Mechanisms whereby glucose deprivation triggers metabolic preconditioning in the isolated rat heart

Transient glucose deprivation of the heart [GLU (-)] confers a precondition ing-like protection against subsequent ischemic/reperfusion (I/R). The mech anisms involved remain unclear. We hypothesized that GLU (-) would induce t he classic ischemic preconditioning activated signaling cascade. Potential metabolic consequences and putative cell signaling events induced by transi ent glucose deprivation were evaluated as candidate mediators of this cardi oprotection. Isolated glucose-perfused rat hearts were subjected to 30 min global ischem ia followed by 30 min reperfusion (index I/R). Cardiac contractile recovery following I/R was used as the functional end-point in these studies. Metab olic preconditioning was stimulated by 15 min GLU (-) followed by 10 min gl ucose repletion prior to the index I/R. The potential metabolic consequence s of GLU (-) were evaluated by using excess octanoate (11 mM OCT Hi) or 11 mM 2-deoxy-D-glucose (2-DG) in place of GLU (-) and by combining GLU (-) wi th fuels known to inhibit glycolysis supply (20 mM pyruvate or 1 mM octanoa te, OCT Lo). The roles of alpha-adrenoceptors, beta-adrenoceptors, adenosin e receptors, protein kinase C (PKC) and mitochondrial K-ATP channels were i nvestigated using inhibitors prazosin (10 mu M), propranolol (10 mu M), 8-( p-sulfophenyl) theophylline, (SPT 100 mu M), chelerythrine (CHEL 10 mu M) a nd 5-hydroxydecanoate (5 HD 100 mu M) respectively. GLU (-) increased mechanical recovery (59.8 +/- 4.0 vs. 32.3 +/- 4.7%; p < 0.01). Protection was abolished by pyruvate 26.6 +/- 3.1; SPT 36.6 +/- 3.0; CHEL 35 +/- 4.8 or 5 HD 23.8 +/- 3.3%. In a separate set of experiments, t he specificity of SPT in this model was tested by preconditioning with aden osine (100 mu M) (34.7 +/- 4 vs. control 16.8 +/- 1.3%, p = 0.01) and block ing this protection with the same dose of SPT (16.3 +/- 1.5%) used in the G LU (-) studies. Protection was unaltered by prazosin (50.2 +/- 3.3%), propr anolol (55.5 +/- 4.0%), or OCT Lo (50.2 +/- 2.5%). Protection was not mimic ked by OCT Hi (35.6 +/- 3.8%) or 2-DG (34 +/- 4.3%). Transient glucose deprivation does not seem to achieve preconditioning-like cardioprotection by decreased glycolysis. Rather, the signal system may in volve enhanced adenosine release, PKC, and activation of the mitochondrial K-ATP channel.