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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.

Impaired Inactivation of L-Type Ca2+ Current as a Potential Mechanism for Variable Arrhythmogenic Liability of HERG K+ Channel Blocking Drugs