Abstract

The preglomerular arteriole of the rat was used to evaluate the contribution of cytochrome P450-derived eicosanoids to the vasoconstrictor effect of endothelin (ET)-1 and to determine the receptors mediating the response. ET-1 (4 × 10⁻¹¹ to 2 × 10⁻⁹ M) produced dose-dependent reductions in the intraluminal diameter of the renal arteriole ranging from 25 ± 8 to 142 ± 16 μm. BMS182874 [(5-dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; 3 μM], an ET_A receptor antagonist, or BQ788 (N-cis-2,6-dimethyl-piperidino-carbonyl-l-γ-methylleucyl-d-1-methoxycarbonyl-tryptophanyl-d-norleucine; 1 μM), an ET_B receptor antagonist, attenuated ET-1 vasoconstriction by 59 ± 4 and 50 ± 10%, respectively. The combined administration of both ET receptor antagonists increased inhibition of ET-1 vasoconstriction to 75 ± 4%. 17-Octadecynoic acid (17-ODYA, 2 μM) or 12,12-dibromododec-enoic acid (2 μM), inhibitors of 20-hydroxyeicosatetraenoic acid (20-HETE) production, attenuated ET-1-induced vasoconstriction by 50 ± 6 and 40 ± 3%, respectively, as did indomethacin (10 μM), an inhibitor of cyclooxygenase. Miconazole (2 μM), the epoxygenase inhibitor, was without effect. 20-HETE (10⁻⁸ and 2 × 10⁻⁸ M) elicited a dose-related vasoconstriction that was inhibited by 10 μM, but not 5 μM, indomethacin. The inhibition by 17-ODYA of ET-1 vasoconstriction was not greater when combined with BMS182874 or BQ788. Moreover, vasoconstriction induced by ET-3, an ET_B-selective agonist, was inhibited by 17-ODYA. These data indicate that both ET_A and ET_B receptors mediate ET-1 vasoconstriction and that 20-HETE production linked to both receptors makes a major contribution to ET-1-induced renal arteriolar vasoconstriction in the rat.