Trimetazidine improved Ca2+ handling in isoprenaline-mediated myocardial injury of rats.
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.
Research Institute of Cardiovascular Disease, First Affiliated Hospital, Human Functional Genetics Laboratory of Jiangsu Province of Nanjing Medical University, Nanjing, 210029 [corrected] China. dmeng@sibs.ac.cn
Dan
D
Meng
Lin
L
Feng
Xiang-Jian
XJ
Chen
Di
D
Yang
Ji-Nan
JN
Zhang
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000008:administration & dosage; D004195:Disease Models, Animal; D004338:Drug Combinations; D007545:Isoproterenol; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D014292:Trimetazidine / Q000008:administration & dosage*; D014665:Vasodilator Agents / Q000008:administration & dosage
D002316:Cardiotonic Agents; D004338:Drug Combinations; D014665:Vasodilator Agents; D000255:Adenosine Triphosphate; D007545:Isoproterenol; D014292:Trimetazidine; D002118:Calcium