Electropharmacological properties of telmisartan in blocking hKv1.5 and HERG potassium channels expressed on Xenopus laevis oocytes.
OBJECTIVE
The objectives of this study were to investigate the inhibitory action of telmisartan, a selective angiotensin II type 1 receptor antagonist, on hKv1.5 and human ether-a-go-go-related gene (HERG) channels expressed on Xenopus laevis oocytes.


METHODS
hKv1.5 and HERG channels were expressed on Xenopus laevis oocytes and studied using the 2-microelectrode voltage clamp technique.


RESULTS
In hKv1.5 channels, telmisartan produced a voltage- and concentration-dependent inhibition; the efficacies of blockade were different at peak and 1.5 s end-pulse currents, which were 7.75%+/-2.39% (half-maximal inhibition concentration [IC50]=2.25+/-0.97 micromol/L) and 52.64%+/-3.77% (IC50=0.82+/-0.39 micromol/L) at 1 micromol/L telmisartan, respectively. Meanwhile, telmisartan accelerated the inactivation of the channels. However, telmisartan exhibited a low affinity for HERG channels (IC50=24.35+/-5.06 micromol/L); the blockade was voltage- and concentration-dependent. Telmisartan preferentially blocked open-state HERG channels. The slow time constants of deactivation were accelerated (n=6, P<0.05), which was inconsistent with the "foot-in-the-door"effect.


CONCLUSIONS
Telmisartan blocks hKv1.5 potassium channels involving open and inactivated states at plasma concentration levels of therapeutic doses; whereas the blockade of HERG channels occurs only at supra plasma concentration levels of therapeutic doses and preferentially in open and closed-state channels.
Tu
Dan-na
DN
Research Center of Ion Channelopathy, Department of Cardiology, Institute of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Liao
Yu-hua
YH
Zou
An-ruo
AR
Du
Yi-mei
YM
Run
Qi
Q
Wang
Xian-pei
XP
Li
Lu
L
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D000077333:Telmisartan; D014982:Xenopus laevis
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D051638:Ether-A-Go-Go Potassium Channels; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers; D000077333:Telmisartan