Ischemic preconditioning and glucose metabolism during low-flow ischemia:: Role of the adenosine A1 receptor

Objective: Glycolysis-from-glucose may be more beneficial than glycogenolysis in protecting hearts against ischemia. We tested the hypothesis that ischemic preconditioning is mediated by increased exogenous glucose use during low-how ischemia, an effect triggered by adenosine A(1) receptor activation. Methods: Langendorff rat hearts were subjected to 25 min low-flow ischemia (0.6 ml/min) and 30 min reperfusion. Prior to underperfusion, hearts (n=6 per group) were subjected to two cycles of either preconditioning ischemia (PC), infusion of the adenosine A(1) agonist 2-chloro-N-6-cyclopentyladenosine (CCPA; 0.25 mu mol/l), or PC in the presence of the adenosine antagonist 8-(p-sulfophenyl)theophylline (SPT: 50 mu mol/l). Glycolysis-from-glucose during underperfusion was measured using D-[2-H-3]glucose. Results: At the end of reperfusion, recovery of rate-force product was enhanced in the PC and CCPA groups (62 and 67% of preischemic value) compared to the ischemic control hearts (IC, 32%; P<0.05), whereas protection was abolished in the SPT hearts (20%: P<0.05 vs. PC). PC improved total glycolysis-from-glucose during underperfusion by 31% (P<0.05 vs. IC); SPT abolished this increase. CCPA reduced total lactate release and glucose uptake during ischemia by 47% and 61%, respectively (P<0.05 vs. IC). Abolishment of the preconditioning-associated increase in glucose uptake during underperfusion, by switching to a low glucose buffer, resulted in a loss of functional protection. Conclusions: This study strongly suggests that increased exogenous glucose utilization during low-flow ischemia mediates ischemic preconditioning without increasing total anaerobic glycolytic flux. Although adenosine A, receptor activation reduces ischemic injury, it does not facilitate the increased glucose uptake observed with ischemic preconditioning, suggesting a different mechanism of protection. (C) 1999 Elsevier Science B.V. All rights reserved.