ABT-546 (A-216546) is a potent, highly selective, and active endothelin ETA receptor antagonist with a Ki of 0.46 nM for [125I]endothelin-1 binding to cloned human endothelin ETA.

ETA:0.46 nM (ki)

ABT-546 is ＞25,000-fold more selective for the ETA receptor than for the ETB receptor. ABT-546 blocks endothelin-1-induced arachidonic acid release and phosphatidylinositol hydrolysis (IC50s: 0.59 nM and 3 nM). ABT-546 effectively inhibits specific I endothelin-1 binding to endothelin ETA receptor in membranes prepared from rat pituitary MMQ cells (IC50: 0.56 nM). In membranes prepared from CHO cells stably transfected with the human endothelin ETA and ETB receptors, ABT-546 again effectively inhibits specific [125I]endothelin-1 binding to endothelin ETA receptor (IC50: 0.49 nM), but is less effective in inhibiting specific [125I]endothelin-3 binding to endothelin ETB receptor (IC50: 15,400 nM). In isolated vessels, ABT-546 inhibits endothelin ETA receptor-mediated endothelin-1-induced vasoconstriction, and endothelin ETB receptor-mediated sarafotoxin 6c-induces vasoconstriction with pA2 of 8.29 and 4.57, respectively.

ABT-546 (0-100 mg/kg; p.o.; for 1 hour or 4 hours; male Sprague-Dawley rats) treatment dose-dependently blocks the endothelin-1-induced pressor response in conscious rats.

Animal Model: Male Sprague-Dawley rats (250-350 g) induced with endothelin-1. Dosage: 0.1 mg/kg, 1 mg/kg, 10 mg/kg, 30 mg/kg, 100 mg/kg. Administration: p.o.; for 1 hour or 4 hours