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Opioid Receptors Mediate Cardioprotection

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Opioid Receptors Mediate Cardioprotection Anesthesiology 2006; 105:550–6 Copyright © 2006, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. ␬-Opioid Receptors Mediate Cardioprotection by Remote Preconditioning Shi-zhong Zhang, Ph.D.,* Ning-fu Wang, M.D.,† Jian Xu, M.D.,‡ Qin Gao, Ph.D.,§ Guo-hua Lin, Ph.D.,§ Iain C. Bruce, Ph.D.,࿣ Qiang Xia, Ph.D.# Background: Remote preconditioning is known to be cardio- Subsequently, it was found that RPC by brief ischemia of protective, but the exact mechanism has not been fully eluci- other distant organs, such as intestine,2 kidney,3 and dated. The objective of the current study was to investigate the 4,5 ␬ limb, also provides cardioprotection as effective as the role of -opioid receptors in cardioprotection by remote pre- 6 conditioning and reveal possible underlying mechanisms. classic preconditioning described by Murry et al. Methods: Remote preconditioning was induced in anesthe- Although classic preconditioning has been used clini- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/105/3/550/362148/0000542-200609000-00019.pdf by guest on 29 September 2021 tized male Sprague-Dawley rats by three cycles of 5 min of right cally, such as in percutaneous transluminal coronary femoral artery occlusion followed by 5 min of reperfusion. angioplasty,7 the invasive procedure and the need for a Myocardial ischemia–reperfusion was achieved by ligation of second operation limits this application. In comparison, the left anterior descending coronary artery for 30 min and then reperfusion for 120 min. Infarct size was determined by RPC via a limb is an ideal noninvasive means of inducing 2,3,5-triphenyltetrazolium chloride staining. Levels of lactate cardioprotection and is more easily performed than clas- dehydrogenase, dynorphin, and met-enkephalin in plasma sic preconditioning or other RPC models, such as with were measured. The opening of the mitochondrial permeability kidney or mesenteric tissues. However, the exact mech- transition pore was monitored with fluorescent calcein in iso- anism by which RPC of a limb evokes cardioprotection is lated ventricular myocytes. Results: Both remote preconditioning and U-50,488H (10 still not fully understood. mg/kg intravenous), a ␬-opioid receptor agonist, significantly Recently, opioid receptors, which play an important decreased the infarct size and plasma lactate dehydrogenase part in classic preconditioning,8 were also found to be level induced by ischemia–reperfusion, and these effects were involved in RPC by mesenteric artery occlusion.9 Bind- attenuated by nor-binaltorphimine (10 mg/kg intravenous), a ␬ ␦ ␬ ing studies have identified - and -opioid receptors in -opioid receptor antagonist, and atractyloside (5 mg/kg intra- 10–12 venous), a mitochondrial permeability transition pore activa- myocardium, and both are involved in the cardio- 13 tor. However, administration of naltrindole (5 mg/kg), a ␦-opi- protective effect of ischemic preconditioning. Wein- oid receptor antagonist, had no effect on the cardioprotection ␦ brenner et al. reported that activation of the 1-opioid by remote preconditioning. The dynorphin plasma level was receptor may mediate the cardioprotective effect in RPC increased after remote preconditioning treatment, but the met- initiated by infrarenal artery occlusion.3 However, enkephalin level did not change. In isolated ventricular myo- ␬ cytes loaded with calcein, U-50,488H (300 ␮M) decreased the whether -opioid receptors contribute to the beneficial mitochondrial permeability transition pore opening induced cardiac effect of RPC remains unknown. by calcium (200 ␮M), and this effect was attenuated by cotreat- Therefore, in the current study, we focused on the role ment with nor-binaltorphimine (5 ␮M) or atractyloside (20 ␮M). of the ␬-opioid receptor in the cardioprotection induced ␬ Conclusion: Activation of cardiac -opioid receptors is in- by RPC of a limb and investigated the underlying mech- volved in the cardioprotection induced by remote precondition- ing, and the mitochondrial permeability transition pore may anism. participate in the postreceptor pathway. Materials and Methods IN 1993, Przyklenk et al.1 observed that brief occlusion Surgical Procedures of the circumflex coronary artery extended its cardio- All procedures in this study were approved by the protection from myocardium perfused by that artery to Ethics Committee for the Use of Experimental Animals in myocardium perfused by the left anterior descending Zhejiang University, Hangzhou, Zhejiang, China. Male artery; this was called “remote preconditioning” (RPC). Sprague-Dawley rats weighing 230–260 g were anesthe- tized with chloral hydrate (0.4 g/kg intraperitoneal) sup- * Lecturer, Department