TY - JOUR
T1 - The Anti-Epileptic Drugs Lamotrigine and Valproic Acid Reduce the Cardiac Sodium Current
AU - Jia, Lixia
AU - Verkerk, Arie O.
AU - Tan, Hanno L.
N1 - Funding Information: This research has received funding from the European Union’s Horizon 2020 research and innovation programme under the acronym ESCAPE-NET, registered under grant agreement No 733381, and the COST Action PARQ (grant agreement No CA19137), supported by COST (European Cooperation in Science and Technology), the Netherlands CardioVascular Research Initiative, Dutch Heart Foundation, Dutch Federation of University Medical Centers, Netherlands Organization for Health Research and Development, Royal Netherlands Academy of Sciences—CVON2018-30 Predict2, and the China Scholarship Council (CSC). Publisher Copyright: © 2023 by the authors.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - Anti-epileptic drugs (AEDs) are associated with increased risk of sudden cardiac death. To establish whether gabapentin, lamotrigine, levetiracetam, pregabalin, and valproic acid reduce the Nav1.5 current, we conducted whole-cell patch-clamp studies to study the effects of the five AEDs on currents of human cardiac Nav1.5 channels stably expressed in HEK293 cells, and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. Lamotrigine and valproic acid exhibited inhibitory effects on the Nav1.5 current in a concentration-dependent manner with an IC50 of 142 ± 36 and 2022 ± 25 µM for lamotrigine and valproic acid, respectively. In addition, these drugs caused a hyperpolarizing shift of steady-state inactivation and a delay in recovery from inactivation. The changes on the Nav1.5 properties were reflected by a reduction in AP upstroke velocity (43.0 ± 6.8% (lamotrigine) and 23.7 ± 10.6% (valproic acid) at 1 Hz) and AP amplitude; in contrast, AP duration was not changed. Gabapentin, levetiracetam, and pregabalin had no effect on the Nav1.5 current. Lamotrigine and valproic acid reduce the Nav1.5 current density and affect its gating properties, resulting in a decrease of the AP upstroke velocity. Gabapentin, levetiracetam, and pregabalin have no effects on the Nav1.5 current.
AB - Anti-epileptic drugs (AEDs) are associated with increased risk of sudden cardiac death. To establish whether gabapentin, lamotrigine, levetiracetam, pregabalin, and valproic acid reduce the Nav1.5 current, we conducted whole-cell patch-clamp studies to study the effects of the five AEDs on currents of human cardiac Nav1.5 channels stably expressed in HEK293 cells, and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. Lamotrigine and valproic acid exhibited inhibitory effects on the Nav1.5 current in a concentration-dependent manner with an IC50 of 142 ± 36 and 2022 ± 25 µM for lamotrigine and valproic acid, respectively. In addition, these drugs caused a hyperpolarizing shift of steady-state inactivation and a delay in recovery from inactivation. The changes on the Nav1.5 properties were reflected by a reduction in AP upstroke velocity (43.0 ± 6.8% (lamotrigine) and 23.7 ± 10.6% (valproic acid) at 1 Hz) and AP amplitude; in contrast, AP duration was not changed. Gabapentin, levetiracetam, and pregabalin had no effect on the Nav1.5 current. Lamotrigine and valproic acid reduce the Nav1.5 current density and affect its gating properties, resulting in a decrease of the AP upstroke velocity. Gabapentin, levetiracetam, and pregabalin have no effects on the Nav1.5 current.
KW - action potentials
KW - anti-epileptic drugs
KW - cardiomyocytes
KW - sodium current
KW - sudden cardiac death
UR - http://www.scopus.com/inward/record.url?scp=85148857241&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/biomedicines11020477
DO - https://doi.org/10.3390/biomedicines11020477
M3 - Article
C2 - 36831014
SN - 2227-9059
VL - 11
JO - Biomedicines
JF - Biomedicines
IS - 2
M1 - 477
ER -