Impaired Inactivation of L-Type Ca(2+) Current as a Potential Mechanism for Variable Arrhythmogenic Liability of HERG K(+) Channel Blocking Drugs

The proarrhythmic effects of new drugs have been assessed by measuring rapidly activating delayed-rectifier K(+) current (I(Kr)) antagonist potency. However, recent data suggest that even drugs thought to be highly specific I(Kr) blockers can be arrhythmogenic via a separate, time-dependent pathway such as late Na(+) current augmentation. Here, we report a mechanism for a quinolone antibiotic, sparfloxacin-induced action potential duration (APD) prolongation that involves increase in late L-type Ca(2+) current (I(CaL)) caused by a decrease in Ca(2+)-dependent inactivation (CDI). Acute exposure to sparfloxacin, an I(Kr) blocker with prolongation of QT interval and torsades de pointes (TdP) produced a significant APD prolongation in rat ventricular myocytes, which lack I(Kr) due to E4031 pretreatment. Sparfloxacin reduced peak I(CaL) but increased late I(CaL) by slowing its inactivation. In contrast, ketoconazole, an I(Kr) blocker without prolongation of QT interval and TdP produced reduction of both peak and late I(CaL), suggesting the role of increased late I(CaL) in arrhythmogenic effect. Further analysis showed that sparfloxacin reduced CDI. Consistently, replacement of extracellular Ca(2+) with Ba(2+) abolished the sparfloxacin effects on I(CaL). In addition, sparfloxacin modulated I(CaL) in a use-dependent manner. Cardiomyocytes from adult mouse, which is lack of native I(Kr), demonstrated similar increase in late I(CaL) and afterdepolarizations. The present findings show that sparfloxacin can prolong APD by augmenting late I(CaL). Thus, drugs that cause delayed I(CaL) inactivation and I(Kr) blockage may have more adverse effects than those that selectively block I(Kr). This mechanism may explain the reason for discrepancies between clinically reported proarrhythmic effects and I(Kr) antagonist potencies.