Long-term infusion of Met5-enkephalin fails to protect murine hearts against ischemia-reperfusion injury.
Recently, we reported that exogenous administration of Met(5)-enkephalin (ME) for 24 h reduces infarct size after ischemia-reperfusion in rabbits. In the present study, we tested whether ME-induced cardioprotection is exhibited in murine hearts and whether chronic infusion of this peptide can render hearts tolerant to ischemia. Barbiturate-anesthetized open-chest mice (C57BL/6J) were subjected to regional myocardial ischemia-reperfusion (45 min of occlusion and 20 min of reperfusion). Mice received saline vehicle or ME for 24 h or 2 wk before undergoing regional myocardial ischemia-reperfusion or for 24 h followed by a 24-h delay before regional myocardial ischemia-reperfusion. Infarct size was measured with propidium iodide and is expressed as a percentage of the area at risk. Infarcts were smaller after infusion of ME for 24 h than with vehicle control: 49.2 +/- 9.0% vs. 22.2 +/- 3.2% (P < 0.01). In contrast, administration of ME for 2 wk failed to elicit cardioprotection: 36.5 +/- 9.1% and 41.4 +/- 8.2% for control and ME, respectively (P = not significant). When a 24-h delay was imposed between the end of drug treatment and the onset of the ischemic insult, cardioprotection was lost: 38.5 +/- 6.1% and 42.8 +/- 6.6% for control and ME, respectively (P = not significant). Chronic sustained exogenous infusion of the endogenously produced opioid peptide ME is associated with loss of the cardioprotection that is observed with 24 h of infusion. Furthermore, in this in vivo murine model, ME failed to induce delayed tolerance to myocardial ischemia-reperfusion.
Kuzume
Koh
K
Research Services, VA Medical Center, 3710 SW US Veterans Hospital Rd., Portland, OR 97239-2999, USA.
Kuzume
Kazuyo
K
Cao
Zhiping
Z
Liu
Lijuan
L
Van Winkle
Donna M
DM
D000818:Animals; D001794:Blood Pressure; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004744:Enkephalin, Methionine / Q000494:pharmacology*; D006339:Heart Rate; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D013618:Tachyphylaxis; D017211:Treatment Failure
D002316:Cardiotonic Agents; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D004744:Enkephalin, Methionine; D000242:Cyclic AMP