Related Experiment Videos
Extracellular magnesium and cardiotonic steroid toxicity in isolated myocardial preparations
R Kafiluddi1, R H Kennedy, E Seifen
1Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock.
Abstract:
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.
Insights
Extracellular magnesium (Mg++0) reduces sensitivity to cardiotonic steroid-induced arrhythmias in guinea pig hearts. This effect is not due to changes in receptor binding or Na+-pump activity.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Biochemistry
Background:
- Cardiotonic steroids (e.g., digoxin) are used to treat heart failure.
- Their therapeutic use is limited by toxic side effects, including arrhythmias.
- Extracellular magnesium (Mg++0) is a critical ion in cardiac function.
Purpose of the Study:
- To investigate the direct effects of extracellular magnesium (Mg++0) on the positive inotropic and toxic actions of cardiotonic steroids.
- To determine the mechanisms underlying Mg++0's influence on cardiotonic steroid toxicity.
Main Methods:
- Isolated guinea pig left atrial muscle preparations were used to assess inotropic and arrhythmogenic effects.
- Experiments were conducted using partially purified membrane preparations to study [3H]ouabain binding and Na+,K+-adenosine triphosphatase activity.
- Fractional occupancy estimates were used to evaluate receptor binding levels.
Main Results:
- Increased Mg++0 concentrations demonstrated a negative inotropic effect and reduced sensitivity to digoxin-induced arrhythmias.
- Mg++0 did not alter maximum developed tension before dysrhythmic activity or affect contracture sensitivity.
- Elevated Mg++ enhanced affinity for [3H]ouabain in membrane preparations but did not affect binding site density or Na+-pump activity in intact tissue.
Conclusions:
- Extracellular magnesium (Mg++0) directly antagonizes cardiotonic steroid-induced arrhythmias in the myocardium.
- The observed protective effect of Mg++0 is likely mediated by altered responsiveness rather than changes in receptor binding or Na+-pump capacity.