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Digitalis cardiotoxicity: cellular calcium overload a possible mechanism
J C Khatter1, M Agbanyo, S Navaratnam
1Department of Medicine, University of Manitoba, Winnipeg, Canada.
Abstract:
Isolated perfused guinea pig (Langendorff) heart was employed to determine if the myocardial mechanical dysfunction (mechanical toxicity) produced by toxic concentration of ouabain (1 microM) was accompanied by alterations in mitochondrial function. Ouabain (1 microM) produces a transient increase in the myocardial contractile force and then a continuous decline in the left ventricular mechanical function. Mitochondria isolated from ouabain perfused hearts showed a significantly higher rate of 45Ca2+ uptake and reduction in oxidative phosphorylation. The rate of ATP generation was reduced by almost 50% at the time of contracture development. Verapamil or nifedipine, when combined with ouabain in the perfusion medium, delayed or abolished the mechanical toxicity in a dose dependent manner. The mitochondria isolated from these hearts demonstrated normal rate of Ca2+ uptake and ATP generation capacity. The data indicate that the cardiac mechanical dysfunction induced by toxic doses of ouabain may be associated with mitochondrial Ca2+ overload and dysfunction and that the Ca2+ channel blockers may have a protective effect.
Insights
Toxic ouabain concentrations harm heart muscle function by impairing mitochondria. Calcium channel blockers like verapamil and nifedipine protect against this cardiac toxicity, preserving mitochondrial function.
Area of Science:
- Cardiovascular Physiology
- Mitochondrial Biology
- Pharmacology
Background:
- Ouabain (1 microM) induces myocardial mechanical dysfunction.
- This dysfunction involves alterations in myocardial contractile force and left ventricular function.
Purpose of the Study:
- To investigate the relationship between ouabain-induced cardiac mechanical dysfunction and mitochondrial function.
- To determine the protective effects of calcium channel blockers against ouabain toxicity.
Main Methods:
- Isolated perfused guinea pig (Langendorff) heart model.
- Assessment of mitochondrial function, including 45Ca2+ uptake and oxidative phosphorylation.
- Evaluation of ATP generation rates.
- Administration of ouabain with and without verapamil or nifedipine.
Main Results:
- Ouabain (1 microM) significantly increased mitochondrial 45Ca2+ uptake and reduced oxidative phosphorylation.
- ATP generation rate decreased by approximately 50% during contracture development.
- Verapamil and nifedipine dose-dependently delayed or abolished mechanical toxicity.
- Mitochondria from hearts treated with ouabain and calcium channel blockers showed normal Ca2+ uptake and ATP generation.
Conclusions:
- Cardiac mechanical dysfunction from toxic ouabain doses is linked to mitochondrial calcium overload and dysfunction.
- Calcium channel blockers demonstrate a protective effect against ouabain-induced cardiac toxicity.
- Mitochondrial dysfunction plays a key role in ouabain cardiotoxicity.