Extending the cardioprotective window using a novel delta-opioid agonist fentanyl isothiocyanate via the PI3-kinase pathway.
Selective delta-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 delta-opioid agonist, fentanyl isothiocyanate (FIT), which binds irreversibly to the delta-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 microg/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 microg/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.
Gross
Eric R
ER
Medical College of Wisconsin, Dept. of Pharmacology and Toxicology, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA. ggross@mcw.edu
Peart
Jason N
JN
Hsu
Anna K
AK
Auchampach
John A
JA
Gross
Garrett J
GJ
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006339:Heart Rate; D006439:Hemodynamics; D019194:Ischemic Preconditioning / Q000379:methods*; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*
D000701:Analgesics, Opioid; D017879:Isothiocyanates; D017465:Receptors, Opioid, delta; C037091:fentanyl isothiocyanate; D019869:Phosphatidylinositol 3-Kinases; D005283:Fentanyl