Concerted suppressive effects of carisbamate, an anti-epileptic alkyl-carbamate drug, on voltage-gated Na and hyperpolarization-activated cation currents.

Carisbamate (CRS, RWJ-333369) is a new anti-seizure medication. It remains unclear whether and how CRS can perturb the magnitude and/or gating kinetics of membrane ionic currents, despite a few reports demonstrating its ability to suppress voltage-gated Na currents. In this study, we observed a set of whole-cell current recordings and found that CRS effectively suppressed the voltage-gated Na () and hyperpolarization-activated cation currents () intrinsically in electrically excitable cells (GH cells). The effective IC values of CRS for the differential suppression of transient () and late () were 56.4 and 11.4 μM, respectively. However, CRS strongly decreased the strength (i.e., Δarea) of the nonlinear window component of (), which was activated by a short ascending ramp voltage (); the subsequent addition of deltamethrin (DLT, 10 μM) counteracted the ability of CRS (100 μM, continuous exposure) to suppress . CRS strikingly decreased the decay time constant of evoked during pulse train stimulation; however, the addition of telmisartan (10 μM) effectively attenuated the CRS (30 μM, continuous exposure)-mediated decrease in the decay time constant of the current. During continued exposure to deltamethrin (10 μM), known to be a pyrethroid insecticide, the addition of CRS resulted in differential suppression of the amplitudes of and . The amplitude of activated by a 2-s membrane hyperpolarization was diminished by CRS in a concentration-dependent manner, with an IC value of 38 μM. For , CRS altered the steady-state relationship and attenuated the strength of voltage-dependent hysteresis (Hys) activated by an inverted isosceles-triangular . Moreover, the addition of oxaliplatin effectively reversed the CRS-mediated suppression of Hys. The predicted docking interaction between CRS and with a model of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel or between CRS and the hNa1.7 channel reflects the ability of CRS to bind to amino acid residues in HCN or hNa1.7 channel via hydrogen bonds and hydrophobic interactions. These findings reveal the propensity of CRS to modify and differentially and to effectively suppress the magnitude of . and are thus potential targets of the actions of CRS in terms of modulating cellular excitability.