INHIBITION OF 20-HETE PRODUCTION CONTRIBUTES TO THE VASCULAR-RESPONSES TO NITRIC-OXIDE

Nitric oxide (NO) inhibits a variety of heme-containing enzymes, inclu ding NO synthase and cytochrome P4501A1 and 2B1. The present study exa mined whether NO inhibits the production of 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P4504A enzymes and whether blockade of t he production of this substance contributes to the vascular effects of NO. Sodium nitroprusside (SNP; 10(-5), 10(-4), and 10(-3) mol/L) redu ced the production of 20-HETE by renal microsomes incubated with arach idonic acid to 71 +/- 5%, 29 +/- 4%, and 4 +/- 2% of control, respecti vely (n = 5). Similar results were obtained with the use of 1-propanam ine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) (n = 3). To determine w hether inhibition of 20-HETE contributes to the vasodilatory effects o f NO, the effects of dibromo-dodecenyl-methylsulfimide (DDMS), a selec tive inhibitor of the formation of 20-HETE, on the response to SNP (10 (-7) to 10(-3) mol/L) were examined in rat renal arterioles preconstri cted with phenylephrine (n = 5). SNP increased vascular diameter in a concentration-dependent manner to 82 +/- 4% of control. After DDMS (25 mu mol/L), SNP (10(-3) mol/L) increased vascular diameter by only 17 +/- 3%. The effects of DDMS on the mean arterial pressure (MAP) and re nal blood flow (RBF) responses to infusion of an NO donor and a syntha se inhibitor were also examined in thiobutabarbital-anesthetized, Spra gue-Dawley rats. infusion of MAHMA NONOate at 1, 3, 5, and 10 nmol/min reduced MAP by 16 +/- 2, 30 +/- 3, 40 +/- 5, and 48 +/- 5 mm Hg and l owered renal vascular resistance (RVR) by 15 +/- 3%, 26 +/- 2%, 30 +/- 3%, and 34 +/- 4% of control. After DDMS (10 mg/kg, n = 7 rats), the MAP and RVR responses to 1-hexamine, 6-(2-hydroxy-1-methyl-2-nitrohydr azino)N-methyl (MAHMA NONOate) averaged only 20% of those seen during control. In other experiments, MAP increased by 32 +/- 4% and RBF fell to 56 +/- 5% of control after administration of N-nitro-L-arginine (L -NArg) (10 mg/kg IV). After DDMS (10 mg/kg, n = 7 rats), MAP increased by only 19 +/- 4% and RBF fell by only 7 +/- 4% after L-NArg. These r esults indicate that NO inhibits cytochrome P4504A enzymes and that in hibition of the production of 20-HETE contributes to the vasodilatory effects of NO.