κ-Opioid receptor stimulation induces arrhythmia in the isolated rat heart via the protein kinase C/Na+-H+ exchange pathway

The present study attempted to determine whether the protein kinase C (PKC)/Na+-H+ exchange (NHE) pathway would mediate the arrhythmogenic action of kappa-opioid receptor (OR) stimulation. We first determined the effects of U50.488H, a selective kappa-OR agonist, on PKC activity and cardiac rhythm in the isolated perfused rat heart, and intracellular pH (pH(i)), and Ca2+ ([Ca2+](i)) and Na+ ([Na+](i)) concentrations in the isolated ventricular myocyte. At 5-40 mu M U50,488H concentration dependently increased the particulate PKC activity and pH(i), and induced arrhythmia. 40 mu M U50,488H also increased [Na+](i) and [Ca2+](i). The arrhythmogenic effects of 40 mu M U50,488H were abolished by nor-binaltorphimine, a selective kappa-OR antagonist. Blockade of PKC and NHE with respective blockers, 1 mu M bisindolylmaleimide 1 or 0.5 mu M calphostin C, and 1 mu M 5-[N-methyl-N-isobutyl]amiloride or 1 mu M 5-([N-ethyl-N-isopropopyl]amiloride, abolished and significantly attenuated, respectively, the effects of kappa-OR stimulation on pH(i), [Na+], and [Ca2+](i), and arrhythmia. To determine the role of pH(i), we observed U50,488H-induced arrhythmia at pH(i) 6.8. At this pH(i), the pH(i) increased gradually both in the presence and absence of 40 mu M U50,488H to a similar extent. While the increase in response to U50,488H was significantly less at pH(i) 6.8 (from 0.09 to 0.10) than that at pH(i) 7.1 (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, 5 mu M monensin, a sodium ionophore, increased [Na+](i) and [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, kappa-OR stimulation induces arrhythmia via PKC/NHE. [Na+](i) and [Ca2+](i), but not pH(i), may be directly responsible for arrhythmia induced by kappa-OR stimulation. (C) 2000 Academic Press.