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Articles in PresS, published online ahead of print May 7, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00193.2002
Submitted on March 6, 2002
Accepted on April 30, 2002
1 Pharmacology, Weill Medical College of Cornell University, New York, NY, USA
* To whom correspondence should be addressed. E-mail: hhszeto{at}med.cornell.edu.
We recently discovered an opioid peptide analgesic, [Dmt1]DALDA (Dmt-D-Arg-Phe-Lys-NH2; Dmt-2',6'-dimethyltyrosine), 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), while 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.
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