Ca 2+ ‐sensitizing effect is involved in the positive inotropic effect of troglitazone

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 Ca 2+ handling. 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 Ca 2+ channel antagonist), thapsigargin (Ca 2+ ‐adenosine triphosphatase inhibitor) or ryanodine (ryanodine receptor opener). Radioimmunoassay showed that the cyclic adenosine monophosphate concentration in the left ventricle was not increased by troglitazone. Whole‐cell patch clamp analysis revealed that troglitazone had no effect on inward Ca 2+ currents in cardiomyocytes. In fura‐2 loaded perfused rat hearts, troglitazone exerted its positive inotropic effect without increasing Ca 2+ concentration. These results suggest that neither the inward Ca 2+ currents nor Ca 2+ 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 Ca 2+ . In conclusion, the positive inotropic effect of troglitazone is mediated by a sensitization of Ca 2+ .British Journal of Pharmacology (2001) 133 , 1307–1313; doi: 10.1038/sj.bjp.0704212