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Electrocardiograms of normal rats and those rendered hypertensive by potassium deficiency have been compared. The unipolar chest leads were found to be useful in the recognition of spurious patterns among normal animals as well as in evaluating the severity of the hypertension. Backward orientation of the spatial QRS vector in the horizontal phane was the single most consistent finding in the hypertensive animals.

Surgical thyroparathyroidectomy (thyroidectomy) prevented the rise in systolic blood pressure to hypertensive levels in rats whose kidneys were bilaterally encapsulated with latex envelopes. This treatment also reduced the systolic blood pressure of ‘normal,’ nonencapsulated rats. The antithyroid drug, propylthiouracil (PTU), acted in the same fashion as surgical thyroidectomy on blood pressure of both kidney encapsulated and nonencapsulated rats. However, PTU appeared to be a more effective treatment than thyroidectomy since blood pressures of both PTU-treated, kidney encapsulated and PTU-treated, nonencapsulated rats were reduced to a greater extent than were the blood pressures of their surgically thyroidectomized counterparts. It was not possible to lower further the blood pressure of surgically thyroidectomized, kidney-encapsulated rats by treatment with PTU, even though the treatment was continued for 20 weeks. Other results of the two treatments were also similar and differed only in degree, viz. decreased growth rate, decreased food intake and anemia. Surgical thyroidectomy decreased water intake of nonencapsulated rats while PTU treatment increased it above that of controls. In the encapsulated groups, however, both treatments decreased water intake below that of control encapsulated rats. Thyroidectomy performed after the kidneys had been encapsulated for 9–19 weeks had only slight effect on blood pressure.

The delay in onset of diastolic hypertension following treatment with DCA can be largely abolished by the concurrent administration of small doses of pitressin. Conversely, the delay is exaggerated by previous neurohypophyscal denervation. These observations support the view that the rate of development of DCA hypertension is inversely related to the efficiency of compensatory neurohypophyseal inhibition.

Since hog renin is effective in the treatment and prophylaxis of chronic experimental renal hypertension in the dog, probably through antirenin, a study was made of the prophylactic effect of crude and semipurified hog renins from cortex and from whole kidney on the hypertension, arteriolonecrosis, and course of experimental renal malignant hypertension in the dog. In the absence of medullary protein, protection against the hypertension was found to be well correlated with the antirenin titer. More importantly, the nonrenin fraction of crude hog renin from cortex significantly protected against the arteriolonecrotic lesions and death.

The suggestion that the pathogenesis of adrenal-regeneration hypertension might involve sensitization to the hypertensive properties of corticosterone by the period of cortical insufficiency which follows adrenal enucleation has been investigated. Nonhypertensive doses of corticosterone were given to uninephrectomized, salt-treated and adrenalectomized rats after periods of insufficiency of variable length and to similar rats bearing regenerating adrenals, beginning such treatment at intervals after enucleation. The following conclusions have been drawn from the data obtained: (1) Adrenal cortical insufficiency for as long as 2 weeks did not sensitize to the hypertension-inducing property of corticosterone; (2) Corticosterone administration to rats bearing regenerating adrenals, beginning treatment up to 3 weeks after operation, did not enhance the development of hypertension or increase the severity of vascular lesions.

No increased renin concentration was detected in the systemic blood of rats with desoxycorti-costerone and metacorticoid hypertension, using the guinea-pig; ileum method of renin estimation. Re-establishment of the circulation through totally ischemic rat kidney is followed by the liberation of large amounts of renin.

Three antihistamine agents, Phenergan, Benzodionole, and Trimeton have been studied for their ability to antagonize the hypertensive and cardiovascular-renal effects of desoxycorticosterone acetate in the unilaterally-nephrectomized, salt-treated, castrate male rat. In the order named all compounds produced only slight inhibition of the hypertensive and cardiotrophic action of desoxycorticosterone acetate and afforded virtually no protection against either the nephrotrophic or angiotoxic effects of this steroid as seen in the kidney, heart, and pancreatic, arterioles.

ADMINISTRATION of renin to rats pretreated with salt and desoxy-corticosterone (DCA), cortisone or 17-hydroxycorticosterone (cortisol) (1, 2, 3) elicits an eclampsia-like state associated with widespread acute destructive vascular lesions. This condition is attributable, in part, to the enhanced pressor effect of renin associated with the presence of excess adrenosteroids (4). Recently, a somewhat similar syndrome has been described in rats given thyroxin together with salt and DCA plus cortisone (5). In this situation the pressor and nephrosclerotic actions of thyroxine (6) may be additive to those of the steroids or it may act by specific sensitization of pressor mechanisms. The present experiments constitute a comparative study of the effects of thyroxine and renin in animals treated with adrenosteroids and also in animals with regenerating adrenals; the latter condition is stimulated by thyroxine (7) and is believed to be associated with hyperfunction or imbalance in steroid secretions (8).

