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1 Pharmacology, University of Alberta, Edmonton, Canada
2 Anesthesiology and Pain Medicine, University of Alberta, Edmonton, Canada
3 Pediatrics, University of Alberta, Edmonton, Canada
* To whom correspondence should be addressed. E-mail: sandy.clanachan{at}ualberta.ca.
p38 MAPK and 5'-AMP activated protein kinase (AMPK) are activated by metabolic stresses and are implicated in the regulation of glucose utilization, and ischemia-reperfusion (IR) injury. This study tested the hypothesis that inhibition of p38 MAPK restores the cardioprotective effects of adenosine in stressed hearts by preventing activation of AMPK and the uncoupling of glycolysis from glucose oxidation. Working rat hearts were perfused with Krebs solution (1.2 mM palmitate, 11 mM [3H/14C]glucose and 100 mU/L insulin). Hearts were stressed by transient antecedent IR (2 X 10 min I / 5 min R), prior to severe IR (30 min I / 30 min R). Hearts were treated with vehicle, p38 MAPK inhibitor (SB202190, 10 -µM), adenosine (500 -µM), or their combination prior to severe IR. Following severe IR, the phosphorylation (arbitrary density units) of p38 MAPK and AMPK, rates of glucose metabolism (-µmol/g dry wt/min) and recovery of LV work (Joules) were similar in vehicle-, SB202190- and adenosine-treated hearts. Treatment with SB202190+adenosine versus adenosine alone decreased p38 MAPK (0.03±0.01, n=3 vs 0.48±0.10, n=3, P<0.05) and AMPK (0.00±0.00, n=3 vs 0.26±0.08, n=3 P<0.05) phosphorylation. This was accompanied by attenuated rates of glycolysis (1.51±0.40, n=7 vs 3.95±0.65, n=7, P<0.05), and H+ production (2.12±0.76, n=7 vs 6.96±1.48, n=7, P<0.05), increased glycogen synthesis (1.91±0.25, n=6 vs, 0.27±0.28, n=6, P<0.05), and improved recovery of LV work (0.81±0.08, n=7 vs 0.30±15, n=8, P<0.05). These data indicate that inhibition of p38 MAPK abolishes subsequent phosphorylation of AMPK, and improves the coupling of glucose metabolism, thereby restoring adenosine-induced cardioprotection.
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