Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization

Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization

Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of Ca²⁺ channel current (<i>I</i>_Ca) might increase the risk of arrhythmia. In this study we investigated the electrophysiologicaleffects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated K⁺ channel currents (<i>I</i>_Kr, <i>I</i>_Ks) and voltage-gated Na+ channel current (<i>I</i>_Na). The concentration-dependent inhibition of Ca²⁺ channel currents (<i>I</i>_Ca) was examined in rat cardiomyocytes; these CCBs have similar potency on <i>I</i>_Ca channel blocking with IC₅₀ (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both APD₅₀ and APD₉₀ already at 1 μM whereas NIC and AML shortened APD₅₀ but not APD₉₀ up to 30 μM. According to ion channel studies, NIC and AML concentration-dependently inhibited <i>I</i>_Kr and <i>I</i>_Ks while ISR had only partial inhibitory effects (&lt;50% at 30 μM). Inhibition of <i>I</i>_Na was similarly observed in the three CCBs. Since the <i>I</i>_Kr and <i>I</i>_Ks mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of <i>I</i>_Ca.