The pharmacological characterization of a nonpeptide endothelin (ET)-receptor antagonist, PABSA [(R)-(--)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropyl-phenylsulfon yl)-2-(6-methyl-2-propylpyridin-3-yloxy)-acetamide hydrochloride] was studied. PABSA competitively inhibited the binding of [125I]-ET-1 to A7r5 cells expressing ET(A) receptors and of [125I]-ET-3 to COS cells expressing porcine ET(B) receptors with Ki values of 0.11 and 25 nM, respectively. PABSA inhibited ET(A) receptor-mediated and ET(B) receptor-mediated vasocontraction and ET(B) receptor-mediated vasorelaxation in isolated rabbit vessels with K(b) values of 0.46, 94, and 26 nM, respectively. The antagonist potency of PABSA for ET(A) receptor-mediated vasocontraction was 63- and 87-fold more potent than those of BQ-123 and bosentan, respectively, and was similar to those of TAK-044 and SB209670. Oral administration of PABSA (1-10 mg/kg) caused dose-dependent inhibition of the pressor response to exogenous ET- 1 (0.1 nmol/kg) in conscious normotensive rats. PABSA (10-100 mg/kg, p.o.) reduced blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, spontaneously hypertensive rats (SHRs), and stroke-prone spontaneously hypertensive rats (SHRSPs). The hypotensive effect of PABSA was sustained for > or =24 h in these rats. These results suggest that PABSA is a highly potent ET(A)-receptor antagonist with weak ET(B)-receptor antagonist activity. Because PABSA has a long duration of action in vivo, this antagonist should be useful in the therapy of ET-related disease.