Carbamazepine Increases the Risk of Sudden Cardiac Arrest by a Reduction of the Cardiac Sodium Current

FIGURE 1. Carbamazepine (CBZ) reduces the action potential (AP) upstroke velocity and AP amplitude of rabbit ventricular cardiomyocytes. (A) AP recording illustrating the analyzed AP parameters. Inset: time derivative (dV/dt) of the AP upstroke on an expanded time scale. RMP, resting membrane potential; APA, AP amplitude; APD90, AP duration at 90% of repolarization; dV/dtmax, maximal AP upstroke velocity. (B) Superimposed representative APs at 1 Hz under baseline conditions, in presence of 100 µM CBZ, and upon washout of the drug. Inset: time derivatives of the AP upstrokes. (C) Average AP characteristics at 1 Hz (top panels) and individual (paired) data points (bottom panels). *p < 0.05 CBZ versus baseline (One-Way RM ANOVA). (D,E) Average normalized dV/dtmax (D) and APA (E) at 1 Hz in response to 1, 10, 30, and 100 µM CBZ. Values are normalized to the values measured under baseline conditions. Numbers near symbols indicate the number of cells (n) measured at a given concentration. *p < 0.05 CBZ versus baseline (One-Way RM ANOVA); § p < 0.05 CBZ 100 µM versus lower concentrations (One-Way ANOVA).

FIGURE 2. Carbamazepine (CBZ) reduces the AP upstroke velocity and amplitude of rabbit ventricular cardiomyocytes in a frequency dependent manner. (A) Superimposed typical time derivatives (dV/dt) during the AP upstroke phase at stimulus frequencies ranging from 0.2 to 4 Hz under baseline conditions (left) and in presence of 100 µM CBZ (right). (B) Average dV/dtmax under baseline conditions (filled squares) and in response to 1–100 µM CBZ (open circles) at stimulus frequencies ranging from 0.2 to 4 Hz. Values are normalized to the highest dV/dtmax measured at 0.2–4 Hz under baseline conditions. *p < 0.05 CBZ versus baseline (Two-Way RM ANOVA). See Supplementary Figure S2 for statistical significance of the frequency dependent effects. (C) Average APA under baseline conditions (filled squares) and in response to 1–100 µM CBZ (open circles) at stimulus frequencies ranging from 0.2 to 4 Hz. Values are normalized to the highest APA measured at 0.2–4 Hz under baseline conditions. *p < 0.05 CBZ versus baseline (Two-Way RM ANOVA).

FIGURE 3. Carbamazepine (CBZ) reduces the sodium current (INa) of rabbit ventricular cardiomyocytes in a use-dependent manner. (A) Typical INa recordings between −80 and 0 mV under baseline conditions and in presence of 100 µM CBZ. Inset: double-pulse voltage clamp protocol used to measure current-voltage (I–V) relationships (B) as well as the voltage dependency of (in)activation (D). Cycle length was 5 s. (B) Average I-V relationship of INa under baseline conditions and in presence of 100 µM CBZ. INa was normalized to the maximal peak amplitude under baseline conditions, but peak current was set to −1 to retain the well-known inward direction of INa. *p < 0.05 CBZ versus baseline (Two-Way RM ANOVA). (C) Concentration dependency of the CBZ effects on INa amplitude at −35 mV *p < 0.05 CBZ versus baseline (One-Way RM ANOVA); § p < 0.05 higher versus lower CBZ concentrations (One-Way ANOVA). (D) Voltage dependency of (in)activation. Solid lines are Boltzmann fits to the average data. *p < 0.05 CBZ versus baseline (Two-Way RM ANOVA). (E,F) Recovery from INa inactivation measured with a double-pulse protocol (E, inset). (E) Typical INa recordings under baseline conditions and in presence of 100…

FIGURE 4. Carbamazepine (CBZ) reduces the L-type Ca2+ current of rabbit ventricular cardiomyocytes without affecting K+ currents. (A) Typical recordings of the L-type Ca2+ current (ICa,L) at 0 mV under baseline conditions and in presence of 100 µM CBZ. Inset: voltage clamp protocol used. Cycle length was 2 s. (B) Average I-V relationship of ICa,L under baseline conditions and in presence of 100 µM CBZ. ICa,L was normalized to the maximal peak amplitude under baseline conditions, but peak current was set to −1 to retain the well-known inward direction of ICa,L. *p < 0.05 CBZ versus baseline (Two-Way RM ANOVA). (C) Concentration dependency of the CBZ effect on ICa,L amplitude measured at 0 mV. *p < 0.05 CBZ versus baseline (One-Way RM ANOVA); § p < 0.05 CBZ 100 µM versus lower concentrations (One-Way ANOVA). (D) Typical recordings of the delayed rectifier K+ current (IK; at +60 mV) and inward rectifier K+ current (IK1; at −100 mV) under baseline conditions and in presence of 100 µM CBZ. Voltage clamp protocol as in panel (A). (E) Average I-V relationships of IK and IK1 under baseline conditions and in presence of 100 µM CBZ. The currents were normalized to the current measured at −100 mV…

FIGURE 5. Carbamazepine (CBZ) affects human atrial electrophysiology. (A) Superimposed representative human atrial APs at a stimulus frequency of 1 Hz in control conditions and in presence of 100 µM CBZ. Inset: time derivatives during the AP upstroke phase. (B) Average AP characteristics at a stimulus frequency of 1 Hz under baseline conditions and in presence of 100 µM CBZ (top panels) and individual (paired) data points (bottom panels). *p < 0.05 CBZ versus baseline (One-Way RM ANOVA). (C) Average dV/dtmax in response to 100 µM CBZ at stimulus frequencies ranging from 0.2 to 4 Hz. Values are normalized to the highest dV/dtmax measured under baseline conditions. *p < 0.05 CBZ versus baseline (Two-Way RM ANOVA). (D) Average I-V relationship of INa under baseline conditions and in presence of 100 µM CBZ (top panel) and V1/2 and k of activation (bottom panels). Inset: voltage clamp protocol used. Cycle length was 5 s. INa was normalized to the maximal peak amplitude under baseline conditions, but peak current was set to −1 to retain the well-known inward direction of INa. *p < 0.05 CBZ versus baseline (Two-Way RM ANOVA).