A highly potent peptide analgesic that protects against ischemia-reperfusion-induced myocardial stunning |
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Authors: | Wu Dunli Soong Yi Zhao Guo-Min Szeto Hazel H |
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Institution: | Department of Pharmacology, Joan and Sanford I. Weill Medical College, Cornell University, 1300 York Avenue, New York, NY 10021, USA. |
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Abstract: | We recently discovered an opioid peptide analgesic, 2',6'-dimethyltyrosine (Dmt)-D-Arg-Phe-Lys-NH(2) (Dmt(1)]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 Dmt(1)]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. Dmt(1)]DALDA inhibited (3)H]NE uptake into cardiac synaptosomes in vitro (IC(50) = 3.9 microM), whereas morphine had no effect. Surprisingly, protection against myocardial stunning was apparent even when hearts were perfused with Dmt(1)]DALDA only upon reperfusion, whereas reperfusion with morphine had no effect. Binding studies with (3)H]Dmt(1)]DALDA revealed no high-affinity specific binding in cardiac membranes, suggesting that the cardioprotective actions of Dmt(1)]DALDA are not mediated via opioid receptors. These findings suggest that Dmt(1)]DALDA is a potent analgesic that may be useful for myocardial stunning resulting from cardiac interventions or myocardial ischemia. |
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