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(Hypertension. 1997;29:254.)
© 1997 American Heart Association, Inc.

Arthur C. Corcoran Memorial Lecture

Selective Guanylyl Cyclase Inhibitor Reverses Nitric Oxide-Induced Vasorelaxation

Linda J. Olson; Edward T. Knych, Jr; Thomas C. Herzig; James G. Drewett

From the Department of Pharmacology and Toxicology (L.J.O., J.G.D.), Department of Physiology (T.C.H.), and the Cardiovascular Research Center, Medical College of Wisconsin (Milwaukee); and the Department of Pharmacology, University of Minnesota-Duluth School of Medicine (E.T.K.).

Reprint requests to James G. Drewett, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226-4801

Effects of a novel soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), were characterized on guanylyl cyclase activity in cytosolic fraction of COS-7 cells overexpressing the ₁ and ß₁ subunits of the rat soluble enzyme. ODQ was a noncompetitive inhibitor of soluble guanylyl cyclase with respect to Mn²⁺ or Mn²⁺-GTP and was a mixed competitive/noncompetitive inhibitor with respect to nitric oxide (NO) donation. ODQ (10 µmol/L) reduced deta nonoate-stimulated cGMP production in COS-7 cells overexpressing soluble guanylyl cyclase and in rat aortic vascular smooth muscle cells. ODQ did not inhibit particulate forms of the enzyme rat guanylyl cyclase-A, -B, or -C, did not block NO synthase, and did not auto-oxidize deta nonoate-donated NO in the presence of cells at physiological pH. Therefore, ODQ is a selective inhibitor of soluble guanylyl cyclase. Using ODQ in isolated aortic ring preparations, we tested the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with NO. Phenylephrine (100 nmol/L)-precontracted, isolated rat aortas were relaxed in a concentration-dependent manner by deta nonoate (0.01 to 100 µmol/L) and nitroglycerin (0.01 to 300 µmol/L). ODQ (10 µmol/L) attenuated deta nonoate- and nitroglycerin-mediated relaxation of contracted aortas. ODQ had no effect on natriuretic peptide-, 8-bromo-cGMP-, isoproterenol-, or bimak-alim-mediated aortic relaxation. These results support the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with nitric oxide.

Key Words: cyclic GMP • endothelium-derived relaxing factor • guanylyl cyclase • nitric oxide • nitric oxide synthase • natriuretic peptides • vasodilatation

Abbreviations: 8-bromo-cGMP = 8-bromo-guanosine 3':5'-monophosphate • ANP = type A natriuretic peptide • BNP = type B natriuretic peptide • CNP = type C natriuretic peptide • GC-A, -B, -C = guanylyl cyclase-A, -B, -C • LY83583 = 6-anilino-5,8-quinolinedione • NO(S) = nitric oxide (synthase) • ODQ = 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one • sGC = soluble guanylyl cyclase

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