Cardioprotection Mediated By κ-opioid Receptor And Underlying Anti-arrhythmic Mechanism

Objective: To investigate Cardioprotection mediated by -opioid receptor and underlying anti-arrhythmic mechanism in rats subjected to myocardial ischemia/reperfusion injury and to discuss the modulating effects of K -opioid receptor activation on the contents of CK, LDH, AngII, ET and NO in plasma.Methods: Male Sprague-Dawley rats weighing 250~350g were used for all experiments. The rats were randomly divided into different groups according to experiment protocol, they were control group, ischemia/reperfusion (I/R) group, U50488H group, U50488H+ I/R group and Nor-BNI+U50488H+ I/R group. Animal model of myocardial ischemia and reperfusion injuries: The surgical procedures used here were similar to those previously employed by others. The rats were anesthetized with ip injection of 30 mg-kg-1bentobarbitone and supplemental doses were given i.v. when necessary to ensure a adequate level of anesthesia. The trachea was cannulated and all rats were artificially ventilated. The right jugular vein was cannulated for injection of drugs. After thoracic cavity was opened, a 5/0 silk thread was passed around the left anterior descending coronary artery (LAD) with a taper needle, and the ends were passed through a small vinyl tube to form a snare. The acute myocardial ischemia induced by LAD occlusion resulting from pulling the snare was confirmed by regional cyanosis and a substantial fall in left ventricular pressure. Reperfusion was achieved by releasing the snare. Electrocardiogram, heart rate (HR), arterial blood pressure (ABP), left ventricular pressure (LVP), contractive function (+dp/dtmax) and diastolic function (-dp/dtmax) were monitored in the course of experiment. When the experiment was over, bloods of rats were gathered to measure the contents of CK, LDH, Ang II , ET and NO in plasma. Finally, the rats were killed and the hearts were used for the examination of the myocardial ultra-structures and the measurement of the infarction sizes.Results: 1. Hemodynamics data:(1) In comparison with control group, U50488H elicited no effect on hemodynamics in rats at low dose (0.5 mg-kg-1) (P>0.05), While at dose of 1.5 mg-kg-1, HR, ABP, LVP and 卤dp/dtmax of rats were significantly decreased with the administration of U50488H(2) Compared with control group, no change occurred in HR of rats in I/R group during I/R (P>0.05). While ABP, LVP and 卤 dp/dtmax in the rats with ischemia/reperfusion injury were loweredafter occlusion of LAD (P<0.01). During reperfusion, these indexes were restored, but were still lower than those before ischemia. In U50488H+ I/R group, with the administration of U50488H only, the cardiac functions were immediately decreased (P<0.01). After the further disposal of I/R, no further decrease was observed (P>0.05). The negative inotropic effects of U50488H were abolished in the presence of Nor-BNI.2. Myocardial ultra-structures:Similar to control group, there was no significant change of the myocardial ultra-structures in U50488H group. The structures of cardiac muscle fiber and endoplasmic reticulum were in order, the lumens of capillary were open. But myocardial ultra-structures in I/R group and BNI+U50488H+ I/R group were messed up, and there were a few of microthrombus in the lumens of capillary. Following U50488H intravenously injected 15 min before I/R, the injuries of the myocardial ultra-structure caused by ischemia/reperfusion were attenuated significantly.3. Myocardial infarction size:In the rat hearts of I/R group, there appeared obvious myocardial infarction. With the administration of U50488H in advance, the myocardial infarction size was reduced (P<0.01). The effect of U50488H was, although not completely, abolished by Nor-BNI (P<0.01).4. Anti-arrhythmic effects and mechanisms mediated by -opioid receptor:(1) Anti-arrhythmic effects mediated by -opioid receptor in rats subjected to myocardial ischemia/reperfusion injury:Similar to control group, few ventricular premature contractionswere observed in the rats of U50488H group, but no ventricular tachycard...