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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.
Basic Research in Cardiology
|November 1, 1989
Summary
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.