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Vol. 292, Issue 2, 737-742, February 2000

Differential Sensitivity among Nitric Oxide Donors toward ODQ-Mediated Inhibition of Vascular Relaxation1

Chih-Ming Leo Tseng2 4, Mohammad A. Tabrizi-Fard3 4 and Ho-Leung Fung

Department of Pharmaceutics, School of Pharmacy, University at Buffalo, State University of New York, Buffalo, New York.

Nitric oxide (NO) donors are believed to exert their vasodilatory action through the activation of soluble guanylate cyclase (sGC), the heme site of which can be specifically inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). We examined the vascular relaxation of the rat aorta mediated by eight different NO donors in the presence of ODQ (0.1, 1, or 10 µM), and demonstrated that these NO donors displayed different sensitivities toward ODQ inhibition (ANOVA, P < .05). Among the NO donors studied, S-nitrosothiols such as S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione exhibited partial resistance toward ODQ inhibition at 0.1 µM ODQ, whereas nitroglycerin (NTG) showed nearly complete inhibition at this concentration of ODQ. Three NO donors representing increasing sensitivity toward ODQ inhibition, SNAP < sodium nitroprusside (SNP) < NTG, were chosen for additional mechanistic studies. ODQ (1 µM) inhibition of vascular relaxation by SNAP and SNP, but not that by NTG, was partially reversed by a sulfhydryl donor, N-acetylpenicillamine (100 µM), and by a phosphodiesterase inhibitor, zaprinast (10 µM), specific for cGMP. Our results strongly indicate that the vascular relaxation mechanism(s) of NO donors is not identical for each. In the rat aorta, NTG appeared to exhibit its vasodilatory effect exclusively through activation of the heme site of sGC. On the other hand, in the intact vascular tissue, SNAP and SNP could bring about vasodilation through a secondary pathway. These results are consistent with the view that SNAP and SNP, but not NTG, can induce vascular relaxation additionally through the activation of the sulfhydryl site of sGC.

1 This work was supported in part by National Institutes of Health Grant HL22273.

2 Current address: Genetics Institute, One Burtt Rd., Andover, MA 01810.

3 Current address: Coulter Pharmaceutical, 600 Gateway Blvd., South San Francisco, CA 94080.

4 Contributed equally to this work.

0022-3565/00/2922-0737$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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