8-Benzyltheophylline is analogous from a structural standpoint to the synthetic adrenergic-blocking agent, Priscoline, and was prepared along with various related compounds with the hope that the resulting hybridization of structural characteristics would result in an agent useful clinically in treatment of hypertension. The following compounds are reported: 8-benzyltheophylline; 8-(2-methylene-2-imidazoline)-theophylline; 7-benzyltheophylline; and 7-(2-methylene-2-imidazoline)-theophylline. 8-Benzyltheophylline in preliminary pharmacologic tests showed promise of being a potent hypotensive agent, and current studies have as their objective an elaboration of the structure of 8-benzyltheophylline in order to provide a basis for correlation of structure and activity.

Rats were rendered hypertensive by two different technics. Isometric tensions developed by strips of aorta from these rats, when exposed to various concentrations of epinephrine and levarterenol, were compared with those developed by aortic strips from normotensive controls. Almost all of the aortic strips from the DCA-salt hypertensive rats responded with smaller contraction tensions to both pressor agents than did the corresponding control strips from the normotensive animals. The same was true for most of the strips obtained from the renal hypertensive rats. These results do not lend support to the hypothesis that vascular hyperreactivity is the basis of many forms of hypertension.

Since vascular responsiveness to adrenaline, noradrenaline, renin and angiotonin is reduced by suppression of thyroidal function in normotensive dogs, it was a possibility that in neurogenic and renal hypertensive animals suppression of thyroidal function might be associated with decrease in arterial pressure. This possibility was not confirmed, hypertension persisting unaltered in both groups of hypertensive animals over long periods of observation. Changes in vascular reactivity were slight in comparison with those associated with the athyroid state in normotensive dogs.

The administration of maintenance doses of dl-aldosterone, 3 μg/day, and corticosterone 220 μg/day to rats which were unilaterally nephrectomized, bilaterally adrenalectomized, and given 1% saline to drink failed to cause the development of hypertension or the cardiovascular and renal lesions typical of adrenal-regeneration hypertension. The results were the same whether the steroids were administered on the day of operation or after a 7-day period of adrenal deficiency. When given to rats developing adrenal-regeneration hypertension the same doses of steroids increased the severity of this syndrome.

Antirenin to hog renin produced in the dog neutralizes the acute pressor effect of dog as well as hog renin. A course of intramuscular injections of hog renin in chronic renal hypertensive dogs produces an antihypertensive effect which is correlated with the antirenin titers of the plasma. Passive transfer of high titer homologous antiserum to hog renin produces an antihypertensive effect in chronic renal hypertensive dogs which is correlated with the antirenin titer. The results suggest a pathogenetic role for renin in experimental renal hypertension in the dog.

The effect of a large dose of Pitressin (2 iu subcutaneously) on Na and water excretion under load was studied in rats made hypertensive by DCA. This dose is calculated to be within the upper limit of physiological secretion by the neurohypophysis. The excretion pattern was determined during the 4 1/2 hours following gavage with 100 mg of NaCl in 3 cc of water, both for the period immediately following Pitressin administration and for the period 3 hours after administration. These two periods were selected as corresponding to the pressor and depressor phases of Pitressin action, respectively. The procedure was carried out after one, four and eight daily injections of Pitressin. The selection of control and hypertensive animals was based on a preliminary blood pressure determination obtained by direct electromanometry from the femoral artery. The experiments demonstrated that Pitressin at this dose level has a biphasic action on the handling of Na and water as it has on blood pressure. The first phase consists of a limited tendency to accentuate the already accelerated rate of Na and water excretion found in the hypertensive state. This first effect was not obtained after eight injections. The second phase is characterized by a marked decrease in Na and water excretion which appears to be independent both of the antecedent rate of Na and water loss and of the number of injections.

