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Cardiac instability amplified by use-dependent Na channel blockade
C F Starmer1, A R Lancaster, A A Lastra
1Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710.
The American Journal of Physiology
|April 1, 1992
Summary
Certain drugs can increase the risk of cardiac arrhythmias and sudden death by blocking sodium channels. This blockade prolongs the heart
Area of Science:
- Cardiovascular Pharmacology
- Cardiac Electrophysiology
- Computational Biology
Background:
- Drugs causing use-dependent sodium channel blockade are associated with cardiac arrhythmias and sudden death.
- Computer simulations suggest sodium channel blockade increases spatial dispersion of refractoriness, a precursor to arrhythmias.
Purpose of the Study:
- To investigate the proarrhythmic potential of use-dependent sodium channel blockade.
- To establish a model for assessing cardiac instability and drug-induced arrhythmias.
Main Methods:
- Utilized isolated rabbit left atria.
- Employed timed stimuli following conditioning stimuli to identify a vulnerable period.
- Assessed the effect of use-dependent sodium channel blockade on this vulnerable period.
Main Results:
- Identified a vulnerable period in cardiac tissue where single stimuli can initiate arrhythmias.
- Demonstrated that use-dependent sodium channel blockade extends this vulnerable period.
- Validated the rabbit atrial preparation as a model for proarrhythmic potential.
Conclusions:
- Use-dependent sodium channel blockade is a significant risk factor for cardiac arrhythmias.
- The extended vulnerable period serves as a quantifiable measure of proarrhythmic potential.
- This model can aid in evaluating the cardiac safety of various drug classes.