The long-term objectives of this proposal are to elucidate the mechanisms involved in the pathogenesis of hypertension and heart failure with special emphasis placed on changes in renal, adrenergic and adrenocortical functions. This proposal focuses on three specific areas of research: 1) renin-angiotensin and adrenergic pressor mechanisms in experimental renal hypertension, 2) the control of aldosterone secretion and biosynthesis, and 3) the control of renin release. Both the angiotensin and sympathetic pressor systems will be evaluated in the acute, subacute and chronic phases of experimental 1K-1C and 2K-1C renovascular hypertension. Plasma renin and catecholamine levels will be measured and the depressor responses to both angiotensin and ganglionic blockade will be determined. The depressor response to renal denervation will be examined also and related to changes in renal function and peripheral adrenergic tone. These experiments will be performed in both sodium replete and sodium deplete hypertensive animals. Experiments are planned to evaluate the roles of calcium and dopamine in the control of aldosterone secretion and renin release; these experiments involve the use of calcium chanel blockers, nifedipine and verapamil, and the dopamine antagonist metoclopramide. Additional experiments will evaluate the relationship of the renal prostaglandins to the intrarenal vascular receptor mechanism for control of renin release. Methodology: 1) animal models include dogs and rats with 1K-1C and 2K-1C renovascular hypertension, and dogs with chronic thoracic inferior vena cava constriction; 2) plasma renin and aldosterone levels and urinary PGE2 are determined by radiommunoassay; 3) renal and plasma catecholamines are determined by radioenzynmatic assay; 4) arterial pressures are determined in conscious animals with chronic vascular catheters.
