Antagonism of N/OFQ attenuates externalization of β1-adrenergic receptor and ventricular arrhythmias in acute myocardial ischemia rat model

Abstract

Nociceptin/orphanin FQ (N/OFQ) and adrenergic activations play roles in promoting cardiac arrhythmia in acute myocardial ischemia but whether N/OFQ and β1-adrenergic activities interact and how they interact in the arrhythmogenesis are still unknown. We designed this study to investigate the potential interaction of N/OFQ and β1-adrenergic activities and the underlying mechanism in arrhythmogenesis in acute myocardial ischemia. Ventricular arrhythmia was evaluated in anaesthetized rats following permanent coronary artery occlusion (CAO), in presence and absence of UFP-101 (a selective antagonist of N/OFQ receptor). The changes of β1-adrenergic receptor (β1-AR) in plasma membrane of cardiomyocytes were quantitatively evaluated and the relations with the alterations of phosphorylated Raf kinase inhibitor protein (p-RKIP) and phosphorylated connexin 43 (p-Cx43) were investigated. The ventricular arrhythmia was 59% less in the animals pre-treated with UFP-101 than the placebo-treated control (difference of means = −2.41; 95% confidence interval (CI) −2.84 to −1.99; P < 0.001). Meanwhile, p-RKIP and membrane β1-AR in the myocardium were downregulated by 59% and 24%, respectively (p-RKIP: difference of means = −6.91; 95% CI -8.38 to −5.45; P < 0.001; membrane β1-AR difference of means = −27.06; 95% CI -29.89 to −24.23; P < 0.001). Artificial upregulation of RKIP by didymin significant increased β1-AR in plasma membrane of the cardiomyocytes in the animals prone to ventricular arrhythmia. The findings may suggest that activation of N/OFQ receptor in acute myocardial ischemia induces upregulation of p-RKIP, externalization of β1-adrenergic receptor and downregulation of p-Cx43 in the cardiomyocytes, which promotes ventricular arrhythmia.