . 1947. B u l l . J o h n s H o p k i n s H o s p . , c i t e d b y W i g g e r s i n A n n . R e v . P h y s i o l . 9 : 2 8 9 37. V i c t o r , J . 194?. H y p e r t e n s i o n P r o d u c e d i n D o g s b y U n i l a t e r a l L i g a t i o n o f P e r i a d r e n a l B l o o d V e s s e l s a n d T i s s u e s . P r o c . S o c . E x p t l . B i o l . M e d . 6 0 : 3 3 2 38. W i g g e r s , C . J . 1947. P e r i p h e r a l C i r c u l a t i o n . A n n . R e v . P h y s i o l . 9 : 2 8 9 39. W i r t s c h a f t e r , Z . T . a n d R . W i d m a n 1947. T h e E l a b o r a t i o n o f H i s t a m i n e i n V i v o . J .Am.Med.Assoc .133:604 40. Y u i l e , C . L . 1944. Am.J .Med.Sc i .2 0 7 : 3 9 4 , c i t e d b y W i g g e r s i n A n n . R e v . P h y s i o l . 9 : 2 8 7 50. A b s t r a c t A l b i n o r a t s h a v e b e e n made h y p e r t e n s i v e b y s i n g l e 1 mgm. 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 ( D C A ) . P r e s s u r e s w e r e d e t e r m i n e d b y t h e i n d i r e c t m e t h o d u s i n g t h e f o o t . E i g h t d a y s a f t e r t h e i n j e c t i o n s m a l e r a t s s h o w e d a n a v e r a g e s y s t o l i c p r e s s u r e 60 mm. H g a b o v e n o r m a l , a n d f e -m a l e s hO mm. H g a b o v e n o r m a l . A f t e r t h e e i g h t h d a y t h e p r e s -s u r e s d r o p p e d r a p i d l y t o n o r m a l . D a i l y f e e d i n g o f 20 mgm. h i s t i d i n e a n d 70 mgm. a s c o r b i c a c i d , s t a r t e d w h e n r a t s w e r e a l r e a d y h y p e r t e n s i v e ( o n t h e f i f t h d a y a f t e r i n j e c t i o n o f D C A ) , a r r e s t e d t h e r i s e i n b l o o d p r e s s u r e a n d o n t h e e i g h t h d a y a f t e r i n j e c t i o n } r a t s s o f e d s h o w e d a l m o s t n o r m a l p r e s s u r e s . I t w a s b e l i e v e d t h a t t h e a m e l i o r a t i o n o f t h e e x p e r i m e n t a l h y p e r t e n s i o n was d u e t o t h e e l a b o r a t i o n o f h i s t a m i n e f r o m h i s t i d i n e . T o c o n f i r m t h i s r a t s i n j e c t e d w i t h DCA a n d f e d a s a b o v e w e r e i n j e c t e d i n t r a m u s c u l a r l y w i t h p e r i o d i c s m a l l d o s e s o f t h e a n t i - h i s t a m i n e c o m p o u n d " a n t i s t i n e " ( t h e h y d r o c h l o r i d e o f t h e m e t h a n e - s u l p h o n a t e o f 2 - p h e n y l b e n z y l a m i n o m e t h y l -i m i d a z o l i n e ) . ' I n g e n e r a l r a t s s o i n j e c t e d s h o w e d s u b s e q u e n t s y s t o l i c b l o o d p r e s s u r e s r e s e m b l i n g t h o s e o f r a t s t h a t h a d r e c e i v e d DCA b u t h a d r e c e i v e d n o a m e l i o r a t i n g t r e a t m e n t . T h e r e w e r e e x c e p t i o n s t o t h i s e f f e c t . T h e c o n c l u s i o n i s d r a w n t h a t t h e a m e l i o r a t i o n o f t h e D C A - i n d u c e d h y p e r t e n s i o n b y h i s t i d i n e a n d a s c o r b i c a c i d f e e d i n g i s , i n a l l p r o b a b i l i t y , d u e t o t h e e l a b o r a t i o n o f h i s t a m i n e f r o m h i s t i d i n e . 

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