Mechanism Of Antiarrhythmic Effect Of к-opioid On Cx43 In Rat Heart Via Inhibting β-adrenergic Receptor Pathway

There are three subtypes of opioid receptors(μreceptor,δreceptor andκreceptor)in the heart, of which theκsubtype is dominant. It has been reported that activationof the opioid receptors in the heart can decrease the arrhythmia score during theprocesses of ischemia and reperfusion, leading to physiological effects such asdecrease in the contractility of cardiomyocytes and the dilation of vascular vessels.The gap junction plays an important role in the process of arrhythmia. The functionof Cx43, which is the most important gap junction protein, is especially important.It is reported that activation ofκopioid receptor can inhibit the arrhythmia byinhibiting the sympathetic nervous system andβadrenergic receptor pathway.However, the definite mechanism is not clear.We studied the effects of activatingκopioid receptor andβadrenergic receptoron Cx43 and its probable mechanism by using U50,488H and isoproterenol. We also studied the changes of Cx43 mRNA and Cx43 protein in order to find themechanism of antiarrhythmic effect ofк-opioid.Main contents of the study:1.Investigate the effects of activation ofκopioid receptor andβadrenergicreceptor on Cx43 in normal cardiac tissue.2.Investigate the effects of activation ofκopioid receptor andβadrenergicreceptor on Cx43 in cardiac tissue of ischemia and reperfusion.Methods:1.Male SD rats (250±20 g ) were randomly divided into groups. Animal models(normal rat or ischemia/reperfusion rat)were given different medicine according toexperiment condition, and at the mean time, the arrhythmia score was recorded. Afterthe experiment, the left ventricular tissue was adorpted for later experiment.2.RT-PCR was used to detect the amount of Cx43 mRNA.3. An immunohistochemical approach was used to detect the expression of Cx43protein in myocardial cell .Main results:Experiment one1.Compared with the normal control group, the expression of Cx43 mRNA wasincreased with administration of isoproterenol(p<0.05). Meanwhile, U50,488H andpropranolol could inhibit the increased expression of Cx43 mRNA induced byisoproterenol(p<0.05).2. Compared with normal control group, the phosphorylated Cx43 wasdecreased with administration of isopreterenol(p<0.05). Meanwhile, U50,488H andpropranolol could inhibit the decreased expression of phosphorylated Cx43 inducedby isoproterenol(p<0.05).The total Cx43 was not siginificantly changed in fivegroups. Experiment two1.Compared with the I/R group, arrhythmia score was increased withadministration of isoproterenol(p<0.05), U50,488H intravenously injected beforeisoproterenol significantly decreased the arrhythmia score(p<0.05).2.Compared with the normal control group, the expression of Cx43 mRNA wasdecreased in the I/R group(p<0.05). With administration of isoproterenol, theamount of Cx43 mRNA was not significantly increased. Meanwhile, U50,488Hinhibited the expression of Cx43 mRNA(p<0.05).3.Compared with normal control group, total and phosphorylated Cx43 proteinswere significantly decreased in the I/R group(p<0.05), and the phosphorylated Cx43was also decreased with administration of isopreterenol. Compared with ISO+I/Rgroup, phosphorylated Cx43 was increased with administration of U50,488H(P<0.05)ConclusionConclusions:1.Isopreterenol can increase the amount of Cx43 mRNA in normal cardiac tissuewhile U50,488H and propranolol can inhibit the increased expression of Cx43mRNA induced by isoproterenol. U50,488H can affect Cx43 viaβ-adrenergicreceptor pathway.2.к-opioid receptor agonist U50,488H antagonizes the arrhythmias through theregulation of Cx43 during myocardial ischemia and reperfusion via inhibtingβ-adrenergic receptor pathway...