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

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 BW373U86 (BW), 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 followed by 2 h of reperfusion. The rats were divided into four groups. First, rats were pretreated with selective opioid receptor antagonists or the antioxidant, 2-mercaptopropionyl glycine (2-MPG), in the presence of BW and allowed to recover for 24 h 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 ischemia-reperfusion protocol. Third, rats underwent ischemic preconditioning (IPC) (1x5 min occlusion) both with and without 2-MPG to determine the role of OFRs in acute cardioprotection. Fourth, rats were pretreated with TAN-67, an opioid agonist known to signal through the delta1 opioid receptor in the presence and absence of 2-MPG. Control rats were injected with saline and allowed to recover for 24 h. BW produced a bell-shaped dose-related reduction in infarct size with a maximal reduction observed at 0.1 mg/kg v control (16+/-3%v 60+/-3%, P<0.001). Surprisingly, the delayed protection induced by BW was only partially blocked by pretreatment with the delta1-selective antagonist, BNTX; however, it was completely blocked by pretreatment with 2-MPG (47+/-5%, P<0.001). Only naloxone given acutely inhibited the protective effects of BW; however, at the dose used, 2-MPG partially reduced the protective effect of acute IPC. TAN-67 (0.1 mg/kg) also produced a significant reduction in infarct size compared to control (18+/-4%v 60+/-3%, P<0.001). This protection was blocked by pretreatment with 2-MPG (42+/-4%, P<0.001). These data suggest that BW and TAN-67 mediate delayed cardioprotection via a free radical mechanism that appears to be only partially dependent on delta opioid receptor stimulation. Furthermore, it is the early burst in OFRs that is crucial to initiating the protective effect.