Electropharmacological properties of telmisartan in blocking hKv1.5 and HERG potassium channels expressed on Xenopus laevis oocytes
Abstract
Aim: 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 μmol/L) and 52.64%±3.77% (IC50=0.82±0.39 μmol/L) at 1 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 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.
Conclusion: 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.
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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 μmol/L) and 52.64%±3.77% (IC50=0.82±0.39 μmol/L) at 1 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 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.
Conclusion: 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.