A potent opiate agonist protects against myocardial stunning during myocardial ischemia and reperfusion in rats.
OBJECTIVE
Opioids have a cardioprotective effect during ischemia. Previously, we showed in an ex-vivo model of myocardial ischemia and reperfusion that 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2, a highly potent and long-acting opioid peptide analgesic with fewer side effects than morphine, provides improved cardioprotection compared with morphine. The purpose of this study was to confirm, in an in-vivo model, the cardioprotective effect of 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2.


METHODS
Rats (n=6/group) were randomized to 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 therapy (intravenous 10 nmol bolus 30 min before ligation and 10 nmol/h continuous infusion), morphine (100 nmol bolus and 100 nmol/h infusion), or placebo, and underwent left anterior descending (LAD) ligation for 10 min followed by reperfusion for 30 min. Continuous transesophageal echocardiogram and electrocardiogram were monitored. Fractional shortening and systolic wall thickening of the ischemic area were calculated. Time to recovery of left ventricular function was the duration of time needed for fractional shortening to recover to 90% of baseline following reperfusion. Duration of reperfusion arrhythmia was the time to the cessation of salvo (at least three consecutive premature ventricular contractions (PVCs)) following reperfusion.


RESULTS
Time to recovery of left ventricular function was significantly shorter in the 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 (4.4+/-2.2 min) and morphine groups (6.0+/-2.5 min) than in the controls (10.5+/-2.2 min; p<0.01). The 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 group showed significantly higher fractional shortening and systolic wall thickening of the ischemic area than the control group. Duration of reperfusion arrhythmia was also significantly shorter in the 2',6'-dimethyltyrosine-D-Arg-Phe-Lys-NH2 (2.8+/-1.7 min) and morphine groups (5.8+/-3.9 min) than in the controls (11.8+/-2.0 min; p<0.05).


CONCLUSIONS
2',6'-Dimethyltyrosine-D-Arg-Phe-Lys-NH2 provides a cardioprotective effect against myocardial ischemia and reperfusion in vivo.
Song
Woohyuk
W
Department of Internal Medicine, Weill Medical College of Cornell University, New York 10021, USA.
Shin
Jinho
J
Lee
Jaeung
J
Kim
Hyunjoong
H
Oh
Dongjoo
D
Edelberg
Jay M
JM
Wong
S Chiu
SC
Szeto
Hazel
H
Hong
Mun K
MK
D000818:Animals; D004195:Disease Models, Animal; D004452:Echocardiography; D015428:Myocardial Reperfusion Injury / Q000150:complications*; D017682:Myocardial Stunning / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D009842:Oligopeptides / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists; D013318:Stroke Volume / Q000187:drug effects; D013599:Systole / Q000187:drug effects / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects
C424424:2',6'-dimethyltyrosyl-arginyl-phenylalanyl-lysinamide; D009842:Oligopeptides; D011957:Receptors, Opioid