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Changes in action potentials and intracellular ionic homeostasis in a ventricular cell model related to a persistent sodium current in SCN5A mutations underlying LQT3

Abstract : In LQT3 patients, SCN5A mutations induce ultraslow inactivation of a small fraction of the hNav1.5 current, i.e. persistent Na+ current (I pNa). We explored the time course of effects of such a change on the intracellular ionic homeostasis in a model of guinea-pig cardiac ventricular cell [Pasek,M., Simurda,J., Orchard,C.H., Christe,G., 2007b. A model of the guinea-pig ventricular cardiomyocyte incorporating a transverse–axial tubular system. Prog. Biophys. Mol. Biol., this issue]. Sudden addition of IpNa prevented action potential (AP) repolarization when its conductance (gpNa) exceeded 0.12% of the maximal conductance of fast INa (gNa). With gpNa at 0.1% gNa, the AP duration at 90% repolarization (APD90) was initially lengthened to 2.6-fold that in control. Under regular stimulation at 1 Hz it shortened progressively to 1.37-fold control APD90,and intracellular [Na+]i increased by 6% with a time constant of 106 s. Further increasing gpNa to 0.2% gNa caused an immediate increase in APD90 to 5.7-fold that in control, which decreased to 2.2-fold that in control in 30 s stimulation at 1 Hz. At this time diastolic [Na+]i and [Ca2+]i were, respectively, 34% and 52% higher than in control and spontaneous erratic SR Ca release occurred. In the presence of IpNa causing 46% lengthening of APD90, the model cell displayed arrhythmogenic behaviour when external [K+] was lowered to 5 mM from an initial value at 5.4 mM. By contrast,when K+ currents IKr and IKs were lowered in the model cell to produce the same lengthening of APD90, no proarrhythmic behaviour was observed, even when external [K+] was lowered to 2.5 mM.
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https://www.hal.inserm.fr/inserm-00325970
Contributor : Georges Christé <>
Submitted on : Monday, October 6, 2008 - 1:44:03 PM
Last modification on : Monday, July 20, 2020 - 1:06:04 PM
Long-term archiving on: : Tuesday, June 28, 2011 - 4:54:51 PM

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Georges Christé, Mohamed Chahine, Philippe Chevalier, Michal Pásek. Changes in action potentials and intracellular ionic homeostasis in a ventricular cell model related to a persistent sodium current in SCN5A mutations underlying LQT3. Progress in Biophysics and Molecular Biology, Elsevier, 2007, 96 (1-3), pp.281-293. ⟨10.1016/j.pbiomolbio.2007.07.023⟩. ⟨inserm-00325970⟩

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