Antiarrhythmic effect mediated by kappa-opioid receptor is associated with Cx43 stabilization.

摘要

OBJECTIVE: Acute myocardial ischemia induces electrical and chemical uncoupling of gap junctions, which contributes to conduction abnormalities and re-entrant arrhythmias. We tested the hypothesis that structure and function of Connexin43 may vibrate during acute myocardial ischemia and reperfusion and kappa-opioid receptor stimulation may stabilize the alteration of Connexin43. DESIGN: An animal intervention study was conducted with comparison to a control group. SETTING: University preclinical research laboratory. SUBJECTS: Age-, weight-, and sex-matched Sprague-Dawley rats. INTERVENTIONS: Adult rat hearts were subjected to ischemia or ischemia/reperfusion, which was induced by temporary occlusion of the left main coronary artery. U50488H was given 10 mins before tissue specimens were taken or before ischemia (1.5 mg/kg, intravenous) and nor-BNI was given 15 mins before tissue specimens were taken or before ischemia (2 mg/kg, intravenous). Tissue samples came from left ventricular myocardium of the rat hearts. MEASUREMENTS AND MAIN RESULTS: Electrocardiogram, immunohistochemistry, immunoblotting, and reverse transcription-polymerase chain reaction were used to measure changes of arrhythmias, protein, and gene expression of Connexin43, respectively. kappa-opioid receptor activation with U50 decreased arrhythmia in a model of myocardial ischemia and reperfusion. In normal hearts, immunohistochemical data showed reduced amount and lateralization of Connexin43 induced by kappa-opioid receptor activation, whereas immunoblotting data demonstrated no significant changes between control and U50 group. During ischemia, however, Connexin43 protein underwent dephosphorylation and degradation, and Connexin43 mRNA was upregulated. These alterations were significantly attenuated on kappa-opioid receptor stimulation. During ischemia and reperfusion, Connexin43 protein underwent dephosphorylation and degradation and recovered slowly during reperfusion. Activation of kappa-opioid receptor accelerated recovery of phosphorylated and total Connexin43. CONCLUSIONS: In normal rat hearts, Connexin43 translocates from intercellular junctions to intracellular locations on kappa-opioid receptor activation. In rat hearts experiencing acute myocardial ischemia and reperfusion, protein and gene expression of Connexin43 undergo vibration. This phenomenon is stabilized when kappa-opioid receptor is activated and by the fact that kappa-opioid receptor produces antiarrhythmic effects.