Troglitazone inhibits voltage-dependent calcium currents in guinea pig cardiac myocytes.

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Abstract
Background —It has been suggested that intracellular Ca 2+ overload in cardiac myocytes leads to the development of diabetic cardiomyopathy. Troglitazone, an insulin-sensitizing agent, is a promising therapeutic agent for diabetes and has been shown to prevent diabetes-induced myocardial changes. To elucidate the underlying mechanism of troglitazone action on cardiac myocytes, the effects of troglitazone on voltage-dependent Ca 2+ currents were examined and compared with classic Ca 2+ antagonists (verapamil and nifedipine). Methods and Results —Whole-cell voltage-clamp techniques were applied in single guinea pig atrial myocytes. Under control conditions with CsCl internal solution, the voltage-dependent Ca 2+ currents consisted of both T-type ( I Ca,T ) and L-type ( I Ca,L ) Ca 2+ currents. Troglitazone effectively reduced the amplitude of I Ca,L in a concentration-dependent manner. Troglitazone also suppressed I Ca,T , but the effect of troglitazone on I Ca,T was less potent than that on I Ca,L . The current-voltage relationships for I Ca,L and the reversal potential for I Ca,L were not altered by troglitazone. The half-maximal inhibitory concentration of troglitazone on I Ca,L measured at a holding potential of −40 mV was 6.3 μmol/L, and 30 μmol/L troglitazone almost completely inhibited I Ca,L . Troglitazone 10 μmol/L did not affect the time courses for inactivation of I Ca,L and inhibited I Ca,L mainly in a use-independent fashion, without shifting the voltage-dependency of inactivation. This effect was different from those of verapamil and nifedipine. Troglitazone also reduced isoproterenol- or cAMP-enhanced I Ca,L . Conclusions —These results demonstrate that troglitazone inhibits voltage-dependent Ca 2+ currents (T-type and L-type) and then antagonizes the effects of isoproterenol in cardiac myocytes, thus possibly playing a role in preventing diabetes-induced intracellular Ca 2+ overload and subsequent myocardial changes.