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opioid agonist fentanyl isothiocyanate via the phosphatidylinositol-3 kinase pathway
1 Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: ggross{at}mcw.edu.
Selective 
opioid agonists produce delayed cardioprotection that lasts for 24-48 hours in rats, however, the maximum length of the cardioprotective window is unclear. In this study, we attempted to prolong the cardioprotective window by 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(10µg/kg) 10 minutes before subjecting hearts to 30 minutes of ischemia and 2 hours of reperfusion followed by infarct size(IS) assessment(Mean±SEM%, *=P<0.01 or +=P<0.001). Acute FIT administration reduced IS when given before ischemia, 5 minutes before reperfusion or 10 seconds after reperfusion compared to control(41.7±1.1+,45.9±2.0*,45.5±2.8*,vs.60.0±1.2%, respectively). IS reduction also occurred following a single dose of FIT at 48, 72, 96 and 120 hours after administration versus control(45.4±1.6*,42.4±3.6+,28.6±3.7+,46.2±1.8*,vs.58.8±1.5%, respectively), with the maximum effect observed at 96 hours. FIT-induced IS reduction at 96 hours was completely abolished when the irreversible PI3k inhibitor, wortmannin(WORT, 15µg/kg) was given prior to FIT during the trigger phase, however, the effect was only partially abrogated when WORT was given 96 hours later(60.2±1.1,45.5±0.5*%, respectively). 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.
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