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A model to check the arrhythmogenic activity of antiarrhythmic drugs
1Department of Pharmacology, University of Kiel, Germany.
Abstract:
1. In order to evaluate a condition which allows to check arrhythmogenic properties of antiarrhythmic drugs first experiences with the following model are presented. 2. Papillary muscles of guinea pig hearts were exposed to subthreshold concentration of aconitine (8 x 10(-8) M) for 30 min. 3. During the last 10 min of this period a lack of oxygen and glucose was additionally imposed on the muscle. 4. After this priming period, reoxygenation with glucose containing Tyrode solution was introduced and aconitine removed from the organ bath. 5. Restoring the normal conditions, the contractile force and the membrane potential completely recovered. Also the amplitude of the action pontial regained the control value. 6. Only the action potential duration displayed a prolongation of the late repolarization phase which can be described as a hump at a potential of about -55 mV. 7. 30 Minutes after the end of the priming period the muscles were exposed to antiarrhythmic drugs. 8. Quinidine, propafenone and gallopamil (at concentrations reducing the contractile force by 50%) induced a further prolongation of the action potential duration and provoked early after-depolarizations thus acting arrhythmogenic. 9. In contrast, lidocaine and phenytoin did not prolong the action potential duration under this condition and were devoid of any arrhythmogenic activity. 10. The proposed model might offer a possibility to differentiate antiarrhythmic drugs with respect to their unwanted arrhythmogenic activity.
Insights
This study introduces a novel guinea pig heart model to assess antiarrhythmic drug safety. The model effectively identified quinidine, propafenone, and gallopamil as arrhythmogenic, while lidocaine and phenytoin showed no adverse effects.
Area of Science:
- Cardiovascular Pharmacology
- Cardiac Electrophysiology
- Drug Safety Assessment
Background:
- Assessing the arrhythmogenic potential of antiarrhythmic drugs is crucial for patient safety.
- Existing models may not fully capture the complex electrophysiological changes induced by drug-cardiac interactions.
Purpose of the Study:
- To evaluate a novel experimental model for testing the arrhythmogenic properties of antiarrhythmic drugs.
- To differentiate between drugs that prolong action potential duration and induce early afterdepolarizations versus those that do not.
Main Methods:
- Guinea pig papillary muscles were exposed to aconitine and hypoxia/glucose deprivation.
- Following a recovery period, muscles were treated with various antiarrhythmic drugs.
- Contractile force, membrane potential, and action potential duration were monitored.
Main Results:
- The model induced a specific prolongation of the action potential duration with a 'hump' at -55 mV.
- Quinidine, propafenone, and gallopamil prolonged action potential duration and caused early afterdepolarizations.
- Lidocaine and phenytoin did not exhibit arrhythmogenic activity in this model.
Conclusions:
- The proposed model effectively differentiates antiarrhythmic drugs based on their arrhythmogenic activity.
- This model may serve as a valuable tool for preclinical safety evaluation of antiarrhythmic agents.
- Identifying drugs with unwanted pro-arrhythmic effects is essential for therapeutic development.