kappa-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 k appa-opioid receptor (OR) stimulation. We first determined the effects of U 50.488H, a selective kappa-OR agonist, on PKC activity and cardiac rhythm i n the isolated perfused rat heart, and intracellular pH (pH(i)), and Ca2+ ( [Ca2+](i)) and Na+ ([Na+](i)) concentrations in the isolated ventricular my ocyte. At 5-40 mu M U50,488H concentration dependently increased the partic ulate 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 U5 0,488H were abolished by nor-binaltorphimine, a selective kappa-OR antagoni st. Blockade of PKC and NHE with respective blockers, 1 mu M bisindolylmale imide 1 or 0.5 mu M calphostin C, and 1 mu M 5-[N-methyl-N-isobutyl]amilori de or 1 mu M 5-([N-ethyl-N-isopropopyl]amiloride, abolished and significant ly 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 ob served U50,488H-induced arrhythmia at pH(i) 6.8. At this pH(i), the pH(i) i ncreased 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 significan tly 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, increa sed [Na+](i) and [Ca2+](i), and induced arrhythmia to similar extents as U5 0, 488H. PKC and NHE inhibitors, that significantly attenuated the effects induced by U50,488H, had no effect on those induced by monensin. In conclus ion, 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.