Novel Dual Action AT₁ and ET_A Receptor Antagonists Reduce Blood Pressure in Experimental Hypertension

Angiotensin II and endothelin-1 activate their respective AT1 and ETA receptors on vascular smooth muscle cells, producing vasoconstriction, and both peptides are implicated in the pathogenesis of essential hypertension. Angiotensin II potentiates the production of endothelin, and conversely endothelin augments the synthesis of angiotensin II. Both AT1 and ETA receptor antagonists lower blood pressure in hypertensive patients; thus, a combination AT1/ETA receptor antagonist may have greater efficacy and broader utility compared with each drug alone. By rational drug design a biphenyl ETA receptor blocker was modified to acquire AT1 receptor antagonism. These compounds (C and D) decreased Sar-Ile-Angiotensin II binding to AT1 receptors and endothelin-1 binding to ETA receptors, and compound C inhibited angiotensin II- and endothelin-1-mediated Ca2+ transients. In rats compounds C and D reduced blood pressure elevations caused by intravenous infusion of angiotensin II or big endothelin-1. Compound C decreased blood pressure in Na+-depleted spontaneously hypertensive rats and in rats with mineralocorticoid hypertension. Compound D was more efficacious than AT1 receptor antagonists at reducing blood pressure in spontaneously hypertensive rats, and its superiority was likely due to its partial blockade of ETA receptors. Therefore compounds C and D are novel agents for treating a broad spectrum of patients with essential hypertension and other cardiovascular diseases.