title: Ischemic preconditioning targets the reperfusion phase.
abstract: Emerging studies suggest that signaling during the myocardial reperfusion phase contributes to ischemic preconditioning (IPC). Whether the activation of PKC, the opening of the mKATP channel, redox signaling and transient acidosis specifically at the time of myocardial reperfusion are required to mediate IPC-induced protection is not known. Langendorff-perfused rat hearts were subjected to 35 min ischemia followed by 120 min reperfusion at the end of which infarct size was determined by tetrazolium staining. Control and IPC-treated hearts were randomized to receive for the first 15 min of reperfusion: (1) DMSO (0.02%) vehicle control; (2) chelerythrine (10 micromol/l), a PKC antagonist; (3) 5 hydroxydecanoate (5- HD,100 micromol/l), a mKATP channel blocker; (4) N-mercaptopropionylglycine (MPG,1 mmol/l), a reactive oxygen species scavenger; (5) NaHCO3 (pH 7.6), to counteract any acidosis. Interestingly, all four agents given at the time of myocardial reperfusion abolished the infarct reduction elicited by IPC (N>6/group): (1) DMSO at reperfusion: 49.3+/-3.6% in control versus 21.0+/-3.6% with IPC:P<0.05; (2) chelerythrine at reperfusion: 57.1+/-2.5% in control versus 60.1+/-3.3% with IPC:P=NS; (3) 5-HD at reperfusion: 53.4+/-6.5 % in control versus 42.6+/-4.4% with IPC:P=NS; (4) MPG at reperfusion: 55.3+/-4.6% in control versus 43.9+/-5.2% with IPC:P=NS; (5) NaHCO3 at reperfusion 53.4+/-2.5% in control versus 59.0+/-3.3% with IPC:P=NS. In conclusion, we report for the first time that PKC activation, mKATP channel opening, redox signaling and a low pH at the time of myocardial reperfusion are required to mediate the cardioprotection elicited by ischemic preconditioning.
authors.affiliation: The Hatter Cardiovascular Institute, University College London Hospital and Medical School, 67 Chenies Mews, London, WC1E 6HX, UK.
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Hausenloy
authors.forename: Abigail M
authors.initials: AM
authors.lastname: Wynne
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D053119:Benzophenanthridines / Q000494:pharmacology; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism* / Q000517:prevention & control*; D015425:Myocardial Reperfusion; D010084:Oxidation-Reduction; D015221:Potassium Channels / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; C016299:chelerythrine; D011493:Protein Kinase C