Mechanisms of Preventive Effect of Nicorandil on Ischaemia‐Induced Ventricular Tachyarrhythmia in Isolated Arterially Perfused Canine Left Ventricular Wedges

Abstract

Whether nicorandil is effective at preventing ventricular tachyarrhythmia (VT) during acute myocardial ischaemia is still controversial. We examined effects of nicorandil on the induction of VT during acute myocardial ischaemia. Optical action potentials were recorded from the entire transmural wall of arterially perfused canine left ventricular wedges. Ischaemia was produced by arterial occlusion for 20 min. During endocardial pacing, nicorandil shortened mean action potential duration (APD) in the transmural wall before ischaemia and further shortened it during ischaemia without increasing dispersion of APD. HMR1098, a selective blocker of sarcolemmal ATP-sensitive K + channels, inhibited the shortening of APD by nicorandil before and during ischaemia. Ischaemia decreased transmural conduction velocity (CV). Nicorandil partially restored CV to a similar extent in the absence and presence of HMR1098. In contrast, HMR1098 did not suppress the ischaemic conduction slowing in the absence of nicorandil. Nicorandil suppressed the increased dispersion of local CV during ischaemia. Isochrone maps on the initiation of VT showed that reentry in the transmural surface resulted from the excitation of the epicardial region of transmural surface. Nicorandil significantly increased the size of non-excited area in the epicardial region of the transmural wall, thereby significantly reducing the incidence of VT induced during ischaemia. HMR1098 inhibited this effect of nicorandil. These results suggest that nicorandil prevents VT during acute global ischaemia primarily by augmenting the inactivation of epicardial muscle through the activation of sarcolemmal K ATP channels.

Nicorandil ameliorates impulse conduction disturbances during ischemia in isolated arterially perfused canine atria

“…HMR1098 also abolished the protective effect of nicorandil on the conduction failure. In contrast to atria, HMR1098 had no effect on nicorandil-induced attenuation of ischemic conduction slowing in ventricle [9]. These results suggest that the mechanisms of nicorandil-induced protection against ischemic conduction disturbances in atria are different from those in ventricle.…”

“…However, a recent study has demonstrated the different structure of atrial and ventricular sarcolemmal K ATP channels in mice [15]: a sulfonylurea receptor 1 (SUR1) is an essential component of atrial but not ventricular K ATP channels, although SUR2A was expressed in both atrium and ventricle. Our studies demonstrated that nicorandil dosedependently shortened APD in the left ventricle [9] but not in the left atrium before ischemia, suggesting the differences in structure of sarcolemmal K ATP channels between atrium and ventricle in canine. Nevertheless, our results suggest the same mechanism of nicorandilinduced ischemic APD shortening between atria and ventricles.…”

“…Our previous study Table 1 Sinus cycle length (SCL) and action potential duration (APD), and local conduction velocity (CV) before the left atrial ischemia. demonstrated that nicorandil potentiated the ischemia-induced APD shortening in canine ventricle and HMR1098 suppressed the effects [9]. These results suggest that the mechanisms of nicorandil-induced ischemic APD shortening in atria are similar to those in ventricle.…”

“…It also increased the degree of ischemia-induced conduction failure compared with the control even in the presence of nicorandil. Our previous study demonstrated that nicorandil-induced attenuation of ischemic conduction slowing did not depend on the activation of sarcolemmal K ATP channels in canine ventricle [9]. In addition, Jain et al [19] demonstrated that diazoxide, which is thought to selectively activate mitochondrial K ATP channels in cardiac myocytes, delayed the electrical uncoupling of cardiac ventricular myocytes during ischemia.…”

“…In addition, Patel et al [8] showed that nicorandil reduced non-sustained ventricular tachyarrhythmia (VT) in patients with unstable angina. Moreover, we recently demonstrated that nicorandil suppressed the slowing of conduction and the increased dispersion of conduction in ischemic canine ventricles and reduced the induction of VT [9]. However, whether nicorandil has a protective effect on ischemia-induced impulse conduction disturbances in atrium is still uncertain.…”