Abstract

The proarrhythmic effects of new drugs have been assessed by measuring rapidly activating delayed-rectifier K+ current (IKr) antagonist potency. However, recent data suggest that even drugs thought to be highly specific IKr 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 Ca2+ current (ICaL) caused by a decrease in Ca2+-dependent inactivation (CDI). Acute exposure to sparfloxacin, an IKr blocker with prolongation of QT interval and torsades de pointes (TdP) produced a significant APD prolongation in rat ventricular myocytes, which lack IKr due to E4031 pretreatment. Sparfloxacin reduced peak ICaL but increased late ICaL by slowing its inactivation. In contrast, ketoconazole, an IKr blocker without prolongation of QT interval and TdP produced reduction of both peak and late ICaL, suggesting the role of increased late ICaL in arrhythmogenic effect. Further analysis showed that sparfloxacin reduced CDI. Consistently, replacement of extracellular Ca2+ with Ba2+ abolished the sparfloxacin effects on ICaL. In addition, sparfloxacin modulated ICaL in a use-dependent manner. Cardiomyocytes from adult mouse, which is lack of native IKr, demonstrated similar increase in late ICaL and afterdepolarizations. The present findings show that sparfloxacin can prolong APD by augmenting late ICaL. Thus, drugs that cause delayed ICaL inactivation and IKr blockage may have more adverse effects than those that selectively block IKr. This mechanism may explain the reason for discrepancies between clinically reported proarrhythmic effects and IKr antagonist potencies.

Highlights

  • Drug-induced QT interval prolongation and the appearance of torsade de pointes (TdPs) are recognized as potential risks associated with the use of a wide range of noncardiovascular drugs including antibiotics [1,2,3,4]

  • To test the hypothesis that factors other than rapidly activating delayedrectifier K+ current (IKr) modulation play important roles in SPXinduced action potential duration (APD) prolongation, the effects of SPX applied at concentrations between 10 and 300 μM were investigated in 2-week-old rat ventricular myocytes in the presence of E4031, a selective IKr blocker

  • Our data showed that SPX markedly prolonged APD in a concentration-dependent manner in cardiac myocytes that lack IKr, suggesting that SPX can be arrhthmogenic via an IKr-independent pathway

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Summary

Introduction

Drug-induced QT interval prolongation and the appearance of torsade de pointes (TdPs) are recognized as potential risks associated with the use of a wide range of noncardiovascular drugs including antibiotics [1,2,3,4]. The quinolone antibiotic sparfloxacin (SPX) has been withdrawn from U.S drug market, because it was shown to induce QT interval prolongation and ventricular arrhythmia [5, 6]. Another quinolone, grepafloxacin, was withdrawn because it induced TdP, a polymorphic ventricular tachycardia (VT) linked to excessive QT interval prolongation [7]. The antibiotic moxifloxacin blocks IKr but has been associated with drug-induced long QT syndrome (LQT) only very rarely [8, 9]

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