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Hypertension. 1997;29:320-325

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*Compound via MeSH
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Hazardous Substances DB
*NITRIC OXIDE

(Hypertension. 1997;29:320.)
© 1997 American Heart Association, Inc.


Arthur C. Corcoran Memorial Lecture

Inhibition of 20-HETE Production Contributes to the Vascular Responses to Nitric Oxide

Magdalena Alonso-Galicia; Heather A. Drummond; K. Kishta Reddy; John R. Falck; Richard J. Roman

From the Department of Physiology, Medical College of Wisconsin, Milwaukee (M.A.-G., H.A.D., R.J.D.); and the Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas (K.K.R., J.R.F.).

Correspondence to Dr Richard J. Roman, Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226-0509. E-mail rroman{at}post.its.mcw.edu

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 µmol/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.


Key Words: nitric oxide • vasculature • enzymes

Abbreviations: AA = arachidonic acid • DDMS = dibromo-dodecenyl-methylsulfimide • DiHETEs = dihydroxyeicosatetraenoic acids • EETs = eicosatrienoic acids • 20-HETE = 20-hydroxyeicosatetraenoic acid • HPLC = high-performance liquid chromatography • L-NArg = N-nitro-L-arginine • MAHMA NONate = 1-hexamine, 6-(2-hydroxy-1-methyl-2-nitrosohydrazino)N-methyl • MAP = mean arterial pressure • NO = nitric oxide • 17-ODYA = 17-octadecynoic acid • PAPA NONOate = 1-propanamine, 3-(2-hydroxy-2-nitroso-1-propylhydrazino) • RBF = renal blood flow • SNP = sodium nitroprusside




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