Preconditioning enhanced glucose uptake is mediated by p38 MAP kinase not by phosphatidylinositol 3-kinase

Ischemia is reported to stimulate glucose uptake, but the signaling pathway s involved are poorly understood. Modulation of glucose transport could be important for the cardioprotective effects of brief intermittent periods of ischemia and reperfusion, termed ischemic preconditioning, Previous work i ndicates that preconditioning reduces production of acid and lactate during subsequent sustained ischemia, consistent with decreased glucose utilizati on, However, there are also data that preconditioning enhances glucose upta ke. The present study examines whether preconditioning alters glucose trans port and whether this is mediated by either phosphatidylinositol 3-kinase ( PI3K) or p38 MAP kinase, Langendorff-perfused rat hearts were preconditione d with 4 cycles of 5 min of ischemia and 5 min of reperfusion, with glucose as substrate. During the last reflow, glucose was replaced with 5 mM aceta te and 5 mM 2-deoxyglucose (2DG), and hexose transport was measured from th e rate of production of 2-deoxyglucose 6-phosphate (2DG6P), using P-31 nucl ear magnetic resonance. Preconditioning stimulated 2DG uptake; after 15 min of perfusion with 2DG, 2DG6P levels were 165% of initial ATP in preconditi oned hearts compared with 96% in control hearts (p < 0.05). Wortmannin, an inhibitor of PI3K, did not block the preconditioning induced stimulation of 2DG6P production, but perfusion with SB202190, an inhibitor of p38 MAP kin ase, did attenuate 2DG6P accumulation (111% of initial ATP, p < 0.05 compar ed with preconditioned hearts), SB202190 had no effect on 2DG6P accumulatio n in nonpreconditioned hearts. Preconditioning stimulation of translocation of GLUT I: to the plasma membrane was not inhibited by wortmannin, The dat a demonstrate that ischemic preconditioning increases hexose transport and that this is mediated by p38 MAP kinase and is PI3K-independent.