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+.
Furuse
Y
Y
Division of Cardiology, Department of Medicine, Faculty of Medicine, Tottori University, 36 - 1 Nishi-machi, Yonago, 683 - 8504, Japan.
Ogino
K
K
Shimoyama
M
M
Sasaki
N
N
Hisatome
I
I
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D000077288:Troglitazone; D017725:Ventricular Pressure / Q000187:drug effects*
D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D002839:Chromans; D013844:Thiazoles; D045162:Thiazolidinediones; D012433:Ryanodine; D019284:Thapsigargin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000077288:Troglitazone; D007545:Isoproterenol; D002118:Calcium