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κ-opioid Receptor Activation Prevents Against Arrhythmias by Preserving Cx43 Protein Via Alleviation of Intracellular Calcium

Shi, Quan-Xing PhD1; Zhang, Li-Jun PhD1; Yao, Yuan PhD1; Zhang, Quan-Yu PhD2; Wang, Wei MS1; Li, Juan PhD1; Shang, Yu-Long PhD1; Bi, Hui PhD1; Zhang, Shu-Miao PhD1; Guo, Hai-Tao PhD1; Wang, Yue-Min PhD1; Yu, Shi-Qiang PhD3; Yi, Ding-Hua PhD3; Bueno, Franklin Rivera MS4; Kaye, Alan David MD, PhD4,5,*; Pei, Jian-Ming PhD1,*

doi: 10.1097/MJT.0b013e3182456676
Original Article

κ-opioid receptor (κ-OR) activation with U50,488H, a selective κ-OR agonist, has been previously demonstrated to prevent against cardiac arrhythmias via stabilizing the synthesis and degradation of an integral membrane protein, Cx43, in gap junctions. However, the exact prevention mechanism remains unclear. The present study tested the hypothesis that the kappa OR agonist U50,488H mediates the prevention of arrhythmia through the regulation of intracellular calcium leading to the preservation of Cx43 protein. By performing electrocardiogram monitoring and immunoblotting in isolated Langendorff-perfused rat hearts, high concentrations of calcium-perfused rat hearts exhibited increased cardiac arrhythmias. Diminished expression of Cx43 protein was observed. The utilization of a whole-cell patch clamp technique revealed that U50,488H inhibited L-type calcium current in single ventricular myocytes in a dose-dependent manner. These effects were blocked by nor-binaltorphimine, potent and selective κ-OR antagonists. Administration of U50,488H before myocardial ischemia resulted in an attenuated of total arrhythmia scores. The attenuation effect was blocked by nor-binaltorphimine. The attenuation effect was antagonized both by Bay K8644, a L-type calcium channel agonist, and also by the Cx43 uncoupler heptanol. Finally, immunoblotting data demonstrated that the preservation of Cx43 protein conferred by U50,488H was reversed in the presence of Bay K8644. In summary, the present study demonstrates κ-OR activation with U50,488H may confer antiarrhythmic effects via modulation of the calcium-Cx43 pathway.

1Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi’an, China

2Department of Cardiology, Institute for Cardiovascular Research, General Hospital of Shenyang Military Region, Shenyang, China

3Department of Cardiosurgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China

4Department of Anesthesiology, Louisiana State University School of Medicine, New Orleans, LA

5Department of Pharmacology, Louisiana State University School of Medicine, New Orleans, LA.

Address for correspondence: Department of Physiology, National Key Discipline of Cell Biology, Fourth Military Medical University, Xi’an 710032, China. E-mail:

Supported by grants from the National Natural Science Foundation of China (No. 30971060, 30770802, 30900535), and New Medicine Research Fund (No. 2009ZX09103-671 and 2009ZX09301-009-BD11).

The authors have no conflicts of interest.

© 2013 by Lippincott Williams & Wilkins.