Cyclic GMP in nicorandil-induced vasodilatation and tolerance development

Nicorandil (SG-75) is a new organic nitrate with pronounced vasodilator properties. We studied whether nicorandil, in analogy to other nitrovasodilatators, exerted its relaxing effects on vascular smooth muscle by stimulating guanylate cyclase, and whether this effect was susceptible to tolerance development. Dose-response curves for the relaxing and cyclic guanosine monophosphate (cGMP) increasing effects of nicorandil were obtained in isolated strips of bovine coronary arteries and compared with those of other nitrovasodilatators. It was found that nicorandil dose-dependently relaxed the strips precontracted with 26.7 mM K+ and that this effect was closely associated with increases in cGMP levels (measured by RIA under various conditions). The correlation between relaxation and rises in cGMP was steeper than with other nitrovasodilatators, suggesting that nicorandil, in addition to its cGMP-mediated effect, also relaxed vascular smooth muscle by a cGMP independent mechanism. In contrast to nitroglycerin (NG), nicorandil caused little development of tolerance or cross-tolerance toward ISDN or IS-5-MN when tested after preincubation of the strips toward the respective substance. Pretreatment with N-acetylcysteine during the preincubation period prevented tolerance towards nicorandil. The results indicate that the relaxant effects of nicorandil consist of a larger cGMP-mediated component and a smaller one which is independent of this nucleotide.