Trimetazidine improved Ca2+ handling in isoprenaline-mediated myocardial injury of rats
Trimetazidine improved Ca2+ handling in isoprenaline-mediated myocardial injury of rats
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DOI：
10.1113/expphysiol.2005.032615
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发表时间：
2006-05-01
影响因子：
2.7
通讯作者：
Zhang, JN
中科院分区：
文献类型：
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作者：
Meng, D;Feng, L;Zhang, JN
细胞内钙稳态失调在介导心肌损伤中起重要作用。我们验证了曲美他嗪(TMZ)治疗可以改善大鼠心肌损伤时细胞内钙离子转运的假说。对照组给予生理盐水10ml·kg~(-1)·d~(-1)，共7天。第二组，异丙肾上腺素(ISO；5 mg kg(-1)day(-1)，S.C.)连续给药2天，造成大鼠急性心肌损伤。第三组：TMZ(10 mg·kg~(-1)·d~(-1)，ip)。于给药前1d开始给药，持续7d(每组7只)。组织病理学评价显示TMZ可预防异丙肾上腺素所致的心肌损伤。与ISO处理组相比，TMZ保留了心肌组织中的ATP水平，降低了丙二醛(MDA)含量。经Fura-2 AM负荷后，ISO处理组大鼠心肌细胞舒张期[Ca~(2+)](I)较对照组显著升高。TMZ可阻止ISO引起的舒张期[Ca~(2+)](I)升高和咖啡因诱导的Ca~(2+)瞬变的抑制。TMZ可逆转ISO组大鼠心肌细胞肌浆网(SR)钙含量和肌浆网(SR)钙-ATPase活性的降低，但对照组、ISO和ISO+7 mZ组大鼠心肌肌浆网(SR)钙-ATPase蛋白水平无明显差异。此外，TMZ还可拮抗ISO引起的心肌细胞膜L钙电流密度的降低。上述结果表明，在异丙肾上腺素所致的大鼠心肌损伤中，TMZ可抑制心肌细胞舒张期[Ca~(2+)](I)的升高，阻止心肌细胞SR~(2+)含量、SR~(2+)-ATPase活性和L钙电流密度的下降。这些钙离子通道的变化可能有助于解释TMZ在心肌损伤中的有利作用。
Dysregulation of intracellular Ca2+ homeostasis plays an important role in mediating myocardial injury. We tested the hypothesis that treatment with trimetazidine (TMZ) would improve intracellular Ca2+ handling in myocardial injury of rats. The control group received saline only (10 ml kg(-1) day(-1), I.P) for 7 days. In a second group, isoprenaline (ISO; 5 mg kg(-1) day(-1), S.C.) was administered to rats for 2 days to induce an acute injury of the myocardium. In a third group, treatment with TMZ (10 mg kg(-1) day(-1), I.P.) was initiated 1 day before ISO administration and continued for 7 days (n = 7 rats in each group). Histopathological evaluation showed that TMZ prevented ISO-induced myocardial damage. TMZ preserved the ATP levels and decreased the maleic dialdehyde (MDA) content in the hearts compared with ISO-treated rats. The diastolic [Ca2+](i) measured by loading with fura-2 AM in isolated cardiomyocytes was increased significantly in ISO-treated rats compared to the control animals. TMZ prevented the rise of diastolic [Ca2+](i) and the depression of caffeine-induced Ca2+ transients caused by ISO administration. The reduction in sarcoplasmic reticulum (SR) Ca2+ content in the heart cells and in cardiac SR Ca2+-ATPase activity in ISO-treated rats was abolished by TMZ, although there were no differences in SR Ca2+-ATPase protein levels between the control, ISO and ISO + 7 mz-treated rats. In addition, TMZ prevented the reduction in sarcolemmal L-type Ca2+ current density in the heart cells induced by ISO treatment. These results demonstrate that the treatment of rats with TMZ inhibited the increase of diastolic [Ca2+](i) and prevented the decrease of SR Ca2+ content, SR Ca2+-ATPase activity and L-type Ca2+ current density in cardiomyocytes in ISO-mediated myocardial injury of rats. These changes in Ca2+ handling could help to explain the favourable action of TMZ in myocardial injury.