Recently, the involvement of sarcolemmal K ATP (sarcK ATP ) channels in ischemic and pharmacological preconditioning (IPC and PPC) has been minimized by numerous studies suggesting a primary role for mitochondrial K ATP (mitoK ATP ) channels in early and delayed cardioprotection. Although the mitoK ATP channel has clearly been shown to be a distal effector of delayed IPC and PPC, studies implicating it as a trigger of protection in delayed IPC are lacking. Accordingly, we characterized the role of cardiac K ATP channels as triggers or distal effectors of delayed cardioprotection induced by opioids in rats, and the data suggest that the sarcK ATP channel triggers and that the mitoK ATP channel is a distal effector of opioid-induced delayed cardioprotection. P rotection from myocardial infarction via ischemic preconditioning (IPC) has been described to be a biphasic event. The early phase occurs immediately after IPC and lasts 1 to 3 hours 1 ; the late phase of protection is seen 12 to 24 hours after the initial stimulus and lasts up to 72 hours. 2,3 We have previously shown that ␦ opioid agonists induce a delayed cardioprotective effect that appears to be mediated by a burst of reactive oxygen species (ROS). 4 In recent investigations, the mitochondrial ATP-dependent K ϩ (mitoK ATP ) channel has received considerable attention as being the trigger of early IPC. Studies in the isolated rabbit heart 5 and in isolated myocytes 6,7 have suggested that this channel contributes to protective signals via a redox-sensitive mechanism. 8,9 Similarly, data suggest that the mitoK ATP channel could be either a trigger that induces the expression of proteins or a distal effector in delayed IPC. However, little information is available on the triggering role of the sarcolemmal K ATP (sarcK ATP ) channel in delayed IPC.Therefore, we investigated the role of the sarcK ATP channel as a trigger or distal effector of delayed cardioprotection induced by ␦ opioid agonists. We present evidence suggesting that the sarcK ATP channel functions as the trigger and the mitoK ATP channel as a distal effector in opioid-induced delayed PC.
Materials and MethodsThis study was performed in accordance with the guidelines of the Animal Care Committee of the Medical College of Wisconsin, which is accredited by the American Association of Laboratory Animal Care.
Study Groups and Experimental ProtocolsMale Sprague-Dawley rats (250 to 300 g) were obtained from Charles River Laboratories, Wilmington, Mass, and randomly divided into groups and subjected to pretreatment with SNC-121 (0.1 mg/kg, IV), a ␦ opioid agonist, followed by a 24-hour recovery period. Selective and nonselective K ATP channel blockers were administered intravenously either with opioid pretreatment or after the recovery period just before index ischemia. All rats underwent 30 minutes of index ischemia followed by 2 hours of reperfusion.
General Surgical Procedure and Infarct DeterminationGeneral surgical procedures and infarct determination were performed as described previously. 4 Br...