Nicorandil as a hybrid between nitrates and potassium channel activators.
Nicorandil, although structurally a nitrate, differs from classic nitrates in several respects. It preferentially dilates resistive vessels. Its effect on venous return in dogs is not unanimously a decrease but rather an increase. In high doses or concentrations it suppresses myocardial contraction and ventricular automaticity, nearly sparing sinoatrial nodal automaticity and atrioventricular nodal conduction. It shortens the effective refractory period of myocardium. These cardiac effects of nicorandil have been explained by its mechanism of action as a potassium (K) channel activator. However, what part of the vascular effects of nicorandil this mechanism is responsible for has not been determined. BRL 34915 and pinacidil, nonnitrate vasodilators with a K-channel activator action, have essentially the same cardiovascular profile as nicorandil in isolated, blood-perfused canine heart preparations. In anesthetized, open-chest dogs the 2 K-channel activators decreased systemic blood pressure and increased venous return and cardiac output without elevating heart rate, unless the cardiodepressant effect emerged. The increase in venous return or cardiac output survived elimination of baroceptor functions. These results taken together with previous results on nicorandil suggest the following: (1) The property of nicorandil as a resistive vessel dilator highly selective for vasculature originates in its mechanism of action as a K-channel activator. The nonunanimous effect of nicorandil on venous return is a result of the opposing actions as a capacitive (action as a nitrate) and a resistive vessel dilator. Nicorandil, with its hybrid nature, is advantageous over specific K-channel activators and classic nitrates in therapeutic implications.
Taira
N
N
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
D000818:Animals; D004285:Dogs; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D005996:Nitroglycerin / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects*; D013268:Stimulation, Chemical; D014665:Vasodilator Agents / Q000494:pharmacology*
D015221:Potassium Channels; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; D005996:Nitroglycerin