G. M. C. Masson

Hypertensive Vascular Disease Produced by Homologous Renin

Administration of rat renin to uninephrectomized rats reproduced most, if not all, the changes (hypertension, vascular disease, hypertrophy of the zona glomerulosa of the adrenals) found after partial constriction of the renal artery. This is taken as evidence that the renal pressor system plays a major role in the pathogenesis of renal hypertension.

Production of Hypertension and Vascular Disease by Kidney Extracts

Hypertension was induced in rats by constricting the aorta between the origins of the renal arteries. The left kidney, which became ischemic and atrophic (“endocrine kidney”), caused a malignant type of hypertension associated with weight loss, cardiac hypertrophy, hypertension, cardiac necrosis, nephrosclerosis of the right kidney, and arteritis. Amounts of pressor substances were increased in the left kidney and decreased in the right as compared with those in kidneys of normal rats. Aqueous extracts of ischemic kidneys, of kidneys contralateral to ischemic kidneys and of normal kidneys were prepared and the supernatant solutions were injected subcutaneously into test rats which had been uninephrectomized a few hours previously. Extracts of ischemic kidneys caused hypertension, cardiac hypertrophy, weight loss, and renal and vascular lesions mimicking the signs which result from renal ischemia. The extracts from the other kidneys were inactive. Administration of renin in doses roughly equivalent in pressor activity to the extracts of ischemic kidneys caused a rise in pressure, diuresis, and proteinuria but no lesions when given subcutaneously. It is proposed as a working hypothesis that renal hypertensive disease results not only from increased secretion of renin and formation of angiotensin but from simultaneous release from kidneys with reduced perfusion pressure of a substance which augments the enzymatic formation of angiotensin. This substance is presumably absent from normal kidneys and from semipurified renin preparations.

Vascular Reactivity of Rats and Dogs Treated with Desoxycorticosterone Acetate.

Summary Chronic treatment with DCA of dogs and rats, does not increase significantly vascular response to epinephrine, renin and angiotonin to explain DCA-hypertension on the basis of vascular hypersensitivity.

Release of Pressor Substances from Renal Grafts Originating from Rats with Renal Hypertension

A method is described for grafting kidneys on bilaterally nephrectomized rats without interrupting renal blood flow. Under these conditions, normal kidneys caused a pressor response characterized by a gradual rise in pressure suggesting a continuous endocrine secretion. Kidneys from rats made hypertensive by unilateral clipping of the renal artery, renal encapsulation, or partial infarction were tested during the acute and chronic stages of the experimental disease. Wrapped and infarcted kidneys, as well as the untouched contralateral organs, released little or no pressor substances. On the other hand, clipped kidneys released normal or slightly greater amounts of pressor substances; the eontralateral untouched kidney did not elicit any pressor effect. Morphological examination showed a relationship between presence of nephroselerotic lesions and absence of, or decrease of, reninlike pressor substance released. Both changes are believed to be due to high renal vascular pressure against which the partly clipped kidney is protected. These observations suggest that, if renin is a primary factor in the pathogenesis of renal hypertension, hypertension due to renal artery constriction has a mechanism different from that caused by renal manipulation or infarction.

Interrelationships of desoxycorticosterone, cortisone and vitamin C in the genesis of mesenchymal lesions.

Summary Cortisone inhibits many of the manifestations of scurvy in the guinea pig while desoxycorticosterone aggravates the condition. These activities of the hormones probably depend on their action on mesenchymal tissues. The scorbutic guinea pig, untreated or treated with DCA, may be a valuable test subject for the assay of anti-arthritic compounds.

Hypertensive Vascular Disease Induced by Heterologous Renin

Chronic treatment with crude hog, or rat, renin administered subcutaneously to uninephrectomized rats elicits hypertension, renal and vascular lesions, hypertrophy of the zona glomerulosa of the adrenals, and renin depletion in the remaining kidney. Semipurified hog renin given in equipressor doses also causes renin depletion and stimulation of the zona glomerulosa, but no hypertension nor vascular disease. However, semipurified hog renin becomes as effective as the crude preparation after addition of retarding substances such as gelatin, oil, or cholesterol. Thus, a prolonged and sustained resorption of renin seems to be a prerequisite for the development of hypertension. Since hypertension takes place only after a latent period during which arterial pressure remains within the normal range, it does not appear that hypertension can be attributed to the acute pressor effect of renin. It is proposed as a working hypothesis that renin, through angiotensin, initiates nervous mechanisms which are responsible for the development of benign hypertension and that the acute pressor effect of angiotensin is more specifically associated with the malignant phase of hypertension.

Role of Renin in the Regulation of Angiotensinogen Levels in Plasma

Summary The role of renin in the regulation of its substrate was evaluated after administration of homologous renin. In normal rats, increases in plasma renin were associated with decreases in substrate. In nephrectomized rats, renin delayed but did not prevent the rise in substrate seen in nephrectomized controls, in spite of the high levels of plasma renin. An inverse relationship between renin and substrate levels was found after adrenalectomy and during pregnancy, but not after delivery. It is concluded that substrate consumption by renin plays a minor role in regulating substrate levels.

Angiotonin induction of vascular lesions in desoxycorticosterone-treated rats.

Summary 1. Hourly intraperitoneal administration of angiotonin to rats pretreated with DCA and salt elicited edema, convulsions, a positive fluid balance and increased fluid intake, together with proteinuria, visceral hemorrhages and acute necrotizing lesions in small arteries and arterioles. 2. The same series of changes occurred in similarly pretreated rats given renin subcutaneously. 3. We conclude that the vascular lesions elicited by renin in sensitized animals are very likely due to the action of renin as such, effected by liberation of angiotonin and are not, as hitherto seemed possible, attributable to vasculo-toxic factors in renin preparations or to an action of renin independent of formation of angiotonin.

Adrenal Cortex and Renal Pressor Function

The pressor response of the nephrectomized rat to the injection of kidney extracts and to a renal graft, was used as an index of the renal content and secretion of pressor substances during adrenal insufficiency or treatment with corticosteroids. Adrenalectomy caused an elevation of both content and secretion, which was best demonstrated after two to three weeks of maintenance therapy. Treatment with cortisone and cortisol decreased slightly but significantly the secretion of pressor substances without altering renal content. ACTH had no effect on either function. Sequential studies of content and secretion of pressor substances during treatment with DCA plus salt showed first a rapid disappearance of prossor activity from renal vein blood followed by a decrease in renal content to near zero levels; DCA without excess salt elicited the same effects but more gradually; administration of 1% saline alone decreased secretion without altering content. It is concluded that salt active corticosteroids specifically inhibit the formation and secretion of renal pressor substances and that determination of the index of secretion constitutes a more reliable and sensitive indicator of the renal pressor function than determination of the pressor activity in kidney extracts.

Pressor and Myotrophic Activities of Incubated Plasma.

Summary Incubation of normal human, dog or rat plasma at 37°C for 12 or 24 hours unmasks a pressor and myotrophic activity which is not due to known vasoactive substances.