Differential sensitivity among nitric oxide donors toward ODQ-mediated inhibition of vascular relaxation

Nitric oxide (NO) donors are believed to exert their vasodilatory action th rough the activation of soluble guanylate cyclase (sGC), the heme site of w hich 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 mu M), and demonstrated that these NO donors displayed different sensitivities tow ard ODQ inhibition (ANOVA, P < .05). Among the NO donors studied, S-nitroso thiols such as S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathi one exhibited partial resistance toward ODQ inhibition at 0.1 mM ODQ, where as nitroglycerin (NTG) showed nearly complete inhibition at this concentrat ion of ODQ. Three NO donors representing increasing sensitivity toward ODQ inhibition, SNAP, sodium nitroprusside (SNP), NTG, were chosen for addition al mechanistic studies. ODQ (1 mu M) inhibition of vascular relaxation by S NAP and SNP, but not that by NTG, was partially reversed by a sulfhydryl do nor, N-acetylpenicillamine (100 mu M), and by a phosphodiesterase inhibitor , zaprinast (10 mu M), specific for cGMP. Our results strongly indicate tha t the vascular relaxation mechanism(s) of NO donors is not identical for ea ch. In the rat aorta, NTG appeared to exhibit its vasodilatory effect exclu sively through activation of the heme site of sGC. On the other hand, in th e intact vascular tissue, SNAP and SNP could bring about vasodilation throu gh a secondary pathway. These results are consistent with the view that SNA P and SNP, but not NTG, can induce vascular relaxation additionally through the activation of the sulfhydryl site of sGC.