Anti-arrhythmic Effect Mediated By κ-opioid Receptor Is Associated With Cx43 Stabilization

BackgroundIschemic heart disease currently has the highest mortality among cardiovascular diseases. There is an increased incidence as our country becomes an aging society. Arrhythmia, particularly ventricular fibrillation induced by myocardial ischemia, is the main cause of sudden death. Here we study the pathogenesis and treatment strategies of ischemia-induced arrhythmia.Uncoupling induced by abnormal structure and function of Gap junction (GJ) is a key factor in the pathogenesis of ischemic arrhythmia. GJ, which is the basis of intercellular communication, mainly distributes in junctions between cardiocytes. Its function is to aid in electrical signal coupling and exchange of chemical signals. Connexin, particularly Cx43, is the major component of GJ in mammals. Recent studies have shown that calcium overload during cardiocyte-induced ischemia may lead to changes of both structure and function of Cx43. Dysfunction of Cx43 may lead to uncoupling and reentry, which induce ventricular arrhythmias.On the basis of our study of the relationship between opioid/opioid receptors and cardiovascular system, we further explored the mechanisms of the anti-arrhythmic effect of opioid via the Cx43 pathway. Our results may offer new pharmacological targets for prevention and resolution of ischemic heart disease. We offer theoretical foundations for the clinical use of opioids in the treatment of ischemic heart disease.AimsTo study whether the anti-arrhythmic effect of opioid/opioid receptor is accomplished by regulating the structure and function of Cx43. MethodsSprague Dawley (SD) rats were randomly divided into different groups. Subdermal electrodes were placed to allow the determination of a lead II electrocardiogram (ECG). Myocardial ischemia was induced by temporary occlusion of the left main coronary artery. The tissue specimen was then preserved.Immunohistochemical analysis was used to investigate the distribution, structure and function of Cx43. RT-PCR analysis was used to investigate changes of Cx43 mRNA.Western blotting analysis was used to investigate content and function of Cx43. ResultsChanges of Cx43 whenκ-opioid receptor was activated in normal myocardiumCx43 protein translocated to intracellular loci and Cx43 mRNA decreased whenκ-opioid receptor was activated.Changes of Cx43 whenκ-opioid receptor was activated in ischemic myocardiumCx43 protein translocated from cell junction to cell side during myocardial ischemia. Both total Cx43 and phosphorylated Cx43 protein decreased but Cx43 mRNA was upregulated. Arrhythmia score was also simultaneously increased. The phenomenon described above was prevented when ?-opioid receptor was activated.Changes of Cx43 whenκ-opioid receptor was activated in reperfused myocardiumIschemia/reperfusion injury induced dephosphorylation and degradation of Cx43 in myocardium. Cx43 synthesis was restored in reperfusion but to a very low degree. Activation ofκ-opioid receptor (κ-OR) may preserve Cx43 against dephosphorylation and degradation in ischemia/reperfusion injury.Correlations between anti-arrhythmic effect ofκ-OR and Cx43 Heptanol, a Cx43 uncoupler, induced more serious arrhythmia during ischemia. Anti-arrhythmic effect of opioid may be totally blocked by heptanol.ConclusionsOur study, for the first time, explored changes of Cx43 protein and mRNA during myocardial ischemia/reperfusion. During myocardial ischemia/reperfusion, the self- protective mechanism of the cardiomyocytes closes up the gap junction via mediating total Cx43 and phosphorylated Cx43 protein to localize injury. However, Cx43 protein reduction initiates transcription, which upregulates Cx43 mRNA. Finally, dysfunction of gap junction causes arrhythmia.Our studies suggest that acute myocardial ischemia and reperfusion induce Cx43 vibration. This phenomenon is stabilized whenκ-opioid receptor was activated andκ-opioid receptor produced anti-arrhythmic effects.