RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 421
OP 429
DO 10.1124/jpet.109.165175
VO 333
IS 2
A1 Mahmood Khan
A1 Sarath Meduru
A1 Mahmoud Mostafa
A1 Saniya Khan
A1 Kàlmàn Hideg
A1 Periannan Kuppusamy
YR 2010
UL http://jpet.aspetjournals.org/content/333/2/421.abstract
AB 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