Ca(2+)-sensitizing effect is involved in the positive inotropic effect of troglitazone

1. Troglitazone, an insulin sensitizing agent, has a direct positive inotropic effect. However, the mechanism of this effect remains unclear. Thus, we examined the inotropic effect of troglitazone while focusing on intracellular Ca2+ handling. 2. Troglitazone significantly increased peak isovolumic left ventricular pressure (LVP(max)), peak rate of rise of LVP (dP/dt(max)), peak rate of fall of LVP (dP/dt(min)) in isolated rat hearts perfused at a constant coronary flow and heart rate. This inotropic effect of troglitazone was not inhibited by pretreatment with carbachol (muscarine receptor agonist), H89 (protein kinase A inhibitor), U73122 (phospholipase C inhibitor), H7 (protein kinase C inhibitor), verapamil (L-type Ca2+ channel antagonist), thapsigargin (Ca(2+)-adenosine triphosphatase inhibitor) or ryanodine (ryanodine receptor opener). 3. Radioimmunoassay showed that the cyclic adenosine monophosphate concentration in the left ventricle was not increased by troglitazone. 4. Whole-cell patch clamp analysis revealed that troglitazone had no effect on inward Ca2+ currents in cardiomyocytes. 5. In fura-2 loaded perfused rat hearts, troglitazone exerted its positive inotropic effect without increasing Ca2+ concentration. 6. These results suggest that neither the inward Ca2+ currents nor Ca2+ handling in the sarcoplasmic reticulum was involved in the inotropic effect of troglitazone. Furthermore, troglitazone exerted its positive inotropic effect without affecting the intracellular concentration of Ca2+. 7. In conclusion, the positive inotropic effect of troglitazone is mediated by a sensitization of Ca2+.