BW373U86, a delta opioid agonist, partially mediates delayed cardioprotection via a free radical mechanism that is independent of opioid receptor stimulation

H. H. PATEL, A. HSU, J. MOORE AND G. J. GROSS, BW373US86, a delta Opioid Ag onist, Partially Mediates Delayed Cardioprotection via a Free Radical Mecha nism that is Independent of Opioid Receptor Stimulation. Journal of Molecul ar and Cellular Cardiology (2001) 33, 1455-1465, Opioids have been shown to produce both an early and delayed phase of cardioprotection; however, the signaling pathways involved, particularly in the delayed response, have not been well defined, Therefore, we investigated the potential of BM373U86 (B W), a potent delta opioid agonist, to produce delayed cardioprotection and characterized the role of opioid receptors and oxygen-derived free radicals (OFRs) in this delayed response, All rats underwent 30 min of ischemia fol lowed by 2 h of reperfusion. The rats were divided into four groups. First, rats were pretreated with selective opioid receptor antagonists or the ant ioxidant, 2-mercaptopropionyl glycine (2-MPG), in the presence of BW and al lowed to recover for 24h before the ischemia-reperfusion protocol. Second, rats were pretreated with BW, allowed to recover for 24 h, and subsequently treated with either opioid antagonists or 2-MPG, 10 min prior to the ische mia-reperfusion protocol. Third, rats underwent ischemic preconditioning (T PC) (1 x 5 min occlusion) both with and without 2-MPG to determine the role of OFRs in acute cardioprotection. Fourth, rats were pretreated with TAN-6 7, an opioid agonist known to signal through the delta (1) opioid receptor in the presence and absence of 2-MPG. Control rats were injected with salin e and allowed to recover for 24 h. BW produced a bell-shaped dose-related r eduction in infarct size with a maximal reduction observed at 0.1 mg/kg v c ontrol (16 +/- 3% v 60 +/- 3%, P < 0.001). Surprisingly the delayed protect -ion induced by BW was only partially blocked by pretreatment with the delt a (1)-selective antagonist, BNTX: however, it was completely blocked by pre treatment with 2-MPG (47 +/- 5%. P < 0.001). Only naloxone given acutely in hibited the protective effects of BW; however, at the dose used, 2-MPG part ially reduced the protective effect of acute IPC, TAN-67 (0.1 mg/kg) also p roduced a significant reduction in infarct size compared to control (18 +/- 4% v 60 +/- 3%, P < 0.001). This protection was blocked by pretreatment wi th 2-MPG (42 +/- 4%, P < 0.001). These data suggest that BW and TAN-67 medi ate delayed cardioprotection via a free radical mechanism that appears to b e only partially dependent on delta opioid receptor stimulation. Furthermor e, it is the early burst in OFRs that is crucial to initiating the protecti ve effect.