Cyclic GMP as possible mediator of coronary arterial relaxation by nicorandil (SG-75).

Since nicorandil (SG-75) is a potent vasodilator, has a terminal NO2 group, resembles nitroglycerin in its hemodynamic actions, which are likely to be mediated by cyclic GMP (cGMP), whether or not nicorandil relaxes vascular smooth muscle by a similar mechanism was investigated in isolated circular strips of bovine coronary arteries. It was found that nicorandil at concentrations producing dose-dependent relaxation up to 94% (0.47-473 microM) similar raised cGMP levels in the strips up to 10-fold of the control value, and that this effect preceded the mechanical response. When the breakdown of cGMP was blocked by a predominant inhibitor of cGMP phosphodiesterase, 2-o-propoxyphenyl-8-azapurin-6-one, both actions of nicorandil (cGMP increase and relaxation) were significantly potentiated. Inhibition of cGMP formation by methylene blue and, to a lesser extent, by ferricyanide, which antagonize guanylate cyclase activation by NO-yielding substances, significantly attenuated both actions of nicorandil under study. It was further demonstrated that nicorandil as well as nitroglycerin was a potent stimulator of soluble guanylate cyclase activity from bovine coronary arteries in vitro, an effect that was also susceptible to blockade by methylene blue or ferricyanide. These results indicate that nicorandil relaxes vascular smooth muscle, at least in part, through cGMP.