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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
4 Dept of Pharmacology, University of Alberta, Edmonton, Canada
* To whom correspondence should be addressed. E-mail: sandy.clanachan{at}ualberta.ca.
Adenosine-induced acceleration of glycolysis in hearts stressed by transient ischemia is accompanied by suppression of glycogen synthesis, and by increases in activity of 5'-AMP activated protein kinase (AMPK). As p38 mitogen activated protein kinase (MAPK) may regulate glucose metabolism and may be activated downstream of AMPK, this study determined the effects of the p38 MAPK inhibitors, SB202190 and SB203580, on adenosine-induced alterations in glucose utilization and AMPK activity. Studies were performed in working rat hearts perfused aerobically following stressing by transient ischemia (2x10 min ischemia followed by 5 min reperfusion). Phosphorylation of AMPK and p38 MAPK were each increased 4-fold by adenosine, and these effects were inhibited by either SB202190 or SB203580. Neither of these inhibitors directly affected AMPK activity. Attenuation of the adenosine-induced increase in AMPK and p38 MAPK phosphorylation by SB202190 and SB203580, occurred independent of any change in tissue ATP/AMP ratio, did not alter glucose uptake, but was accompanied by an increase in glycogen synthesis and glycogen content, and by inhibition of glycolysis and proton production. There was a significant inverse correlation between the rate of glycogen synthesis and AMPK activity and between AMPK activity and glycogen content. These data demonstrate that AMPK is likely downstream of p38 MAPK in mediating the effects of adenosine on glucose utilization in hearts stressed by transient ischemia. The ability of p38 MAPK inhibitors to relieve the inhibition of glycogen synthesis and to inhibit glycolysis and proton production suggests that these agents may restore adenosine-induced cardioprotection in stressed hearts.
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