TY - JOUR T1 - Pharmacological characterization of A-127722: an orally active and highly potent ETA-selective receptor antagonist. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 473 LP - 481 VL - 276 IS - 2 AU - T J Opgenorth AU - A L Adler AU - S V Calzadilla AU - W J Chiou AU - B D Dayton AU - D B Dixon AU - L J Gehrke AU - L Hernandez AU - S R Magnuson AU - K C Marsh AU - E I Novosad AU - T W Von Geldern AU - J L Wessale AU - M Winn AU - J R Wu-Wong Y1 - 1996/02/01 UR - http://jpet.aspetjournals.org/content/276/2/473.abstract N2 - Endothelins (ET) are potent vasoactive peptides implicated in the pathogenesis of a number of vascular diseases. The effects of ET on mammalian organs and cells are initiated by binding to ETA or ETB receptors. In this report, we document the pharmacology of A-127722, a novel ETA-selective receptor antagonist. A-127722 inhibits [125I]ET-1 binding to cloned human ETA and ETB receptors competitively with Ki values of 69 pM and 139 nM, respectively. A-127722 exhibits a dose-dependent inhibition of ET-1-induced arachidonic acid release in human pericardium smooth muscle cells with a pA2 value of 10.5 and inhibits ET-1-induced vasoconstriction in isolated rat aorta with a pA2 value of 9.2. In vivo, A-127722 dose-dependently blocks the pressor response to ET-1 (0.3 nmol/kg i.v.) in conscious rats. Statistically significant (P < .05) antagonism is seen at doses greater than 0.1 mg/kg p.o. Maximal inhibition, at 10 mg/kg, remains constant for at least 8 hr after dosing. No effect is seen on the ETB-mediated transient vasodepressor effect of exogenous ET-1. In conclusion, A-127722 is ETA-selective, orally bioavailable and efficacious for inhibiting the effects of ET in the rat, and A-127722 is the most potent ET receptor antagonist yet reported. ER -