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

Article

关键词: RAT VENTRICULAR MYOCYTES;    II DIABETES-MELLITUS;    ATRIAL CELLS;    POTASSIUM CURRENTS;    CARDIOMYOPATHY;    CHANNELS;    MUSCLE;    HEART;    VERAPAMIL;    MEMBRANE;   

DOI  :  10.1161/01.CIR.99.22.2942

来源: SCIE

【 摘 要 】

Background-It has been suggested that intracellular Ca2+ 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 Ca2+ currents were examined and compared with classic Ca2+ 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 Ca2+ currents consisted of both T-type (I-Ca,I-T) and L-type (I-Ca,I-L) Ca2+ currents. Troglitazone effectively reduced the amplitude of I-Ca,I-L in a concentration-dependent manner. Troglitazone also suppressed I-Ca,I-T but the effect of troglitazone on I-Ca,I-L was less potent than that on I-Ca,I-L. The current-voltage relationships for I-Ca,I-L and the reversal potential fur I-Ca,I-L were not altered by troglitazone. The half-maximal inhibitory concentration of troglitazone on I-Ca,I-L measured at a holding potential of -40 mV was 6.3 mu mol/L, and 30 mu mol/L troglitazone almost completely inhibited I-Ca,I-L Troglitazone 10 mu mol/L did not affect the time courses for inactivation of I-Ca,I-L and inhibited I-Ca,I-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,I-L. Conclusions-These results demonstrate that troglitazone inhibits voltage-dependent Ca2+ 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 Ca2+ overload and subsequent myocardial changes.

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