RT Journal Article
T1 Diltiazem inhibits hKv1.5 and Kv4.3 currents at therapeutic concentrations
A1 Caballero Collado, Ricardo
A1 Gómez García, Ricardo
A1 Núñez Fernández, Lucía
A1 Moreno Fernández, Ignacio
A1 Tamargo Menéndez, Juan
A1 Delpón Mosquera, María Eva
AB AbstractObjective: In the present study we examined the effects of diltiazem, an L-type Ca(2+) channel blocker widely used for the control of the ventricular rate in patients with supraventricular arrhythmias, on hKv1.5 and Kv4.3 channels that generate the cardiac ultrarapid delayed rectifier (I(Kur)) and the 4-aminopyridine sensitive transient outward (I(to)) K(+) currents, respectively.Methods: hKv1.5 and Kv4.3 channels were stably and transiently expressed in mouse fibroblast and Chinese hamster ovary cells, respectively. Currents were recorded using the whole-cell patch clamp.Results: Diltiazem (0.01 nM-500 muM) blocked hKv1.5 channels, in a frequency-dependent manner exhibiting a biphasic dose-response curve (IC(50)=4.8+/-1.5 nM and 42.3+/-3.6 muM). Diltiazem delayed the initial phase of the tail current decline and shifted the midpoint of the activation (Vh=-16.5+/-2.1 mV vs -20.4+/-2.6 mV, P<0.001) and inactivation (Vh=-22.4+/-0.7 mV vs. -28.2+/-1.9 mV, P<0.001) curves to more negative potentials. The analysis of the development of the diltiazem-induced block yielded apparent association (k) and dissociation (P) rate constants of (1.6+/-0.2) x 10(6) M(-1)s(-1) and 46.8+/-4.8 s(-1), respectively. Diltiazem (0.1 nM-100 muM) also blocked Kv4.3 channels in a frequency-dependent manner exhibiting a biphasic dose-response curve (IC(50)=62.6+/-11.1 nM and 109.9+/-12.8 muM). Diltiazem decreased the peak current and, at concentrations > or =0.1 microM, accelerated the inactivation time course. The apparent association and dissociation rate constants resulted (1.7+/-0.2) x 10(6) M(-1)s(-1) and 258.6+/-38.1 s(-1), respectively. Diltiazem, 10 nM, shifted to more negative potentials the voltage-dependence of Kv4.3 channel inactivation (Vh=-33.1+/-2.3 mV vs -38.2+/-3.5 mV, n=6, Plt;0.05) the blockade increasing at potentials at which the amount of inactivated channels increased.Conclusion: The results demonstrated for the first time that diltiazem, at therapeutic concentrations, decreased hKv1.5 and Kv4.3 currents by binding to the open and the inactivated state of the channels.
PB Oxford University Press
SN 0008-6363
YR 2004
FD 2004
LK https://hdl.handle.net/20.500.14352/91706
UL https://hdl.handle.net/20.500.14352/91706
LA eng
NO Ricardo Caballero, Ricardo Gómez, Lucía Núñez, Ignacio Moreno, Juan Tamargo, Eva Delpón, Diltiazem inhibits hKv1.5 and Kv4.3 currents at therapeutic concentrations, Cardiovascular Research, Volume 64, Issue 3, December 2004, Pages 457–466, https://doi.org/10.1016/j.cardiores.2004.07.022
NO Pfizer Foundation
NO Ministerio de Ciencia e Innovación (España)
DS Docta Complutense
RD 4 abr 2025