Mechanisms whereby glucose deprivation triggers metabolic preconditioning in the isolated rat heart.
Transient glucose deprivation of the heart [GLU (-)] confers a preconditioning-like protection against subsequent ischemic/reperfusion (I/R). The mechanisms involved remain unclear. We hypothesized that GLU (-) would induce the classic ischemic preconditioning activated signaling cascade. Potential metabolic consequences and putative cell signaling events induced by transient glucose deprivation were evaluated as candidate mediators of this cardioprotection. Isolated glucose-perfused rat hearts were subjected to 30 min global ischemia followed by 30 min reperfusion (index I/R). Cardiac contractile recovery following I/R was used as the functional end-point in these studies. Metabolic preconditioning was stimulated by 15 min GLU (-) followed by 10 min glucose repletion prior to the index I/R. The potential metabolic consequences 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 (-) with fuels known to inhibit glycolysis supply (20 mM pyruvate or 1 mM octanoate, OCT Lo). The roles of alpha-adrenoceptors, beta-adrenoceptors, adenosine receptors, protein kinase C (PKC) and mitochondrial K(ATP) channels were investigated using inhibitors prazosin (10 microM), propranolol (10 microM), 8-(p-sulfophenyl) theophylline, (SPT 100 microM), chelerythrine (CHEL 10 microM) and 5-hydroxydecanoate (5 HD 100 microM) 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, the specificity of SPT in this model was tested by preconditioning with adenosine (100 microM) (34.7 +/- 4 vs. control 16.8 +/- 1.3%, p = 0.01) and blocking this protection with the same dose of SPT (16.3 +/- 1 .5%) used in the GLU (-) studies. Protection was unaltered by prazosin (50.2 +/- 3.3%), propranolol (55.5 +/- 4.0%), or OCT Lo (50.2 +/- 2.5%). Protection was not mimicked 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 involve enhanced adenosine release, PKC, and activation of the mitochondrial K(ATP) channel.
Awan
M M
MM
MRC/UCT Heart Research Unit of the Interuniversity Cape Heart Group, Cape Heart Centre, University of Cape Town Medical School, South Africa.
Makaula
S
S
Forresti
S
S
Sack
M N
MN
Opie
L H
LH
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000470:Alkaloids; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D053119:Benzophenanthridines; D002210:Caprylates / Q000494:pharmacology; D003652:Decanoic Acids / Q000494:pharmacology; D003847:Deoxyglucose / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000031:analogs & derivatives / Q000378:metabolism*; D006880:Hydroxy Acids / Q000494:pharmacology; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010617:Phenanthridines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D015398:Signal Transduction; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D000470:Alkaloids; D000889:Anti-Arrhythmia Agents; D053119:Benzophenanthridines; D002210:Caprylates; D003652:Decanoic Acids; D004791:Enzyme Inhibitors; D006880:Hydroxy Acids; D010617:Phenanthridines; C052853:5-hydroxydecanoic acid; C031433:8-(4-sulfophenyl)theophylline; D003847:Deoxyglucose; D011433:Propranolol; D013806:Theophylline; C016299:chelerythrine; D005947:Glucose; D011224:Prazosin