7-benzylidenenaltrexone and Heart-Diseases

The relative roles of free-radical production, mitochondrial ATP-sensitive K+ (mitoKATP) channels and possible receptor cross-talk in both opioid and adenosine A1 receptor (A1AR) mediated protection were assessed in a rat model of myocardial infarction. Sprague-Dawley rats were subjected to 30 min of occlusion and 90 min of reperfusion. The untreated rats exhibited an infarct of 58.8 +/- 2.9% [infarct size (IS)/area at risk (AAR), %] at the end of reperfusion. Pretreatment with either the nonselective opioid receptor agonist morphine or the selective A1AR agonist 2-chloro-cyclopentyladenosine (CCPA) dramatically reduced IS/AAR to 41.1 +/- 2.2% and 37.9 +/- 5.5%, respectively (P < 0.05). Protection afforded by either morphine or CCPA was abolished by the reactive oxygen species scavenger N-(2-mercaptopropionyl)glycine or the mitoKATP channel blocker 5-hydroxydecanoate. Both morphine- and CCPA-mediated protection were attenuated by the selective A1AR antagonist 1,3-dipropyl-8-cyclopentylxanthine and the selective delta1-opioid receptor (DOR) antagonist 7-benzylidenealtrexone. Simultaneous administration of morphine and CCPA failed to enhance the infarct-sparing effect of either agonist alone. These data suggest that both DOR and A1AR-mediated cardioprotection are mitoKATP and reactive oxygen species dependent. Furthermore, these data suggest that there are converging pathways and/or receptor cross-talk between A1AR- and DOR-mediated cardioprotection.

Topics: Adenosine; Analgesics, Opioid; Animals; ATP-Binding Cassette Transporters; Benzylidene Compounds; Free Radicals; Heart Diseases; In Vitro Techniques; KATP Channels; Mitochondria, Heart; Morphine; Myocardial Infarction; Myocardial Reperfusion Injury; Naltrexone; Potassium Channels; Potassium Channels, Inwardly Rectifying; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptor Cross-Talk; Receptors, Opioid, delta; Receptors, Purinergic P1