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

We investigated the cardiovascular profile of nicorandil, an antianginal ag ent, in humans. Pharmacologically, nicorandil acts as both an adenosine tri phosphate (ATP)sensitive K+ (K-ATP) channel opener and a nitrate. We examin ed which of these mechanistic components has a predominant vasodilatory eff ect 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 corona ry blood flow velocity measured using an intravascular Doppler catheter. We compared the hemodynamic responses to nicorandil with those to the intraco ronary injection of nitroglycerin (250 mu g) and papaverine (12 mg). The ep icardial coronary arteries responded to nicorandil at the lowest plasma con centration examined (dilation of +14.0 +/- 3.3% at similar to 170 ng/ml); w hereas dilation of the coronary resistance arteries (i.e., a decrease in co ronary 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 resistan ce (1.6 +/- 0.3 to 0.4 +/- 0.1 mm Hg/ml/min; p < 0.05). Nicorandil signific antly decreased pulmonary capillary wedge pressure (i.e., reduced cardiac p reload) at a plasma level of >200 ng/ml, but did not change either systemic or pulmonary vascular resistance. Thus nicorandil preferentially dilated e picardial coronary arteries rather than coronary resistance arteries, and h ad a stronger effect on preload than on afterload. These changes in human c oronary hemodynamics suggest that the nitrate actions of nicorandil as a co ronary vasodilator predominate over those as a K-ATP opener.