title: Effects of BAY K-8644 on inotropic and arrhythmogenic actions of digoxin.
abstract: Myocardial intracellular 'Ca2+ overload' may be involved in the direct arrhythmogenic actions of cardiotonic steroids. This proposal was examined by determining if the sensitivity of guinea-pig atrial muscle to digoxin-induced arrhythmias was affected by BAY K-8644, a 1,4-dihydropyridine derivative which promotes Ca2+ influx via slow channels. BAY K-8644 significantly reduced both the time required for a given concentration of digoxin to produce arrhythmias and the amount of digoxin bound to atrial muscle at the onset of arrhythmias. In addition, BAY K-8644 increased the maximum developed tension observed in the presence of digoxin before the onset of arrhythmias. Similar results were obtained with increasing concentrations of buffer Ca2+. In contrast, A23187, a Ca2+ ionophore, enhanced the sensitivity to digoxin-induced arrhythmias without affecting maximum developed tension. These results suggest that increases in intracellular Ca2+ enhance cardiac sensitivity to digoxin-induced arrhythmias and that the arrhythmogenic action may involve Ca2+ overload at a pool other than that which activates contractile proteins.
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D000818:Animals; D000889:Anti-Arrhythmia Agents; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004077:Digoxin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006027:Glycosides / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D009543:Nifedipine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000889:Anti-Arrhythmia Agents; D006027:Glycosides; D000001:Calcimycin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D004077:Digoxin; D009543:Nifedipine; D002118:Calcium