Chlorthalidone inhibits the KvLQT1 potassium current in guinea-pig ventricular myocytes and oocytes from Xenopus laevis.
OBJECTIVE
Chlorthalidone is used for the treatment of hypertension as it produces a lengthening of the cardiac action potential. However, there is no experimental evidence that chlorthalidone has electrophysiological effects on the potassium currents involved in cardiac repolarization.


METHODS
Ventricular myocytes and oocytes, transfected with human ionic channels that produce IK current, were exposed to different concentrations of chlorthalidone. Action potentials and potassium currents were recorded using a patch clamp technique. To determine which component of the current was affected by chlorthalidone, human channel proteins (hERG, minK and KvLQT1) were used.


RESULTS
Chlorthalidone prolonged the ventricular action potential at 50 and 90% by 13 and 14%, respectively. The cardiac potassium currents I(to) and IK(1) were not affected by chlorthalidone at any concentration, whereas the delayed rectifier potassium current, IK, was blocked in a dose-response, voltage-independent fashion. In our preparation, 100 microM chlorthalidone blocked the two components of the delayed rectifier potassium current with the same potency (50.1+/-5% for IK(r) and 54.6+/-6% for IK(s)) (n=7, P<0.05). The chlorthalidone-sensitive current was slow and saturated at potentials greater than +30 mV. In our conditions only the KvLQT1 potassium current was affected by the drug, by 14%.


CONCLUSIONS
Chlorthalidone was demonstrated to have a direct effect on cardiac ventricular myocytes; it blocked the delayed rectifier potassium current (IK), specifically the KvLQT1 component of the potassium current. These results indicate that it has potential for use as an antiarrhythmic but further studies are needed.
Mancilla-Simbro
C
C
Instituto de Fisiología, B. Universidad Autónoma de Puebla, Ciudad Universitaria, Puebla, Puebla, México.
López
A
A
Martinez-Morales
E
E
Soto-Perez-de-Celis
E
E
Millan-PerezPeña
L
L
Tsushima
R
R
Salinas-Stefanon
E M
EM
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002752:Chlorthalidone / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000037:antagonists & inhibitors*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000378:metabolism; D014982:Xenopus laevis
D000959:Antihypertensive Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C489622:KCNE1 protein, human; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D002752:Chlorthalidone