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Extending the cardioprotective window using a novel -opioid agonist fentanyl isothiocyanate via the PI3-kinase pathway

Medical College of Wisconsin, Department of Pharmacology and Toxicology, Milwaukee, Wisconsin

Submitted 2 September 2004 ; accepted in final form 7 January 2005

Selective -opioid agonists produce delayed cardioprotection that lasts for 24–48 h in rats; however, the maximum length of the cardioprotective window is unclear. In this study, we attempted to prolong the cardioprotective window using a unique -opioid agonist, fentanyl isothiocyanate (FIT), which binds irreversibly to the -receptor, and determined the role of the phosphatidylinositol 3-kinase (PI3K) pathway as a trigger or end effector of FIT-induced cardioprotection. Initially, male rats were administered FIT (10 µg/kg) 10 min before hearts were subjected to 30 min of ischemia and 2 h of reperfusion followed by infarct size (IS) assessment. Acute FIT administration reduced IS when given before ischemia, 5 min before reperfusion, or 10 s after reperfusion compared with control. IS reduction also occurred following a single dose of FIT at 48, 72, 96, and 120 h after administration vs. control, with the maximum effect observed at 96 h. FIT-induced IS reduction at 96 h was completely abolished when the irreversible PI3K inhibitor wortmannin (15 µg/kg) was given before FIT during the trigger phase; however, the effect was only partially abrogated when wortmannin was given 96 h later. These data suggest that FIT has a prolonged cardioprotective window greater than that of any previously described cardioprotective agent that requires PI3K primarily in the trigger phase but also partially, as a mediator or end effector.

delayed cardioprotection; phosphatidylinositol 3-kinase; opioids; BW373U86; postconditioning

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