monensin and Arrhythmias--Cardiac

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 Ca(2+)([Ca(2+)](i)) and Na(+)([Na(+)](i)) concentrations in the isolated ventricular myocyte. At 5-40 microm U50,488H concentration dependently increased the particulate PKC activity and pH(i), and induced arrhythmia. 40 microm U50,488H also increased [Na(+)](i)and [Ca(2+)](i). The arrhythmogenic effects of 40 microm U50,488H were abolished by nor-binaltorphimine, a selective kappa -OR antagonist. Blockade of PKC and NHE with respective blockers, 1 microm bisindolylmaleimide I or 0.5 microm calphostin C, and 1 microm 5-[N -methyl- N -isobutyl]amiloride or 1 microm 5-([N -ethyl- N -isopropopyl]amiloride, abolished and significantly attenuated, respectively, the effects of kappa -OR stimulation on pH(i), [Na(+)](i)and [Ca(2+)](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 microm 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 microm monensin, a sodium ionophore, increased [Na(+)](i)and [Ca(2+)](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 [Ca(2+)](i), but not pH(i), may be directly responsible for arrhythmia induced by kappa -OR stimulation.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antihypertensive Agents; Arrhythmias, Cardiac; Calcium; Cells, Cultured; Cytosol; Dose-Response Relationship, Drug; Enzyme Inhibitors; Heart; Hydrogen-Ion Concentration; Ionophores; Male; Monensin; Myocardium; Perfusion; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Sodium; Sodium-Hydrogen Exchangers; Spectrometry, Fluorescence; Time Factors

In high concentrations, the ionophores salinomycin, monensin and X-537A cause cardiac arrhythmias in vivo. To determine if these arrhythmias result from a direct action of these ionophores on cardiac electrophysiology, we studied their effects on automaticity and transmembrane action potentials of isolated canine left ventricular Purkinje fibers. High concentrations of the ionophores suppressed automaticity and shortened action potential duration. These data suggest that high concentrations of the ionophores provoke cardiac arrhythmias in vivo by similar mechanisms despite their diverse cation transport selectivities.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Cations; Dogs; Heart Rate; Ionophores; Lasalocid; Monensin; Nadolol; Propanolamines; Purkinje Fibers; Pyrans

The hypothesis that digitalis-induced arrhythmias occur when Na,K-ATPase inhibition exhausts the sodium pump reserve capacity, producing an accumulation of intracellular Na+, was tested by reducing the reserve capacity in isolated left atrial muscle of guinea pig heart and estimating specific digoxin binding and Na,K-ATPase activity in atrial muscle homogenized at the onset of digoxin-induced arrhythmias. Reductions in reserve capacity were produced by either increasing the stimulation frequency of the atrial muscle or adding a sodium ionophore, monensin, to the media bathing the tissue. As stimulation frequency was increased, both the time required to produce arrhythmias with a given concentration of digoxin and the amount of digoxin bound to sarcolemmal Na,K-ATPase at the onset of arrhythmias were reduced. Similarly, monensin treatment produced reductions in the time to arrhythmia and in digoxin binding and Na,K-ATPase inhibition observed at the onset of arrhythmias. These results support the above proposal suggesting that a decrease in reserve capacity of the sodium pump enhances cardiac sensitivity to digitalis-induced arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Digoxin; Drug Interactions; Electric Stimulation; Furans; Guinea Pigs; Male; Monensin; Myocardial Contraction; Ouabain; Reserpine; Sodium; Sodium-Potassium-Exchanging ATPase; Time Factors