Effects of the antifungal antibiotic clotrimazole on human cardiac repolarization potassium currents

Abstract

1. The antifungal antibiotic clotrimazole (CLT) shows therapeutic effects on cancer, sickle cell disease, malaria, etc. by inhibiting membrane intermediate-conductance Ca 2+-activated K + channels (IK Ca). However, it is unclear whether this drug would affect human cardiac K + currents. The present study was therefore designed to investigate the effects of CLT on transient outward K + current (I tol), and ultra-rapid delayed rectifier K + current (I Kur) in isolated human atrial myocytes, and cloned hERG channel current (I hERG) and recombinant human cardiac KCNQ1/KCNE1 channel current (I Ks) expressed in HEK 293 cells. 2. It was found that CLT inhibited I tol with an IC 50 of 29.5 μM, accelerated I tol inactivation, and decreased recovery of I tol from inactivation. In addition, CLT inhibited human atrial I Kur in a concentration-dependent manner (IC 50 = 7.6 μM). 3. CLT substantially suppressed I hERG (IC 50 = 3.6 μM), and negatively shifted the activation conductance of IhERG- Moreover, CLT inhibited I Ks (IC 50= 15.1 μM), and positively shifted the activation conductance of the current. 4. These results indicate that the antifungal antibiotic CLT substantially inhibits human cardiac repolarization K + currents including I tol, I Kur, I hERG, and I Ks. However, caution is recommended when correlating the observed in vitro effects on cardiac ion currents to the clinical relevance. © 2006 Nature Publishing Group All rights reserved.