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

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-NH 2 ([Dmt 1 ]DALDA), that can protect against ischemia-induced myocardial st...

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Bibliographic Details
Published in:American journal of physiology. Heart and circulatory physiology 2002-08, Vol.283 (2), p.H783-H791
Main Authors: Wu, Dunli, Soong, Yi, Zhao, Guo-Min, Szeto, Hazel H
Format: Article
Language:English
Subjects:
Analgesics - metabolism
Analgesics - pharmacology
Animals
Guinea Pigs
In Vitro Techniques
Myocardial Contraction - drug effects
Myocardial Ischemia - physiopathology
Myocardial Reperfusion Injury - physiopathology
Myocardial Stunning - prevention & control
Myocardium - metabolism
Norepinephrine - metabolism
Oligopeptides - metabolism
Oligopeptides - pharmacology
Synaptosomes - metabolism
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Summary: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-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 µM), 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. myocardial ischemia; norepinephrine uptake; µ-opioid; cardiac contractility; norepinephrine transporter
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00193.2002