Sparfloxacin, a Fluoroquinolone Antibiotic, Slows Inactivation of L-Type Ca2+ Current in Neonatal Rat Ventricular Myocytes

Abstract

Introduction: The proarrhythmic effects of quinolone antibiotics used clinically have been assessed by measuring the IKr antagonist potency. However, the gaps between clinically reported proarrhythmic effects and IKr antagonist potency remain unexplained. We sought to determine the relevance of ICaLin arrhythmogenic effects of one quinolone antibiotic, sparfloxacin (SPX).Methods and Results: In the present study, we investigated possible involvement of ICaL in the SPX-induced APD prolongation in neonatal rat ventricular myocytes using patch clamp technique. In the presence of IKr blocker, E4031, APD prolongation was evident perfused with sparfloxacin at 3 × 10−4 M and stimulated at 2 Hz, indicating the involvement of additional channel in SPX-induced proarrhythmic properties. The APD prolongation was associated with a slowing of inactivation of ICaL. In contrast to SPX, four other quinolones including ciprofloxacin, enoxacin, ofloxacin, and levofloxacin, which are not related to VT, did not affect ICaL. Sparfloxacin increased the inactivation time constants of ICaL in a concentration-dependent manner, resulting larger steady-state currents. Further analysis showed that sparfloxacin reduced Ca2+-dependent component of steady-state inactivation. Consistent with modulation of Ca2+-dependent inactivation (CDI) by sparfloxacin, replacement of extracellular Ca2+ with Ba2+ abolished sparfloxacin action on ICaL inactivation. Use-dependency was measured by applying repetitive voltage pulses at 2 Hz. We found that sparfloxacin modulated Ca2+-dependent inactivation of ICaL in a use-dependent way.Conclusion: The present findings demonstrate the role of ICaLin SPX-induced APD prolongation. We further provide the evidence that SPX modified the shape of ICaL by altering kinetics of Ca2+-dependent inactivation (APD). This study suggests that quinolones causing delay of ICaL inactivation combined with IKr block may have more adverse effects than those with purely selective IKr block.