Faculty Collaboration Database

Selective guanylyl cyclase inhibitor reverses nitric oxide-induced vasorelaxation. Hypertension 1997 Jan;29(1 Pt 2):254-61

Date

01/01/1997

Pubmed ID

9039111

DOI

10.1161/01.hyp.29.1.254

Scopus ID

2-s2.0-0031028506 (requires institutional sign-in at Scopus site)   69 Citations

Abstract

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 alpha 1 and beta 1 subunits of the rat soluble enzyme. ODQ was a noncompetitive inhibitor of soluble guanylyl cyclase with respect to Mn2+ or Mn(2+)-GTP and was a mixed competitive/noncompetitive inhibitor with respect to nitric oxide (NO) donation. ODQ (10 mumol/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 mumol/L) and nitroglycerin (0.01 to 300 mumol/L). ODQ (10 mumol/L) attenuated deta nonoate- and nitroglycerin-mediated relaxation of contracted aortas. ODQ had no effect on natriuretic peptide-, 8-bromo-cGMP-, isoproterenol-, or bimakalim-mediated aortic relaxation. These results support the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with nitric oxide.

Author List

Olson LJ, Knych ET Jr, Herzig TC, Drewett JG

Author

Linda J. Olson PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Aorta
COS Cells
Cyclic GMP
Guanosine Triphosphate
Male
Muscle Relaxation
Muscle, Smooth, Vascular
Nitric Oxide
Nitroglycerin
Nitroso Compounds
Oxadiazoles
Oxidation-Reduction
Phenylephrine
Quinoxalines
Rats
Rats, Sprague-Dawley
Xanthine
Xanthine Oxidase
Xanthines