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Circulation Research. 1998;83:1069-1079

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(Circulation Research. 1998;83:1069-1079.)
© 1998 American Heart Association, Inc.


Original Contributions

Nitric Oxide-20–Hydroxyeicosatetraenoic Acid Interaction in the Regulation of K+ Channel Activity and Vascular Tone in Renal Arterioles

Cheng-Wen Sun, Magdalena Alonso-Galicia, M. Reza Taheri, John R. Falck, David R. Harder, , Richard J. Roman

From the Department of Physiology and Cardiovascular Research Center (C.-W.S., M.A.-G., M.R.T., D.R.H., R.J.R.), Medical College of Wisconsin, Milwaukee and the Department of Molecular Genetics (J.R.F.), University of Texas Southwestern Medical Center, Dallas.

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

Abstract—The present study examined whether inhibition of P4504A enzyme activity and the formation of 20-HETE contributes to the activation of K+ channels and vasodilator effects of nitric oxide (NO) in renal arterioles. Addition of an NO donor to the P4504A2 enzyme that produces 20-HETE increased visible light absorbance at 440 nm indicating that NO binds to heme in this enzyme. NO donors also dose-dependently inhibited the formation of 20-HETE in microsomes prepared from renal arterioles. In patch-clamp experiments, NO donors increased the open-state probability of a voltage-sensitive, large-conductance (195±9 pS) K+ channel recorded with cell-attached patches on renal arteriolar smooth muscle cells. Blockade of guanylyl cyclase with [1H-[1,2,4]Oxadiazolo[4,3-a] quinoxalin-1-one] (ODQ, 10 µmol/L), or cGMP-dependent kinase with 8R,9S,11S-(-)-9-methoxycarbamyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-trizadibenzo-(a,g)-cy-cloocta-(c,d,e)-trinden-1-one (KT-5823) (1 µmol/L) did not alter the effects of NO on this channel. In contrast, inhibition of the formation of 20-HETE with 17-octadecynoic acid (1 µmol/L) activated this channel and masked the response to NO. Preventing the NO-induced reduction in intracellular 20-HETE levels also blocked the effects of NO on this channel. Sodium nitroprusside (SNP) increased the diameter of renal interlobular arteries preconstricted with phenylephrine to 80±4% of control. Blockade of guanylyl cyclase with ODQ (10 µmol/L) attenuated the response to SNP by 26±2%; however, fixing 20-HETE levels at 100 nmol/L reduced the response by 67±8%. Blockade of both pathways eliminated the response to SNP. These results indicate that inhibition of the formation of 20-HETE contributes to the activation of K+ channels and the vasodilator effects of NO in the renal microcirculation.


Key Words: arachidonic acid • cytochrome P450 • renal circulation • vascular smooth muscle




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