title: κ-opioid receptor activation prevents against arrhythmias by preserving Cx43 protein via alleviation of intracellular calcium.
abstract: 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.
authors.affiliation: 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.
authors.forename: Quan-Xing
authors.initials: QX
authors.lastname: Shi
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Zhang
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yao
authors.forename: Quan-Yu
authors.initials: QY
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Yu-Long
authors.initials: YL
authors.lastname: Shang
authors.forename: Hui
authors.initials: H
authors.lastname: Bi
authors.forename: Shu-Miao
authors.initials: SM
authors.lastname: Zhang
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Guo
authors.forename: Yue-Min
authors.initials: YM
authors.lastname: Wang
authors.forename: Shi-Qiang
authors.initials: SQ
authors.lastname: Yu
authors.forename: Ding-Hua
authors.initials: DH
authors.lastname: Yi
authors.forename: Franklin Rivera
authors.initials: FR
authors.lastname: Bueno
authors.forename: Alan David
authors.initials: AD
authors.lastname: Kaye
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Pei
mesh_terms: D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology*; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D018031:Connexin 43 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000037:antagonists & inhibitors
chemical_list: D000959:Antihypertensive Agents; D002120:Calcium Channel Agonists; D018031:Connexin 43; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium