Ca2+-sensitizing effect is involved in the positive inotropic effect of troglitazone

1 Troglitazone, an insulin sensitizing agent, has a direct positive inotrop ic effect. However, the mechanism of this effect remains unclear, Thus, we examined the inotropic effect of troglitazone while focusing on intracellul ar Ca2+ handling. 2 Troglitazone significantly increased peak isovolumic left ventricular pre ssure (LVPmax), 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 fl ow and heart rate. This inotropic effect of troglitazone was not inhibited by pretreatment with carbachol (muscarine receptor agonist), H89 (protein k inase A inhibitor), U73122 (phospholipase C inhibitor), H7 (protein kinase C inhibitor), verapamil (L-type Ca2+ channel antagonist), thapsigargin (Ca2 +-adenosine triphosphatase inhibitor) or ryanodine (ryanodine receptor open er). 3 Radioimmunoassay showed that the cyclic adenosine monophosphate concentra tion 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 i notropic effect without increasing Ca2+ concentration. 6 These results suggest that neither the inward Ca2+ currents nor Ca2+ hand ling in the sarcoplasmic reticulum was involved in the inotropic effect of troglitazone. Furthermore, troglitazone exerted its positive inotropic effe ct without affecting the intracellular concentration of Ca2+. 7 In conclusion, the positive inotropic effect of troglitazone is mediated by a sensitization of Ca2+.