TY - JOUR T1 - Trimetazidine, Administered at the Onset of Reperfusion, Ameliorates Myocardial Dysfunction and Injury by Activation of p38 Mitogen-Activated Protein Kinase and Akt Signaling JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 421 LP - 429 DO - 10.1124/jpet.109.165175 VL - 333 IS - 2 AU - Mahmood Khan AU - Sarath Meduru AU - Mahmoud Mostafa AU - Saniya Khan AU - Kàlmàn Hideg AU - Periannan Kuppusamy Y1 - 2010/05/01 UR - http://jpet.aspetjournals.org/content/333/2/421.abstract N2 - 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 (∼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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics ER -