1. Bei 18 Kaninchen wurden wahrend wiederholter, sich z. T. uber mehrere Wochen erstreckender Noradrenalinbehandlung mit subkutanen und intravenosen Injektionen sowie intravenosen Infusionen unterschiedlicher Dosierung elektrokardiographische Untersuchungen durchgefuhrt und Herz und Aorta nach Totung der Tiere histologisch untersucht. 2. Alle Versuchstiere zeigten im Ekg bei intravenosen Injektionen von 0,03 mg an Veranderungen des Kammerendteiles in Form vonST-Senkungen und negativenT-Zacken. Bei hoheren Dosen gingen diese Veranderungen fast immer in Rhythmusstorungen, vorwiegend Reizbildungsstorungen uber. 3. Die histologische Untersuchung des Herzens ergab bei fast allen Tieren das Vorliegen elektiver Parenchymnekrosen bzw. ihrer Organisationsprodukte. Sie waren in den inneren Schichten der linken Herzkammer bevorzugt lokalisiert und sind in Verbindung mit den fur einen Innenschichtschaden typischen Umformungen des Kammerendteiles im Ekg als Auswirkungen einer Koronarinsuffizienz bei stark erhohter Arbeitsleistung des Herzens infolge der durch Noradrenalin bedingten Hypertonie zu deuten. 4. Fur eine „Noradrenalinmyokarditis” (Szakacs undCannon) ergaben die Untersuchungen keine Anhaltspunkte. 5. Bei 7 Tieren festgestellte Nekrosen und Bindegewebsnarben der Aortenmedia werden ebenfalls auf die Noradrenalinhypertonie zuruckgefuhrt und als Ausdruck einer Ernahrungsstorung durch Oligamie und Ischamie gedeutet.

1. Twelve rabbits were made hypertensive by the application of a clip to the renal artery of a sole remaining kidney. From 119 to 222 days after its application the clip was removed. The effect of this procedure on the blood pressure and on the circulation through the kidney was studied for varying periods up to 240 days after removal of the clip. 2. Eight of the 12 rabbits maintained their hypertension. 3. Rapid serial angiograms showed no obvious change in the intrarenal circulation of any of the animals. The only abnormality seen was a deformity of the renal artery at the site where the clip had been. 4. Histologically, the renal artery at the site of the clip showed fibrosis and a great loss of elastic tissue, but no arterial changes were found in the kidney itself or in other organs. Neoprene casts of the renal blood vessels showed no significant degeneration of the juxtamedullary glomeruli, a finding in keeping with the normal picture of the renal circulation seen in the angiograms. 5. The factor, renal or extrarenal, which was responsible for the maintenance of the hypertension is not known.

Rats made hypertensive by encapsulation of both kidneys with latex envelopes manifest a relative NaCl aversion if given choice between water and .15 m NaCl solution to drink. The specificity of this aversion was tested by offering hypertensive rats choice between salt solutions, other than NaCl, and water. It was observed that hypertensive rats manifested aversions for KCl, Na2SO4, LiCl and Na saccharin which were similar in character to the NaCl aversion. As soon as hypertensive rats were able to differentiate between any of these salt solutions and distilled water offered simultaneously, they rejected the salt solutions in favor of water. These animals never ingested more of any salt solution used than water. With the exception of the Na saccharin solutions, normal rats ingested more salt solution than water and rejected salt solution only at concentrations 3–10 times above preference threshold levels. Hence, it would appear that the NaCl aversion manifested by hypertensive rats is not specific, but part of a general salt aversion.

The responsiveness to norepinephrine of aortic strips from hypertensive rats and from normotensive rats was compared. The strips were set up in a bath of Krebs-Ringer solution, and isometric tension development upon addition of norepinephrine was recorded. The hypertensive strips produced the greatest tension, indicating a greater reactivity to norepinephrine. It was found that the initial tension exerted upon the strip greatly influenced its response, there being an optimal initial tension at which the greatest active response was obtained. These results support the hypothesis that hypertension may be due to an excessive reactivity of vascular smooth muscle.

Sheep with spontaneously occurring or experimentally induced toxemia of pregnancy do not develop hypertension despite the presence of a marked renal ischemia. The present study was undertaken in order to investigate whether pregnant sheep, like pregnant dogs and rats, do not exhibit hypertension when subjected to renal artery constriction. Bilateral constriction of the renal arteries was performed on pregnant ewes by a modified Goldblatt-Wakerlin technique, after control blood pressure had been recorded for several days. Blood pressure and BUN were measured throughout pregnancy and following delivery. All the animals which had renal artery constriction developed severe hypertension with retinal changes similar to those of human hypertension. The pregnancy did not affect the course of the hypertension nor did the hypertension alter the course of pregnancy.

