A revised view of cardiac sodium channel “blockade” in the long-QT syndrome
AUTOR(ES)
Kambouris, Nicholas G.
FONTE
American Society for Clinical Investigation
RESUMO
Mutations in SCN5A, encoding the cardiac sodium (Na) channel, are linked to a form of the congenital long-QT syndrome (LQT3) that provokes lethal ventricular arrhythmias. These autosomal dominant mutations disrupt Na channel function, inhibiting channel inactivation, thereby causing a sustained ionic current that delays cardiac repolarization. Sodium channel–blocking antiarrhythmics, such as lidocaine, potently inhibit this pathologic Na current (INa) and are being evaluated in patients with LQT3. The mechanism underlying this effect is unknown, although high-affinity “block” of the open Na channel pore has been proposed. Here we report that a recently identified LQT3 mutation (R1623Q) imparts unusual lidocaine sensitivity to the Na channel that is attributable to its altered functional behavior. Studies of lidocaine on individual R1623Q single-channel openings indicate that the open-time distribution is not changed, indicating the drug does not block the open pore as proposed previously. Rather, the mutant channels have a propensity to inactivate without ever opening (“closed-state inactivation”), and lidocaine augments this gating behavior. An allosteric gating model incorporating closed-state inactivation recapitulates the effects of lidocaine on pathologic INa. These findings explain the unusual drug sensitivity of R1623Q and provide a general and unanticipated mechanism for understanding how Na channel–blocking agents may suppress the pathologic, sustained Na current induced by LQT3 mutations.
ACESSO AO ARTIGO
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=300835Documentos Relacionados
- Characterization of human cardiac Na+ channel mutations in the congenital long QT syndrome
- Long QT syndrome, Brugada syndrome, and conduction system disease are linked to a single sodium channel mutation
- Long QT syndrome: novel insights into the mechanisms of cardiac arrhythmias
- Cardiac arrest in a young woman with the long QT syndrome and concomitant astemizole ingestion.
- Pharmacological targeting of long QT mutant sodium channels.