Submitted on March 15, 2004
Accepted on November 13, 2004
Long Term Infusion of Met5-Enkephalin Fails to Protect Murine Hearts Against Ischemia-Reperfusion Injury
Koh Kuzume1, Kazuyo Kuzume1, Zhiping Cao2, Lijuan Liu2, and Donna M Van Winkle3*
1 Department of Research Service, Veterans Affairs Medical Center, Portland, OR, USA
2 Department of Anesthesiology Service, Veterans Affairs Medical Center, Portland, OR, USA
3 Department of Research Service, Veterans Affairs Medical Center, Portland, OR, USA; Department of Anesthesiology Service, Veterans Affairs Medical Center, Portland, OR, USA; Department of Anesthesiology, Oregon Health & Sciences University, Portland, OR, USA
* To whom correspondence should be addressed. E-mail: donna.vanwinkle{at}med.va.gov.
Objective. Recently we reported that 24 hr exogenous administration of Met5-enkephalin (ME) reduces infarct size following ischemia-reperfusion in rabbits. In the current study, we tested if ME-induced cardioprotection is exhibited in murine hearts, and whether chronic infusion of this peptide can render hearts tolerant to ischemia. Methods. Barbiturate-anesthetized open-chest mice (C57BL/6J) were subjected to regional myocardial ischemia-reperfusion (45 min occlusion
and 20 min reperfusion). Mice received saline vehicle or ME for 24 hr or 2 wk before undergoing regional myocardial ischemia-reperfusion, or for 24 hr followed by a 24 hr delay before undergoing regional myocardial ischemia-reperfusion. Infarct size was measured with
propidium iodide and is expressed as a percentage of the area-at-risk. Results. Infusion of ME
for 24 hr resulted in smaller infarcts as compared to vehicle control (49.2 ± 9.0 % control, 22.2 ±3.2 % ME; p<0.01). In contrast, administration of ME for 2 wk failed to elicit cardioprotection (36.5 ± 9.1 % control, 41.4 ± 8.2 % ME; p=NS). When a 24 hr delay was imposed between the end of drug treatment and the onset of the ischemic insult, cardioprotection was lost (38.5 ± 6.1 % control, 42.8 ± 6.6 % ME; p=NS). Conclusion. Chronic sustained exogenous infusion of the endogenously produced opioid peptide, Met5-enkephalin, is associated with loss of the cardioprotection that is observed with 24 hr infusion. Further, in this in vivo murine model, Met5-enkephalin failed to induce delayed tolerance to myocardial ischemia-reperfusion.
