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Am J Physiol Heart Circ Physiol 283: H783-H791, 2002. First published May 9, 2002; doi:10.1152/ajpheart.00193.2002
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Vol. 283, Issue 2, H783-H791, August 2002

A highly potent peptide analgesic that protects against ischemia-reperfusion-induced myocardial stunning

Dunli Wu, Yi Soong, Guo-Min Zhao, and Hazel H. Szeto

Department of Pharmacology, Joan and Sanford I. Weill Medical College, Cornell University, New York, New York 10021

We recently discovered an opioid peptide analgesic, 2',6'-dimethyltyrosine (Dmt)-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA), that can protect against ischemia-induced myocardial stunning. In buffer-perfused hearts, 30-min global ischemia followed by reperfusion resulted in a significant increase in norepinephrine (NE) overflow immediately upon reperfusion and significant decline in contractile force (45%). Pretreatment with [Dmt1]DALDA before ischemia completely abolished myocardial stunning and significantly reduced NE overflow (68%). In contrast, pretreatment with morphine before ischemia only provided brief protection against myocardial stunning and no reduction in NE overflow. [Dmt1]DALDA inhibited [3H]NE uptake into cardiac synaptosomes in vitro (IC50 = 3.9 µM), whereas morphine had no effect. Surprisingly, protection against myocardial stunning was apparent even when hearts were perfused with [Dmt1]DALDA only upon reperfusion, whereas reperfusion with morphine had no effect. Binding studies with [3H][Dmt1]DALDA revealed no high-affinity specific binding in cardiac membranes, suggesting that the cardioprotective actions of [Dmt1]DALDA are not mediated via opioid receptors. These findings suggest that [Dmt1]DALDA is a potent analgesic that may be useful for myocardial stunning resulting from cardiac interventions or myocardial ischemia.

myocardial ischemia; norepinephrine uptake; µ-opioid; cardiac contractility; norepinephrine transporter


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