Extracellular magnesium and cardiotonic steroid toxicity in isolated myocardial preparations

This study examined effects of extracellular magnesium (Mg++0) on the positive inotropic and toxic actions of cardiotonic steroids in cardiac muscle isolated from guinea pig heart. Increasing concentrations of Mg++0 produced a negative inotropic effect in electrically paced, left atrial muscle and decreased the sensitivity to arrhythmogenic actions of digoxin without affecting the maximum developed tension observed before dysrhythmic activity. Other signs of toxicity such as contracture were less sensitive to the antagonistic effects of Mg++0. Estimates of fractional occupancy suggested that the increased tolerance to digoxin-induced arrhythmias was mediated by an altered responsiveness to given levels of receptor binding. Experiments in partially purified membrane preparations demonstrated that elevations in Mg++ increased affinity for 3H]ouabain without affecting binding site density. Na+,K+-adenosine triphosphatase activity in these membrane preparations was also enhanced by Mg++; however, increases in buffer Mg++ concentration had no effect on the Na+-pump in intact tissue. In summary, these results indicate that elevations in Mg++0 act directly on myocardium to diminish the sensitivity to cardiotonic steroid-induced arrhythmias. Furthermore, data suggest that this antagonistic action of Mg++0 is not mediated by alterations in receptor binding or Na+-pump reserve capacity.