The Anti-Epileptic Drugs Lamotrigine and Valproic Acid Reduce the Cardiac Sodium Current

Figures

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  Figure 1. Effects of anti-epileptic drugs on current densities of Nav1.5 channels expressed in HEK293 cells. (A) Typical Nav1.5 current elicited by application of 100 ms depolarizing pulses from −120 to −40 mV. (B–D) Normalized Nav1.5 current in the absence or presence of 100, 300, or 1000 µM gabapentin (B), levetiracetam (C), and pregabalin (D). (E,F) Lamotrigine and valproic acid induced concentration-dependent inhibition of the Nav1.5 current magnitude. Solid lines are Hill fits to the average data. Values are normalized to the values measured under baseline conditions. The yellow parts indicate the therapeutic concentrations of the AEDs. Numbers near symbols indicated the number of cells (n) measured at the given concentrations.

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  Figure 2. Effects of 100 µM lamotrigine on density and gating kinetics of Nav1.5 channels expressed in HEK293 cells. (A) Typical Nav1.5 currents under baseline conditions and in the presence of 100 μM lamotrigine. Inset: voltage clamp protocol used to measure current-voltage (I-V) relationships (B) and the voltage dependency of (in)activation (C). Cycle length was 5 s. (B) The Nav1.5 current-voltage (I-V) relationships before and after the application of 100 μM lamotrigine. The Nav1.5 current was normalized to the maximal peak amplitude under baseline conditions, but the peak current was set to −1 to retain the well-known inward direction of sodium current. (C) Effects of lamotrigine on the voltage dependency of the Nav1.5 current (in)activation. Solid lines are Boltzmann fits to the average data. (D) Use dependency under baseline conditions and in the presence of lamotrigine measured during a train of 30 depolarizing pulses with an interpulse interval of 50 ms. Inset: voltage clamp protocol used to measure (upper panel) and typical Nav1.5 currents under baseline conditions and in the presence of 100 μM lamotrigine (middle panel). (E) Recovery from inactivation of the Nav1.5 current in the…

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  Figure 3. Effects of 2000 µM valproic acid on the density and kinetics of currents from Nav1.5 channels expressed in HEK293 cells. (A) Typical Nav1.5 under baseline conditions and in the presence of 2000 μM valproic acid. Inset: used voltage clamp protocol to measure I-V relationships (B) and the voltage dependency of (in)activation (C). Cycle length was 5 s. (B) Average I-V relationships before and after the application of 2000 μM valproic acid. (C) Effects of valproic acid on Nav1.5 (in)activation. Solid lines are Boltzmann fits to the average data. (D) Use dependency under baseline conditions and in the presence of valproic acid. Inset: voltage clamp protocol used to measure (upper panel) and typical Nav1.5 currents under baseline conditions and in the presence of 2000 μM valproic acid (middle panel). (E) Recovery from inactivation of the Nav1.5 current in the absence and presence of 2000 μM valproic acid measured with a double-pulse protocol with variable interpulse intervals. Inset: voltage clamp protocol used to measure (upper panel) and typical Nav1.5 currents under baseline conditions and in the presence of 2000 μM valproic acid with an interpulse interval of 50 ms (middle panel).…

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  Figure 4. Effects of 100 µM lamotrigine on action potentials (APs) of rabbit ventricular cardiomyocytes. (A) Superimposed representative APs at 1 Hz under baseline conditions and in the presence of 100 µM lamotrigine. Inset: time derivatives of the AP upstrokes. The dV/dtmax are aligned by the peak. (B–E) Average AP characteristics at 1, 2, and 3 Hz of resting membrane potential (RMP, (B)), maximal AP upstroke velocity (dV/dtmax, (C, left panel)) and the inhibition percentage of dV/dtmax induced by lamotrigine (C, right panel), AP duration at 90% of repolarization (APD90, (D)), AP amplitude (APA, (E, left panel)), and the inhibition percentage of APA induced by lamotrigine (E, right panel). Data are mean ± SEM. Numbers below frequencies indicate the number of cells (n) measured at a given frequency. * p < 0.05 lamotrigine versus baseline (Two-Way RM ANOVA or One-Way RM ANOVA).

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  Figure 5. Effects of valproic acid on APs of rabbit ventricular cardiomyocytes. (A) Superimposed representative APs at 1 Hz under baseline conditions and in the presence of 3000 µM valproic acid. Inset: time derivatives of the AP upstrokes. The dV/dtmax are aligned by the peak. (B–E) Average AP characteristics at 1, 2, and 3 Hz of resting membrane potential (RMP, (B)), maximal AP upstroke velocity (dV/dtmax, (C, left panel)), the inhibition percentage of dV/dtmax induced by valproic acid (C, right panel), AP duration at 90% of repolarization (APD90, (D)), AP amplitude (APA, (E, left panel)), and the inhibition percentage of APA induced by valproic acid (E, right panel). Data are mean ± SEM. Numbers below frequencies indicate the number of cells (n) measured at a given frequency. * p < 0.05 valproic acid versus baseline (Two-Way RM ANOVA or One-Way RM ANOVA).