Electropharmacological properties of telmisartan in blocking hKvl.5 and HERG potassium channels expressed on Xenopus laevis oocytes^1  

作　　者：Dan-na TU Yu-hua LIAO An-ruo ZOU Yi-mei DU Qi RUN Xian-pei WANG Lu LI 

机构地区：[1]Research Center of lon Channelopathy, Department of Cardiology, htstitute of Cardiovascular Diseases, Union Hospital, Tongji MedicalColle~e, Huazhong University of Science and Technology, Wuhan 430022, China

出　　处：《Acta Pharmacologica Sinica》2008年第8期913-922,共10页中国药理学报（英文版）

基　　金：Project supported by the National Natural Science Foundation of China （No 30470711）.

摘　　要：Aim： The objectives of this study were to investigate the inhibitory action of telmisartan, a selective angiotensin Ⅱ type 1 receptor antagonist, on hKvl.5 and human ether-a-go-go-related gene （HERG） channels expressed on Xenopus laevis oocytes. Methods： hKvl.5 and HERG channels were expressed on Xenopus laevis oocytes and studied using the 2-microelectrode voltage clamp technique. Results： In hKvl.5 channels, telmisartan produced a voltageand 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±μmol/L） and 52.64%±3.77% （IC50=0.82±0.39μmol/L） at Ⅰ μmol/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 μmol/L）; the blockade was voltage and concentrationdependent. 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. Conclusion： Telmisartan blocks hKvl.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.Aim： The objectives of this study were to investigate the inhibitory action of telmisartan, a selective angiotensin Ⅱ type 1 receptor antagonist, on hKvl.5 and human ether-a-go-go-related gene （HERG） channels expressed on Xenopus laevis oocytes. Methods： hKvl.5 and HERG channels were expressed on Xenopus laevis oocytes and studied using the 2-microelectrode voltage clamp technique. Results： In hKvl.5 channels, telmisartan produced a voltageand 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±μmol/L） and 52.64%±3.77% （IC50=0.82±0.39μmol/L） at Ⅰ μmol/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 μmol/L）; the blockade was voltage and concentrationdependent. 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. Conclusion： Telmisartan blocks hKvl.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.

关 键 词：tehnisartan human ether-a-go-go-related gene hKv 1.5 voltage clamp cardiac repolarization 

分 类 号：R45[医药卫生—治疗学]