Effects of bay K-8644 on inotropic and arrhythmogenic actions of digoxin

Abstract

Myocardial intracellular ‘Ca 2+ 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 Ca 2+ 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 Ca 2+. In contrast, A23187, a Ca 2+ ionophore, enhanced the sensitivity to digoxin-induced arrhythmias without affecting maximum developed tension. These results suggest that increases in intracellular Ca 2+ enhance cardiac sensitivity to digoxin-induced arrhythmias and that the arrhythmogenic action may involve Ca 2+ overload at a pool other than that which activates contractile proteins.