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目的:研究替米沙坦对表达在卵母细胞上的克隆人类Kv1.5通道的作用,探讨其在心脏复极中的潜在效应。方法:在非洲爪蟾卵母细胞上异源表达克隆人类Kv1.5通道基因,使用双电极电压钳技术记录全细胞电流,检测药物对Ikur电流的影响。结果:替米沙坦以电压依赖性和浓度依赖性方式抑制Kv1.5通道电流,且对峰电流及1.5s末端电流的抑制效应不同,在1μmol/L浓度下,抑制效应分别达到(7.75±2.39)和(52.64±3.77),其半抑制浓度(IC50)分别为(2.25±0.97)μmol/L和(0.82±0.39)μmol/L。替米沙坦对通道的稳态失活没有显著改变,在对照条件下,V1/2的值为(14.47±3.71)mV,斜坡因子k为(23.24±3.86)mV;在1μmol/L替米沙坦作用下,V1/2和k的值分别为(14.38±4.62)mV和(26.26±5.04)mV(n=6,P>0.05)。同时,替米沙坦显著加速了Kv1.5通道的失活。在对照条件下,Kv1.5通道的失活慢时间常数是(693.74±23.16)ms,在应用1μmol/L替米沙坦后,其失活的慢时间常数下降为(523.85±10.28)ms(n=5,P<0.05)。结论:替米沙坦在临床有效浓度范围内能显著抑制表达在卵母细胞上的Ikur电流,提示它兼有选择性阻滞Kv1.5通道的作用。
OBJECTIVE: To investigate the effect of telmisartan on the expression of cloned human Kv1.5 channel on oocytes and its potential effect on cardiac repolarization. Methods: The human Kv1.5 gene was cloned heterologously on Xenopus laevis oocytes. Whole cell currents were recorded by two-electrode voltage-clamp technique. The effects of drugs on Ikur currents were examined. RESULTS: Telmisartan inhibited Kv1.5 channel currents in a voltage-dependent and concentration-dependent manner with different inhibitory effects on peak currents and 1.5s end currents, with inhibitory effects reaching 7.75 ± (2.25 ± 0.97) μmol / L and (0.82 ± 0.39) μmol / L, respectively (2.39 and 52.64 ± 3.77, respectively) The steady-state inactivation of telmisartan did not change significantly. Under the control conditions, the value of V1 / 2 was (14.47 ± 3.71) mV and the slope factor k was (23.24 ± 3.86) mV. The values of V1 / 2 and k were (14.38 ± 4.62) mV and (26.26 ± 5.04) mV (n = 6, P> 0.05), respectively, under the influence of sartan. At the same time, telmisartan significantly accelerated Kv1.5 channel inactivation. Under the control conditions, the slow time constant of Kv1.5 channel inactivation was (693.74 ± 23.16) ms, and the slow time constant of inactivation decreased to (523.85 ± 10.28) ms after application of 1 μmol / L telmisartan n = 5, P <0.05). CONCLUSION: Telmisartan can significantly inhibit the Ikur current expressed in oocytes in a clinically effective concentration range, suggesting that it may selectively block the Kv1.5 channel.