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.