Modulation of V1-receptor-mediated renal vasoconstriction by epoxyeicosatrienoic acids

Abstract

This study examined the effects of renal arterial infusion of a selective cytochrome P-450 epoxygenase inhibitor, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH; 2 mg/kg plus 1.5 mg·kg−1·h−1), on renal hemodynamic responses to infusions of [Phe2,Ile3,Orn8]vasopressin and ANG II into the renal artery of anesthetized rabbits. MS-PPOH did not affect basal renal blood flow (RBF) or cortical or medullary blood flow measured by laser-Doppler flowmetry (CLDF/MLDF). In vehicle-treated rabbits, [Phe2,Ile3,Orn8]vasopressin (30 ng·kg−1·min−1) reduced MLDF by 62 ± 7% but CLDF and RBF were unaltered. In MS-PPOH-treated rabbits, RBF and CLDF fell by 51 ± 8 and 59 ± 13%, respectively, when [Phe2,Ile3,Orn8]vasopressin was infused. MS-PPOH had no significant effects on the MLDF response to [Phe2,Ile3,Orn8]vasopressin (43 ± 9% reduction). ANG II (20 ng·kg−1·min−1) reduced RBF by 45 ± 10% and CLDF by 41 ± 14%, but MLDF was not significantly altered. MS-PPOH did not affect blood flow responses to ANG II. Formation of epoxyeicosatrienoic acids (EETs) and dihydroxyeicosatrienoic acids (DiHETEs) was 49% lower in homogenates prepared from the renal cortex of MS-PPOH-treated rabbits than from vehicle-treated rabbits. MS-PPOH had no effect on the renal formation of 20-hydroxyeicosatetraenoic acid (20-HETE). Incubation of renal cortical homogenates from untreated rabbits with [Phe2,Ile3,Orn8]vasopressin (0.2–20 ng/ml) did not affect formation of EETs, DiHETEs, or 20-HETE. These results do not support a role for de novo EET synthesis in modulating renal hemodynamic responses to ANG II. However, EETs appear to selectively oppose V1-receptor-mediated vasoconstriction in the renal cortex but not in the medullary circulation and contribute to the relative insensitivity of medullary blood flow to V1-receptor activation.