Trimetazidine, administered at the onset of reperfusion, ameliorates myocardial dysfunction and injury by activation of p38 mitogen-activated protein kinase and Akt signaling.
Trimetazidine [1-(2,3,4-trimethoxybenzyl)piperazine; TMZ] is an anti-ischemic cardiac drug; however, its efficacy and mechanism of cardioprotection upon reperfusion are largely unknown. The objective of this study was to determine whether TMZ, given before reperfusion, could attenuate myocardial reperfusion injury. Ischemia/reperfusion (I/R) was induced in rat hearts by ligating the left anterior descending (LAD) coronary artery for 30 min followed by 48 h of reperfusion. TMZ (5 mg/kg b.wt.) was administered 5 min before reperfusion. The study used three experimental groups: control (-I/R; -TMZ), I/R (+I/R; -TMZ), and TMZ (+I/R; +TMZ). Echocardiography and EPR oximetry were used to assess cardiac function and oxygenation, respectively. The ejection fraction, which was significantly depressed in the I/R group (62 +/- 5 versus 84 +/- 3% in control), was restored to 72 +/- 3% in the TMZ group. Myocardial pO2 in the TMZ group returned to baseline levels (approximately 20 mm Hg) within 1 h of reperfusion, whereas the I/R group showed a significant hyperoxygenation even after 48 h of reperfusion. The infarct size was significantly reduced in the TMZ group (26 +/- 3 versus 47 +/- 5% in I/R). TMZ treatment significantly attenuated superoxide levels in the tissue. Tissue homogenates showed a significant increase in p38 and p-Akt and decrease in caspase-3 levels in the TMZ group. In summary, the results demonstrated that TMZ is cardioprotective when administered before reperfusion and that this protection appears to be mediated by activation of p38 mitogen-activated protein kinase and Akt signaling. The study emphasizes the importance of administering TMZ before reflow to prevent reperfusion-mediated cardiac injury and dysfunction.
Khan
Mahmood
M
Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio 43210, USA.
Meduru
Sarath
S
Mostafa
Mahmoud
M
Khan
Saniya
S
Hideg
Kàlmàn
K
Kuppusamy
Periannan
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D003402:Creatine Kinase / Q000097:blood; D004452:Echocardiography; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D009569:Nitric Oxide / Q000032:analysis; D010092:Oximetry; D010100:Oxygen / Q000032:analysis; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000032:analysis; D014292:Trimetazidine / Q000494:pharmacology / Q000627:therapeutic use*; D014665:Vasodilator Agents / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*
D016166:Free Radical Scavengers; D014665:Vasodilator Agents; D013481:Superoxides; D009569:Nitric Oxide; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D003402:Creatine Kinase; D014292:Trimetazidine; D010100:Oxygen