of Physiology, Zhejiang University School of Med- plemented with additional doses (0.016 g/kg intraperi- icine, Hangzhou. Department of Cardiology, the First People’s Hospital of Hangzhou, Hangzhou, China. † Chief Physician, ‡ Associate Physician, toneal) every 30 min to maintain effective anesthesia. Department of Cardiology, the First People’s Hospital of Hangzhou, Hangzhou, The rats were tracheotomized and ventilated with room China. § Lecturer, # Professor, Department of Physiology, Zhejiang University School of Medicine, Hangzhou. ࿣ Professor, Department of Physiology, the air enriched with oxygen (tidal volume, 2 ml/stroke; University of Hong Kong, Hong Kong, China. rate, 70 strokes/min14), a condition that maintains arte- Received from the Zhejiang University School of Medicine, Hangzhou, China. rial pH, partial pressure of carbon dioxide, and oxygen Submitted for publication January 17, 2006. Accepted for publication May 26, 2006. Supported by grant Nos. 2005C30026 and 2006C33070 from Zhejiang within the normal physiologic range, as confirmed in our Science and Technology Bureau, Hangzhou, Zhejiang, China, and grant No. preliminary experiments. Body temperature was main- Y204375 from Natural Science Foundation of Zhejiang Province, Hangzhou, Zhejiang, China. tained at 37°C. Address correspondence to Dr. Xia: Department of Physiology, Zhejiang Uni- The left carotid artery was cannulated to permit mea- versity School of Medicine, 353 Yan-an Road, Hangzhou 310031, China. [email protected]. Individual article reprints may be purchased through the surement of blood pressure and heart rate via a pressure Journal Web site, www.anesthesiology.org. transducer connected to a data acquisition system (Med- Anesthesiology, V 105, No 3, Sep 2006 550 ␬-OPIOID RECEPTORS IN CARDIOPROTECTION 551 Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/105/3/550/362148/0000542-200609000-00019.pdf by guest on 29 September 2021 Fig. 1. Experimental protocols used for in atractyloside; I/R ؍ vivo experiments. Atr -nor ؍ ischemia–reperfusion; nor-BNI ؍ -remote precon ؍ binaltorphimine; RPC ditioning. Lab, Nanjing, China). The left femoral vein was cannu- or by inhibiting the receptor by intravenous injection of lated for administration of drugs and/or compensation 10 mg/kg nor-binaltorphimine15 (RPC ϩ nor-BNI group for fluid loss. and U-50,488H ϩ nor-BNI group), a specific ␬-opioid Through a left thoracotomy in the fourth intercostal receptor antagonist, delivered during and 10 min before space, the pericardium was opened, and a 5-0 suture was the RPC procedure, respectively. The contribution of passed below the left descending coronary artery 2–3 ␦-opioid receptors was determined by intravenous injec- mm from its origin. The suture ends were passed tion of naltrindole, a ␦-opioid receptor antagonist, at a through a polytetrafluoroethylene tube, and pulling dose (5 mg/kg) that blocks ␦-opioid receptors in the these occluded the coronary artery. The occlusion was myocardium.16 The effects of mitochondrial permeabil- confirmed by epicardial cyanosis and subsequent de- ity transition pore (MPTP) opening on RPC were deter- crease in blood pressure, while reperfusion was verified mined by intravenous injection of 5 mg/kg atractylo- by epicardial hyperemia. side,14 an activator of the MPTP, 10 min before the RPC The femoral artery of the right hind limb was freed procedure or U-50,488H administration (RPC ϩ Atr from surrounding tissue, a suture was placed below it for group and U-50,488H ϩ Atr group) (fig. 1). later occlusion with an arterial clamp, and reperfusion was initiated by removing the clamp. Infarct Size Measurement Infarct size was determined by the 2,3,5-triphenyltet- Experimental Protocols razolium chloride staining method. At the end of the 120 All rats received 30 min of regional ischemia by liga- min of reperfusion, the heart was quickly excised and tion of the left anterior descending artery followed by mounted on a Langendorff apparatus to wash out the 120 min of reperfusion. RPC was elicited by three cycles blood. The coronary artery was then reoccluded, and of 5 min of right femoral artery occlusion interspersed hearts were perfused with 1% Evans blue to stain the with 5 min of reperfusion before 30 min of regional myocardium, while the risk area remained unstained. ischemia in the heart. The role of ␬-opioid receptors in After that, the hearts were frozen at Ϫ20°C for 2–3 h, cut RPC was determined by activating the receptors by in- into 2-mm slices, and stained with 1% TTC at 37°C for travenous injection of 10 mg/kg U-50,488H14 10–15 min. Infarct (pale) and risk (red) areas were mea- (U-50,488H group), a specific ␬-opioid receptor agonist; sured by planimetry using Image/J software from Na- by intravenous injection of 24 ng/kg dynorphin (dynor- tional Institutes
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