Differential effects of 20-hydroxyeicosatetraenoic acid on intrarenal blood flow in the rat

Abstract

ABSTRACT We recently demonstrated that endothelin-1-induced medullary vasodilation despite a potent cortical vasoconstriction in the rat kidney may be accounted for by 20-hydroxyeicosatetraenoic acid (20-HETE) production. This study characterized the effects of 20-HETE and its metabolites, 20-hydroxy prostaglandin E 2 (20-OH PGE 2 ) and 20-hydroxy prostaglandin F 2␣ (20-OH PGF 2␣ ), and the contribution of nitric oxide (NO) and prostanoids to the changes evoked in cortical blood flow (CBF) and medullary blood flow (MBF). We tested the hypothesis that 20-HETE produces qualitatively different regional hemodynamic effects in the kidney with 20-OH PGF 2␣ or 20-OH PGE 2 , accounting for the vasoconstriction or vasodilation, respectively, in the cortex and medulla. Renal intra-arterial infusion of 1, 2.5, 5, and 10 ng/min 20-HETE decreased CBF by 10 Ϯ 3, 24 Ϯ 4, 40 Ϯ 7, and 58 Ϯ 9 perfusion units (PU), respectively, but increased MBF by 4 Ϯ 2, 16 Ϯ 4, 27 Ϯ 3, and 41 Ϯ 10 PU, respectively. 20-OH PGF 2␣ mimics the effects of 20-HETE, as did PGF 2␣ . However, 20-OH PGE 2 increased both CBF and MBF, as did PGE 2 . Indomethacin (5 mg/kg) blunted the effects of 20-HETE but not that of 20-OH PGE 2 and 20-OH PGF 2␣ . -5-heptenoic acid) (0.1 mg/kg), a prostaglandin H 2 /thromboxane A 2 receptor antagonist, blunted the cortical and medullary hemodynamic effects elicited by 20-HETE, 20-OH PGE 2 , 20-OH PGF 2␣ , and PGF 2␣ but not PGE 2 . N -L-nitro arginine methyl ester (5 mg/kg), the inhibitor of NO synthase, exacerbated the cortical constrictor effects of 20-HETE and 20-OH PGF 2␣ without affecting the medullary perfusion produced by 20-HETE or its metabolites. These findings suggest that 20-HETE, through its hydroxyl metabolites, produced differential effects in the kidney. The medullary perfusion appears to be independent of NO. 20-Hydroxyeicosatetraenoic acid (20-HETE), the major eicosanoid in the kidney, is widely known as a constrictor hormone eliciting potent vasoconstriction of the peripheral arteries of the rabbit, the renal afferent arteriole of the rat, dog, and rabbit 20-HETE and other CYP450 products are good substrates for COX, and their production occurs throughout the kidney. Although the specific metabolic pathways for 20-HETE in the kidney has not been fully identified, a priori, the presence of CO