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 $Ca^{2+}$ channel current ($I_{Ca}$) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated $K^+$ channel currents ($I_{Kr}$, $I_{Ks}$) and voltage-gated $Na^+$ channel current ($I_{Na}$). The concentration-dependent inhibition of $Ca^{2+}$ channel currents ($I_{Ca}$) was examined in rat cardiomyocytes; these CCBs have similar potency on $I_{Ca}$ channel blocking with $IC_{50}$ (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 $APD_{50}$ and $APD_{90}$ already at $1{\mu}M$ whereas NIC and AML shortened $APD_{50}$ but not $APD_{90}$ up to $30{\mu}M$. According to ion channel studies, NIC and AML concentration-dependently inhibited $I_{Kr}$ and $I_{Ks}$ while ISR had only partial inhibitory effects (<50% at $30{\mu}M$). Inhibition of $I_{Na}$ was similarly observed in the three CCBs. Since the $I_{Kr}$ and $I_{Ks}$ mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of $I_{Ca}$.