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A revised view of cardiac sodium channel “blockade” in the long-QT syndrome
Nicholas G. Kambouris, … , Gordon F. Tomaselli, Jeffrey R. Balser
Nicholas G. Kambouris, … , Gordon F. Tomaselli, Jeffrey R. Balser
Published April 15, 2000
Citation Information: J Clin Invest. 2000;105(8):1133-1140. https://doi.org/10.1172/JCI9212.
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A revised view of cardiac sodium channel “blockade” in the long-QT syndrome

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Abstract

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.

Authors

Nicholas G. Kambouris, H. Bradley Nuss, David C. Johns, Eduardo Marbán, Gordon F. Tomaselli, Jeffrey R. Balser

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Figure 6

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Ensemble-average currents and lidocaine. (a) Ensemble-average currents d...
Ensemble-average currents and lidocaine. (a) Ensemble-average currents derived multichannel patches containing wild-type or R1623Q channels in the absence (left) and presence (right) of 200 μM lidocaine. Representative wild-type and R1623Q ensembles are shown superimposed, but shifted on the time axis, to facilitate comparison. Patches were held at –120 mV for 5 seconds and then pulsed to –40 mV for 150 milliseconds at a repetition cycle of either 10 seconds (no drug) or 20 seconds (drug). Approximately 150 consecutive sweeps for each patch were then used to construct Popen ensembles that are corrected for the number of channels in the patch and the unitary current amplitude (∼2.5 pA). (b) Data summarizing the peak probability of channel opening in the presence and absence of 200 μM lidocaine (number of patches: wild-type, n = 3; R1623Q, n = 3; wild-type + lidocaine, n = 3; R1623Q + lidocaine, n = 5).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 2 patents
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