Inhibition of 20-HETE production contributes to the vascular responses to nitric oxide.
Nitric oxide (NO) inhibits a variety of heme-containing enzymes, including NO synthase and cytochrome P4501A1 and 2B1. The present study examined whether NO inhibits the production of 20-hydroxyeicosatetraenoic acid (20-HETE) by cytochrome P4504A enzymes and whether blockade of the production of this substance contributes to the vascular effects of NO. Sodium nitroprusside (SNP; 10(-5), 10(-4), and 10(-3) mol/L) reduced the production of 20-HETE by renal microsomes incubated with arachidonic acid to 71 +/- 5%, 29 +/- 4%, and 4 +/- 2% of control, respectively (n = 5). Similar results were obtained with the use of 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) (n = 3). To determine whether inhibition of 20-HETE contributes to the vasodilatory effects of NO, the effects of dibromo-dodecenyl-methylsulfimide (DDMS), a selective 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 preconstricted with phenylephrine (n = 5). SNP increased vascular diameter in a concentration-dependent manner to 82 +/- 4% of control. After DDMS (25 mumol/L), SNP (10(-3) mol/L) increased vascular diameter by only 17 +/- 3%. The effects of DDMS on the mean arterial pressure (MAP) and renal blood flow (RBF) responses to infusion of an NO donor and a synthase inhibitor were also examined in thiobutabarbital-anesthetized, Sprague-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 lowered 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-nitrohydrazino)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 results indicate that NO inhibits cytochrome P4504A enzymes and that inhibition of the production of 20-HETE contributes to the vasodilatory effects of NO.
Alonso-Galicia
M
M
Department of Physiology, Medical College of Wisconsin, Milwaukee 53226-0509, USA.
Drummond
H A
HA
Reddy
K K
KK
Falck
J R
JR
Roman
R J
RJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001095:Arachidonic Acids / Q000378:metabolism; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007672:Kidney Cortex / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014664:Vasodilation / Q000502:physiology*
D001095:Arachidonic Acids; D065607:Cytochrome P-450 Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D009599:Nitroprusside; D016718:Arachidonic Acid; D009569:Nitric Oxide; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D019001:Nitric Oxide Synthase; C022657:steroid hormone 6-beta-hydroxylase