κ-Opioid receptors mediate cardioprotection by remote preconditioning

Background: Remote preconditioning is known to be cardioprotective, but the exact mechanism has not been fully elucidated. The objective of the current study was to investigate the role Of K-opioid receptors in cardioprotection by remote preconditioning and reveal possible underlying mechanisms. Methods. Remote preconditioning was induced in anesthetized male Sprague-Dawley rats by three cycles of 5 min of right femoral artery occlusion followed by 5 min of reperfusion. Myocardial ischemia-reperfusion was achieved by ligation of the left anterior descending coronary artery for 30 min and then reperfusion for 120 min. Infarct size was determined by 2,3,5-triphenyltetrazolium chloride staining. Levels of lactate dehydrogenase, dynorphin, and met-enkephafin in plasma were measured. The opening of the mitochondrial permeability transition pore was monitored with fluorescent calcein in isolated ventricular myocytes. Results: Both remote preconditioning and U-50,488H (10 mg/kg intravenous), a K-opioid receptor agonist, significantly decreased the infarct size and plasma lactate dehydrogenase level induced by ischemia-reperfusion, and these effects were attenuated by nor-binaltorphimine (10 mg/kg intravenous), a K-opioid receptor antagonist, and atractyloside (5 mg/kg intravenous), a mitochondrial permeability transition pore activator. However, administration of naltrindole (5 mg/kg), a 6-opioid receptor antagonist, had no effect on the cardioprotection by remote preconditioning. The dynorphin plasma level was increased after remote preconditioning treatment, but the metenkephatin level did not change. in isolated ventricular myocytes loaded with calcein, U-50,488H (300 pm) decreased the mitochondrial permeability transition pore opening induced by calcium (200 mu M), and this effect was attenuated by cotreatment with nor-binaltorphimine (5 mu M) or atractyloside (20 mu M). Conclusion: Activation of cardiac K-opioid receptors is involved in the cardioprotection induced by remote preconditioning, and the mitochondrial permeability transition pore may participate in the postreceptor pathway.