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The cardiac persistent sodium current: an appealing therapeutic target?
1School of Molecular and Biomedical Science, University of Adelaide, Adelaide, SA, Australia. david.saint@Adelaide.edu.au
British Journal of Pharmacology
|December 12, 2007
Summary
The slow component of the sodium current (INa(P)) in the heart, though small, contributes to damage during ischemia and is a target for antiarrhythmic drugs. Blocking INa(P) shows therapeutic potential for various cardiac conditions.
Area of Science:
- Cardiac Electrophysiology
- Molecular Cardiology
- Pharmacology
Background:
- Cardiac sodium current comprises multiple kinetic components, not just a single transient decay.
- A slowly inactivating sodium current (INa(P)) is typically 1% of the peak transient current (INa(T)) but is amplified by hypoxia.
- INa(P) contributes to sodium loading, cellular damage in ischemia-reperfusion, and potentially ischemic arrhythmias.
Purpose of the Study:
- To elucidate the role of the slow component of the sodium current (INa(P)) in cardiac pathophysiology.
- To explore the mechanisms by which INa(P) influences cardiac electrophysiology.
- To assess the potential benefits and side effects of blocking INa(P) for therapeutic purposes.
Main Methods:
- Analysis of cardiac sodium current kinetics and components.
- Investigating the effects of hypoxia on INa(P).
- Evaluating the potency of antiarrhythmic agents on INa(P) versus INa(T).
Main Results:
- Class I antiarrhythmic drugs (flecainide, lidocaine, mexiletine) preferentially block INa(P) over INa(T).
- Mutations in SCN5A causing LQT3 syndrome are linked to defective sodium channel inactivation.
- Ranolazine demonstrates potent blockade of INa(P) (10x INa(T)) and shows promise for angina treatment.
Conclusions:
- Targeting INa(P) offers a potential therapeutic strategy for conditions like LQT3 syndrome, ischemic arrhythmias, and diastolic dysfunction.
- Combined blockade of INa(P) and potassium channels may prevent Torsades de Pointe during atrial arrhythmia treatment.
- Further understanding of INa(P) in cardiac pathophysiology and electrophysiology is crucial for developing effective and safe therapeutic interventions.
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