Opioid-induced second window of cardioprotection - Potential role of mitochondrial K-ATP channels

Opioids have been previously shown to confer short-term cardioprotection ag ainst a prolonged ischemic insult. Therefore, the present study was designe d to determine whether opioids can induce a delayed or "second window" of c ardioprotection and to assess the potential involvement of the mitochondria l K-ATP channel. All mts were subjected to 30 minutes of ischemia and 2 hou rs of repel-fusion (I/R), Control animals, injected with saline 24 hours be fore VR, elicited an infarct size/area at risk (IS/AAR) of 62.9+/-3.3. TAN- 67, a delta 1-opioid receptor agonist, was administered 10 or 30 mg/kg TP 1 2, 24, 48, or 72 hours before I/R. TAN-67 (10 mg/kg) 12- or 24-hour pretrea tment did not significantly reduce IS/AAR (62.1+/-6.3 and 43.3+/-7.31 respe ctively). Similarly, 12-hour pretreatment with TAN-67 (30 mg/kg) 12- or 24- hour pretreatment did not reduce IS/AAR (60.0+/-5.6); however, 24-hour pret reatment significantly reduced IS/AAR (34.5+/-5.9), Forty-eight-hour pretre atment with TAN-67 maximally reduced IS/AAR (29.2+/-7.0), and opioid-induce d cardioprotection was lost after 72-hour pretreatment (61.7+/-3.8). TAN-67 -induced cardioprotection could be abolished by pretreatment with the selec tive delta(1)-opioid receptor antagonist 7-benzylidenenaltrexone, BNTX, adm inistered either 30 minutes before TAN-67 given 48 hours before I/R or 10 m inutes before VR in rats previously treated for 48 hours with TAN-67 (59.6/-3.1 and 58.7+/-3.5, respectively). The involvement of the K-ATP channel w as investigated with 2 inhibitors: glibenclamide, a nonselective K-ATP chan nel inhibitor, and 5-hydroxydecanoic acid, selective for the mitochondrial K-ATP channel in rabbits. Glibenclamide, administered 30 minutes before I/R in 48-hour TAN-67-pretreated rats, completely abolished cardioprotection ( 60.4+/-3.2). Similarly, 5-hydroxydecanoic acid, administered 5 minutes befo re I/R in rats pretreated 48 hours previously with TAN-67, completely aboli shed cardioprotection (57.8+/-2.5). These results suggest that delta(1)-opi oid receptor stimulation, 24 to 48 hours before an ischemic insult, produce s a delayed cardioprotective effect that is possibly the result of mitochon drial K-ATP channel activation.