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SC-56525 is a nanomolar inhibitor of plasma renin activity in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, and rabbit but is less active in rat. The oral bioavailability of SC-56525 in conscious dogs at doses of 5 mg/kg IV and 30 mg/kg PO was 66.1 +/- 16.4%. Oral dosing with SC-56525 at 3, 10, and 30 mg/kg in salt-depleted dogs induced a dose-dependent reduction in mean arterial pressure and inhibition of plasma renin activity with no significant effect on heart rate. In two-kidney, one clip renal hypertensive dogs, SC-56525 given orally at 10, 30, and 60 mg/kg daily for 4 days lowered blood pressure significantly. In conscious dogs monitored in their home cages via radiotelemetry, no significant changes in heart rate occurred in response to large drops in blood pressure in both renal hypertensive and salt-depleted dogs with the renin inhibitor SC-56525. SC-56525 is a nanomolar, orally active inhibitor of renin and effectively lowers blood pressure in both salt-depleted and renal hypertensive dogs.

Nonpeptidic imidazole derivatives were recently reported to be angiotensin II receptor antagonists with acute blood pressure-lowering activity. In the present study, we characterized the angiotensin II receptor antagonist properties of one such derivative, 4'-([2-butyl-4-chloro-5-(hydroxymethyl)-1H-imidazol-1-yl]methyl)- [1,1'-biphenyl]-2-carboxylic acid (IMI). In receptor binding studies, IMI displaced bound [125I]angiotensin II from rat uterine membranes with an IC50 of 0.17 microM. In isolated rabbit aortic rings, IMI shifted the angiotensin II concentration-response curve to the right in a parallel and concentration-dependent manner. A Schild plot of these data indicated a pA2 of 7.13 +/- 0.16 and a slope of 0.94 +/- 0.06. In rat kidney slices, IMI shifted the concentration-response curve for angiotensin II-induced inhibition of renin release to the right. Antagonism of the angiotensin II pressor response by IMI was dose dependent and reversible in ganglion-blocked, anesthetized rats. The water intake and pressor responses to intracerebroventricular angiotensin II (100 pmol) were inhibited by intracerebroventricular IMI (25 or 50 nmol) in conscious Sprague-Dawley rats. Similarly, the drinking and pressor responses to intravenous angiotensin II were blocked by intravenous IMI in conscious rats. IMI alone had no effects on mean arterial pressure or drinking when administered either intravenously or intracerebroventricularly. IMI decreased mean arterial pressure throughout 5 days of infusion in spontaneously hypertensive rats. In summary, IMI was a full competitive antagonist without partial agonist activity in peripheral tissues and the central nervous system. Moreover, the chronic administration of this angiotensin II receptor antagonist was antihypertensive in spontaneously hypertensive rats.

The isomyosin composition in left and right ventricles from aldosterone-salt-treated hypertensive rats and from vehicle-infused and aldosterone-infused normotensive control rats was compared. A significant incremental increase (20%) in the percentage of V3 isomyosin and parallel decrease in the percentage of V1 isomyosin occurred in both left and right ventricles from aldosterone-salt-treated animals compared with those in normotensive vehicle-infused controls. No change in the ventricular isomyosin distribution was observed in animals infused with aldosterone without salt, which indicates that aldosterone does not directly affect the ventricular isomyosin composition. The changes in left ventricular isomyosin composition were accompanied by significant left ventricular hypertrophy (38%; p less than 0.05), whereas no hypertrophy was observed in the right ventricle. Plasma thyroxine levels were significantly lower in aldosterone-salt-treated rats (3.7 +/- 0.6 micrograms/dl; p less than 0.05) than in normotensive vehicle-infused (6.0 +/- 0.7 micrograms/dl) or aldosterone-infused (6.7 +/- 0.3 micrograms/dl) controls. These results indicate that factors such as alterations in thyroid status or a volume overload component of this hypertensive model, in addition to increased systolic blood pressure, may contribute to a biventricular shift in isomyosin composition in the aldosterone-salt model of hypertension.