Epilepsy-Induced High Affinity Blockade of the Cardiac Sodium Current INa by Lamotrigine; A Potential for Acquired Arrythmias.

Lamotrigine is widely prescribed to treat bipolar neurological disorder and epilepsy. It exerts its antiepileptic action by blocking voltage-gated sodium channels in neurons. Recently, the US Food and Drug Administration issued a warning on the use of Lamotrigine after observations of conduction anomalies and Brugada syndrome patterns on the electrocardiograms of epileptic patients treated with the drug. Brugada syndrome and conduction disturbance are both associated with alterations of the cardiac sodium current (INa) kinetics and amplitude. In this study, we used the patch clamp technique on cardiomyocytes from epileptic rats to test the hypothesis that Lamotrigine also blocks INa in the heart. We found that Lamotrigine inhibited 60% of INa peak amplitude and reduced cardiac excitability in epileptic rats but had little effect in sham animals. Moreover, Lamotrigine inhibited 67% of INaL and, more importantly, prolonged the action potential refractory period in epileptic animals. Our results suggest that enhanced affinity of Lamotrigine for INa may in part explain the clinical phenotypes observed in epileptic patients.

Sequential interaction of chloride and proton ions with the fast gate steer the voltage-dependent gating in ClC-2 chloride channels.

The interaction of either H(+) or Cl(-) ions with the fast gate is the major source of voltage (V(m)) dependence in ClC Cl(-) channels. However, the mechanism by which these ions confer V(m) dependence to the ClC-2 Cl(-) channel remains unclear. By determining the V(m) dependence of normalized conductance (G(norm)(V(m))), an index of open probability, ClC-2 gating was studied at different [H(+)](i), [H(+)](o) and [Cl(-)](i). Changing [H(+)](i) by five orders of magnitude whilst [Cl(-)](i)/[Cl(-)](o) = 140/140 or 10/140 mm slightly shifted G(norm)(V(m)) to negative V(m) without altering the onset kinetics; however, channel closing was slower at acidic pH(i). A similar change in [H(+)](o) with [Cl(-)](i)/[Cl(-)](o) = 140/140 mm enhanced G(norm) in a bell-shaped manner and shifted G(norm)(V(m)) curves to positive V(m). Importantly, G(norm) was >0 with [H(+)](o) = 10(-10) m but channel closing was slower when [H(+)](o) or [Cl(-)](i) increased implying that ClC-2 was opened without protonation and that external H(+) and/or internal Cl(-) ions stabilized the open conformation. The analysis of kinetics and steady-state properties at different [H(+)](o) and [Cl(-)](i) was carried out using a gating Scheme coupled to Cl(-) permeation. Unlike previous results showing V(m)-dependent protonation, our analysis revealed that fast gate protonation was V(m) and Cl(-) independent and the equilibrium constant for closed­open transition of unprotonated channels was facilitated by elevated [Cl(-)](i) in a V(m)-dependent manner. Hence a V(m) dependence of pore occupancy by Cl(-) induces a conformational change in unprotonated closed channels, before the pore opens, and the open conformation is stabilized by Cl(-) occupancy and V(m)-independent protonation.