Gyógyszerészet, farmakogenomika, gyógyszerkutatás és tervezés, gyógyszeres kezelés
Background and purpose: Ivabradine is clinically administered
to lower the heart rate, proposedly by inhibiting hyperpolarization-activated cyclic
nucleotide-gated cation channels in the sinoatrial node. Recent evidence suggests
that voltage-gated sodium channels (VGSC) are inhibited within the same concentration
range. VGSCs are expressed within the sinoatrial node and throughout the conduction
system of the heart. A block of these channels thus likely contributes to the established
and newly raised clinical indications of ivabradine. We, therefore, investigated the
pharmacological action of ivabradine on VGSCs in sufficient detail in order to gain
a better understanding of the pro- and anti-arrhythmic effects associated with the
administration of this drug.Experimental Approach:
Ivabradine was tested on VGSCs in native cardiomyocytes isolated from mouse ventricles
and the His-Purkinje system and on human Nav1.5 in a heterologous
expression system. We investigated the mechanism of channel inhibition by determining
its voltage-, frequency-, state-, and temperature-dependence, complemented by a molecular
drug docking to the recent Nav1.5 cryoEM structure. Automated
patch-clamp experiments were used to investigate ivabradine-mediated changes in Nav1.5
inactivation parameters and inhibition of different VGSC isoforms.Key
results: Ivabradine inhibited VGSCs in a voltage- and frequency-dependent
manner, but did not alter voltage-dependence of activation and fast inactivation,
nor recovery from fast inactivation. Cardiac (Nav1.5), neuronal
(Nav1.2), and skeletal muscle (Nav1.4) VGSC
isoforms were inhibited by ivabradine within the same concentration range, as were
sodium currents in native cardiomyocytes isolated from the ventricles and the His-Purkinje
system. Molecular drug docking suggested an interaction of ivabradine with the classical
local anesthetic binding site.Conclusion and Implications:
Ivabradine acts as an atypical inhibitor of VGSCs. Inhibition of VGSCs likely contributes
to the heart rate lowering effect of ivabradine, in particular at higher stimulation
frequencies and depolarized membrane potentials, and to the observed slowing of intra-cardiac
conduction. Inhibition of VGSCs in native cardiomyocytes and across channel isoforms
may provide a potential basis for the anti-arrhythmic potential as observed upon administration
of ivabradine.