Heparin (Liquemin „Roche“) senkte in kleinen Dosen bei Ratten mit einem nephrogenen Hochdruck eindeutig den Blutdruck. Der Hochdruck wurde durch einseitige Nephrektomie und Einkapselung der anderen Niere mit einer Perlonhulse erzeugt. Die Blutdrucksenkung war etwa 24–48 Std nach der 1. Heparinapplikation festzustellen. Bei fortlaufender Behandlung (3 mal wochentlich 100 IE/kg) blieb der Blutdruck uber die ganze Beobachtungszeit (bis zu 190 Tagen) gesenkt. Der Blutdruckanstieg nach Einkapselung der Niere wurde durch fortlaufende Heparinzufuhr deutlich gehemmt. Geschlechtsunterschiede liegen nicht vor.

It has been well established that desoxycorticosterone acetate (DCA) administered to normal rats or to rats sensitized by high sodium intake and/or uni-nephrectomy will produce renal and vascular pathology accompanied by arterial hypertension (Selye, Hall, and Rowley, 1943; Friedman, Polley, and Friedman, 1948; Masson, Corcoran, and Page, 1949). Although the etiology of DCA hypertension has not been explained in a manner satisfactory to all workers in the field, there have been searches for agents which will either reverse an established DCA hypertension or prevent the development of DCA hypertension in experimental animals, both because of the possible clinical implications and because the use of such agents would be helpful in research on mechanisms in vascular disease. Agents which have been reported to be effective in preventing the development of DCA hypertension in rats are: Lipo-Adrenal Cortex,1 estradiol2 (Friedman and Friedman, 1950), cortisone acetate2 (Friedman, Friedman, and Nakashima, 1950), ...

The results of these experiments indicate that the carotid and aortic baroceptor mechanisms are reset to the hypertensive pressure levels of animals with chronic perinephritic hypertension. Thus, seemingly, the buffer reflexes tend to maintain, rather than prevent, the chronic phase of renal hypertension and are, presumably, an important component in the mechanism of chronic renal hypertension.

The spontaneous intake of water and saline and their output under load were measured in the early and late stages of perinephritic hypertension in rats. The conclusion was drawn that sodium exchange is increased in the prehypertensive phase, but reverts toward or drops below normal with the development of chronic sustained hypertension.

The renin content of the kidneys from chronic renal hypertensive dogs rises when the kidneys are transplanted to the neck of a normotensive nephrectomized animal. This elevation precedes and accompanies the elevation of the blood pressure of the recipient. This type of experiment does not allow one to draw conclusions concerning the humoral mechanism of chronic renal hypertension.

SummarySix methods useful in producing experimental hypertension in other laboratory animals were studied in rhesus monkeys. Two methods involving direct constriction of the renal arteries either by silk ligatures or small transparent plastic clamps resulted in a significant incidence of hypertension. Of 13 animals which survived 23 days or longer after renal artery constriction, 10 developed hypertension. The degree of constriction was critical, and a significant proportion of the animals succumbed in acute post-operative renal failure. Four other methods used successfully in rats, rabbits, or dogs were ineffective in the monkey. These included: (1) unilateral temporary renal occlusion and contralateral nephrectomy; (2) unilateral silk perinephritis; (3) unilateral silk perinephritis and contralateral nephrectomy; and (4) bilateral silk perinephritis. Administration of large oral doses of sodium chloride per se did not induce hypertension, nor did it increase the effectiveness of any of the above 4 proce...

A course of daily intramuscular injections of dog renin produced a maintained chronic pressor effect persisting for months during and following the renin injections in a majority of renal hypertensive dogs. Semipurified hog renin produced a temporary chronic pressor effect persisting for several weeks or somewhat longer but not throughout the renin injections in a minority of renal hypertensive dogs. The maintained chronic pressor effect was obtained only in the absence of antirenin; the temporary chronic pressor effect was lost when antirenin appeared in the plasma. Normotensive dogs were significantly less responsive to the chronic pressor effect of dog and hog renins than were renal hypertensive dogs. The mechanism of the chronic pressor effects is unknown.

Growth hormone (Connaught) was given in 1 mgm. daily doses to rats either otherwise untreated or given an amount of DCA or Compound F sufficient to elicit a moderate hypertensive response. At the dose level used, growth hormone did not affect either blood pressure or kidney size in treated or untreated animals. The dose used was one-fifth the amount found to increase renal function in the dog and 10 times the dose required for trophic effects in the rat.