Nakajima T, Iwasawa K, Oonuma H, Imuta H, Hazama H, Asano M, Morita T, Nakamura F, Suzuki J, Suzuki S, Kawakami Y, Omata M, Okuda Y
Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Circulation. 1999 Jun 8;99(22):2942-50. doi: 10.1161/01.cir.99.22.2942.
It has been suggested that intracellular Ca2+ overload in cardiac myocytes leads to the development of diabetic cardiomyopathy. Troglitazone, an insulin-sensitizing agent, is a promising therapeutic agent for diabetes and has been shown to prevent diabetes-induced myocardial changes. To elucidate the underlying mechanism of troglitazone action on cardiac myocytes, the effects of troglitazone on voltage-dependent Ca2+ currents were examined and compared with classic Ca2+ antagonists (verapamil and nifedipine).
Whole-cell voltage-clamp techniques were applied in single guinea pig atrial myocytes. Under control conditions with CsCl internal solution, the voltage-dependent Ca2+ currents consisted of both T-type (ICa,T) and L-type (ICa,L) Ca2+ currents. Troglitazone effectively reduced the amplitude of ICa,L in a concentration-dependent manner. Troglitazone also suppressed ICa,T, but the effect of troglitazone on ICa,T was less potent than that on ICa,L. The current-voltage relationships for ICa,L and the reversal potential for ICa,L were not altered by troglitazone. The half-maximal inhibitory concentration of troglitazone on ICa,L measured at a holding potential of -40 mV was 6.3 micromol/L, and 30 micromol/L troglitazone almost completely inhibited ICa,L. Troglitazone 10 micromol/L did not affect the time courses for inactivation of ICa,L and inhibited ICa,L mainly in a use-independent fashion, without shifting the voltage-dependency of inactivation. This effect was different from those of verapamil and nifedipine. Troglitazone also reduced isoproterenol- or cAMP-enhanced ICa,L.
These results demonstrate that troglitazone inhibits voltage-dependent Ca2+ currents (T-type and L-type) and then antagonizes the effects of isoproterenol in cardiac myocytes, thus possibly playing a role in preventing diabetes-induced intracellular Ca2+ overload and subsequent myocardial changes.
有人提出心肌细胞内钙离子超载会导致糖尿病性心肌病的发展。曲格列酮是一种胰岛素增敏剂，是一种很有前景的糖尿病治疗药物，已被证明可预防糖尿病引起的心肌变化。为了阐明曲格列酮对心肌细胞作用的潜在机制，研究了曲格列酮对电压依赖性钙电流的影响，并与经典钙拮抗剂（维拉帕米和硝苯地平）进行了比较。
采用全细胞膜片钳技术记录豚鼠单个心房肌细胞的电流。在使用氯化铯内液的对照条件下，电压依赖性钙电流由T型（ICa,T）和L型（ICa,L）钙电流组成。曲格列酮以浓度依赖性方式有效降低ICa,L的幅度。曲格列酮也抑制ICa,T，但曲格列酮对ICa,T的作用比对ICa,L的作用弱。曲格列酮不改变ICa,L的电流-电压关系和ICa,L的反转电位。在-40 mV的钳制电位下测量，曲格列酮对ICa,L的半数最大抑制浓度为6.3 μmol/L，30 μmol/L曲格列酮几乎完全抑制ICa,L。10 μmol/L曲格列酮不影响ICa,L的失活时间进程，主要以非使用依赖性方式抑制ICa,L，不改变失活的电压依赖性。这种作用与维拉帕米和硝苯地平不同。曲格列酮还降低异丙肾上腺素或环磷酸腺苷增强的ICa,L。
这些结果表明，曲格列酮抑制电压依赖性钙电流（T型和L型），进而拮抗异丙肾上腺素在心肌细胞中的作用，从而可能在预防糖尿病引起的细胞内钙离子超载和随后的心肌变化中发挥作用。
