κ -Opioid Receptor Stimulation Induces Arrhythmia in the Isolated Rat Heart via the Protein Kinase C/Na+–H+Exchange Pathway

• Published in: Journal of molecular and cellular cardiology Vol. 32; no. 8; pp. 1415 - 1427
• Main Authors: Bian, Jin-Song, Pei, Jian-Ming, Cheung, Chi-Sing, Zhang, Wei-Min, Wong, Tak-Ming
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.2000
• Subjects: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer - pharmacology; Animals; Antihypertensive Agents - pharmacology; Arrhythmia; Arrhythmias, Cardiac - metabolism; Calcium - metabolism; Cells, Cultured; Cytosol - enzymology; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Heart - drug effects; Heart - physiology; Hydrogen-Ion Concentration; Intracellular calcium concentration; Intracellular pH; Intracellular sodium concentration; Ionophores - pharmacology; Male; Monensin - pharmacology; Myocardium - enzymology; Myocardium - metabolism; Myocardium - pathology; Opioid receptor; Perfusion; Protein kinase C; Protein Kinase C - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa - metabolism; Sodium - metabolism; Sodium-Hydrogen Exchangers - drug effects; Sodium-Hydrogen Exchangers - metabolism; Sodium–calcium ion exchange; Sodium–hydrogen ion exchange; Spectrometry, Fluorescence; Time Factors; Intracellular pH; Protein kinase C; Arrhythmia; Intracellular calcium concentration; Opioid receptor; Intracellular sodium concentration; Sodium–calcium ion exchange; Sodium–hydrogen ion exchange
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1006/jmcc.2000.1175

The present study attempted to determine whether the protein kinase C (PKC)/Na+–H+exchange (NHE) pathway would mediate the arrhythmogenic action ofκ -opioid receptor (OR) stimulation. We first determined the effects of U50,488H, a selective κ -OR agonist, on PKC activity and cardiac rhythm in the isolated perfused rat heart, and intracellular pH (pHi), and Ca2+([Ca2+]i) and Na+([Na+]i) concentrations in the isolated ventricular myocyte. At 5–40μ m U50,488H concentration dependently increased the particulate PKC activity and pHi, and induced arrhythmia. 40 μ m U50,488H also increased [Na+]iand [Ca2+]i. The arrhythmogenic effects of 40 μ m U50,488H were abolished by nor-binaltorphimine, a selective κ -OR antagonist. Blockade of PKC and NHE with respective blockers, 1 μ m bisindolylmaleimide I or 0.5 μ m calphostin C, and 1 μ m 5-[N -methyl- N -isobutyl]amiloride or 1 μ m 5-([N -ethyl- N -isopropopyl]amiloride, abolished and significantly attenuated, respectively, the effects of κ -OR stimulation on pHi, [Na+]iand [Ca2+]i, and arrhythmia. To determine the role of pHi, we observed U50,488H-induced arrhythmia at pHi6.8. At this pHi, the pHiincreased gradually both in the presence and absence of 40 μ m U50,488H to a similar extent. While the increase in response to U50,488H was significantly less at pHi6.8 (from 0.09 to 0.10) than that at pHi7.1 (from 0.01 to 0.18), the arrhythmia induced by the agonist was the same at both high and low pHs. On the other hand, 5μ m monensin, a sodium ionophore, increased [Na+]iand [Ca2+]i, and induced arrhythmia to similar extents as U50,488H. PKC and NHE inhibitors, that significantly attenuated the effects induced by U50,488H, had no effect on those induced by monensin. In conclusion, κ -OR stimulation induces arrhythmia via PKC/NHE. [Na+]iand [Ca2+]i, but not pHi, may be directly responsible for arrhythmia induced byκ -OR stimulation.