PHARMACOLOGY OF LR-B 057, A NOVEL ORALLY-ACTIVE AT(1) RECEPTOR ANTAGONIST/

We studied the pharmacologic properties of LR-B/057, a novel nonpeptid e angiotensin II (AII) receptor antagonist. The compound potently disp laced [H-3]AII from AT(1) but not from AT(2) receptors in rat adrenal cortex (K-i 3 nM), but did not modify the dissociation rate of the rad ioligand from the receptors. Both its affinity and the nature of its i nteraction with AT(1) receptors (saturation studies) were markedly aff ected by the presence of bovine serum albumin (BSA) in the binding ass ay. In rabbit aorta, LR-B/057 caused nonparallel shifts to the right o f the dose-response curve to AII and decreased the maximal response (p K(B) 9.6). Oral (p.o.) administration of LR-B/057 to conscious rats do se-dependently antagonized the presser response to AII. LR-B/057 admin istered either intravenously (i.v.) or p.o. to conscious renal hyperte nsive rats produced a powerful dose-dependent antihypertensive effect. These results show that LR-B/057 is a potent and selective antagonist at AT(1) receptors and has p.o. bioavailability.