Clotrimazole inhibits the recombinant human cardiac L-type Ca2+channel α1Csubunit

Open Access
Publisher Website
Google Scholar
Abstract
Clotrimazole (CLT) is an antimycotic agent with a potential role in the treatment of cancer. Whole‐cell patch clamp recordings and Fura‐2 AM fluorescence measurements were used to investigate the inhibition by CLT of recombinant human cardiac L‐type Ca2+ channel α1C subunits, stably expressed in human embryonic kidney (HEK 293) cells. CLT (100 nmol l−1 to 25 μmol l−1) reduced Ca2+ channel currents in a concentration‐dependent manner. Inhibition was neither use‐ or voltage‐dependent. The effects of CLT were rapid and maximal effects were attained within 3 min. Application of CLT also caused an acceleration of apparent Ca2+ channel current inactivation. Basal current density and the degree of inhibition due to CLT were not significantly altered by pretreating cells with 3 mmol l−1 1‐aminobenzotriazole for 1 h, or by dialysing cells for 10 min with 2 mmol l−1 α‐napthoflavone via the patch pipette, suggesting that the inhibitory action of CLT was not due to inhibition of cytochrome P‐450. CLT (10 μmol l−1) did not influence [Ca2+]i, as determined by Fura‐2 AM fluorescence measurements. Dialysing cells for 10 min with the non‐specific serine/threonine kinase inhibitor H‐7 (10 μmol l−1) was without effect on basal current density or on the inhibitory response to 10 μmol l−1 CLT, indicating that CLT is not acting via an indirect effect on these kinases. These data suggest that CLT exerts a direct blocking effect on the α1C subunit at therapeutic concentrations. This effect may explain the abbreviation of the action potential duration by CLT observed in cardiac myocytes. British Journal of Pharmacology (2000) 129, 547–554; doi:10.1038/sj.bjp.0703106

This publication has 41 references indexed in Scilit: