Effects of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism

We investigated the cardiovascular profile of nicorandil, an antianginal agent, in humans. Pharmacologically, nicorandil acts as both an adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channel opener and a nitrate. We examined which of these mechanistic components has a predominant vasodilatory effect at clinical doses. Fourteen patients underwent cardiac catheterization. The effects of the continuous intravenous infusion of nicorandil (12 mg/45 min) were examined in angiographically normal coronary arteries. Coronary vascular resistance was calculated from coronary artery diameter and coronary blood flow velocity measured using an intravascular Doppler catheter. We compared the hemodynamic responses to nicorandil with those to the intracoronary injection of nitroglycerin (250 microg) and papaverine (12 mg). The epicardial coronary arteries responded to nicorandil at the lowest plasma concentration examined (dilation of +14.0 +/- 3.3% at approximately 170 ng/ml), whereas dilation of the coronary resistance arteries (i.e., a decrease in coronary vascular resistance) took place only at higher concentrations (>200 ng/ml). Nitroglycerin caused no further changes in coronary artery diameter or coronary vascular resistance. Papaverine caused no further increase in coronary artery diameter, but markedly decreased coronary vascular resistance (1.6 +/- 0.3 to 0.4 +/- 0.1 mm Hg/ml/min; p < 0.05). Nicorandil significantly decreased pulmonary capillary wedge pressure (i.e., reduced cardiac preload) at a plasma level of >200 ng/ml, but did not change either systemic or pulmonary vascular resistance. Thus nicorandil preferentially dilated epicardial coronary arteries rather than coronary resistance arteries, and had a stronger effect on preload than on afterload. These changes in human coronary hemodynamics suggest that the nitrate actions of nicorandil as a coronary vasodilator predominate over those as a K(ATP) opener.