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

被引:13
作者
Furuse, Y [1 ]
Ogino, K [1 ]
Shimoyama, M [1 ]
Sasaki, N [1 ]
Hisatome, I [1 ]
机构
[1] Tottori Univ, Fac Med, Dept Med, Div Cardiol, Yonago, Tottori 6838504, Japan
关键词
troglitazone; thiazolidinedione; positive inotropic effect; Ca2+-sensitizing effect; cardiac function; heart;
D O I
10.1038/sj.bjp.0704212
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 (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 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 (Ca2+-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+.
引用
收藏
页码:1307 / 1313
页数:7
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