Effects of labedipinedilol-A, third-generation dihydropyridine-type calcium blocker, on ouabain-induced arrhythmia

Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist with α/β-adrenoceptor blocking properties, has been reported to produce a cardioprotective effect against ischemia reperfusion injury in rats. We investigated the protective effects of labedipinedilol-A on ouabain-induced tonotropy and arrhythmias in isolated whole atria, and using patch-clamp techniques to study the underlying mechanism of its antiarrhythmic activity on isolated cardiac myocytes. Labedipinedilol-A (10 μM) suppressed the tonotropic effect of ouabain significantly and prolonged the onset time of extra-systole (arrhythmia) induced by ouabain in isolate atria. In the voltage-clamp study, labedipinedilol-A (1-100 μM) reduced the peak amplitude of sodium inward current (I_Na) and L-type calcium current (I _Ca-L), and shifted the current-voltage (I-V) curve upward in a concentration-dependent manner. In contrast, the addition of labedipinedilol-A increased transient outward potassium current (I_to) and inward rectifier potassium current (I_K1) significantly. Labedipinedilol-A (10 μM) also effectively depressed the isoproterenol-induced increase in the Ca²⁺ current. These results show that labedipinedilol-A blocks I _Ca-L and I_Na, and increases I_to and I _K1. These findings indicate that labedipinedilol-A produces direct cardiac action, probably due to the inhibition of cardiac Na⁺ and Ca²⁺ channels. Our results suggest that labedipinedilol-A may reduce the membrane conduction through inhibition of ionic channels which decrease ouabain-induced arrhythmia.