Caballero R, Delpón E, Valenzuela C, Longobardo M, González T, Tamargo J
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Mol Pharmacol. 2001 Apr;59(4):825-36. doi: 10.1124/mol.59.4.825.
In the present study, we analyzed the effects of two angiotensin II type 1 receptor antagonists, candesartan (0.1 microM) and eprosartan (1 microM), on hKv1.5, HERG, KvLQT1+minK, and Kv4.3 channels expressed on Ltk(-) or Chinese hamster ovary cells using the patch-clamp technique. Candesartan and eprosartan produced a voltage-dependent block of hKv1.5 channels decreasing the current at +60 mV by 20.9 +/- 2.3% and 14.3 +/- 1.5%, respectively. The blockade was frequency-dependent, suggesting an open-channel interaction. Eprosartan inhibited the tail amplitude of HERG currents elicited on repolarization after pulses to +60 mV from 239 +/- 78 to 179 +/- 72 pA. Candesartan shifted the activation curve of HERG channels in the hyperpolarizing direction, thus increasing the current amplitude elicited by depolarizations to potentials between -50 and 0 mV. Candesartan reduced the KvLQT1+minK currents elicited by 2-s pulses to +60 mV (38.7 +/- 6.3%). In contrast, eprosartan transiently increased (8.8 +/- 2.7%) and thereafter reduced the KvLQT1+minK current amplitude by 17.7 +/- 3.0%. Eprosartan, but not candesartan, blocked Kv4.3 channels in a voltage-dependent manner (22.2 +/- 3.5% at +50 mV) without modifying the voltage-dependence of Kv4.3 channel inactivation. Candesartan slightly prolonged the action potential duration recorded in guinea pig papillary muscles at all driving rates. Eprosartan prolonged the action potential duration in muscles driven at 0.1 to 1 Hz, but it shortened this parameter at faster rates (2--3 Hz). All these results demonstrated that candesartan and eprosartan exert direct effects on Kv1.5, HERG, KvLQT1+minK, and Kv4.3 currents involved in human cardiac repolarization.
在本研究中，我们运用膜片钳技术分析了两种血管紧张素II 1型受体拮抗剂——坎地沙坦（0.1微摩尔）和依普罗沙坦（1微摩尔）对在Ltk(-)细胞或中国仓鼠卵巢细胞上表达的hKv1.5、HERG、KvLQT1+minK以及Kv4.3通道的影响。坎地沙坦和依普罗沙坦对hKv1.5通道产生电压依赖性阻滞，使+60毫伏时的电流分别降低20.9±2.3%和14.3±1.5%。这种阻滞具有频率依赖性，提示存在开放通道相互作用。依普罗沙坦抑制了从+60毫伏脉冲复极化时诱发的HERG电流的尾电流幅度，从239±78皮安降至179±72皮安。坎地沙坦使HERG通道的激活曲线向超极化方向移动，从而增加了去极化至-50至0毫伏之间电位时诱发的电流幅度。坎地沙坦降低了2秒脉冲至+60毫伏诱发的KvLQT1+minK电流（38.7±6.3%）。相比之下，依普罗沙坦短暂增加（8.8±2.7%），随后使KvLQT1+minK电流幅度降低17.7±3.0%。依普罗沙坦而非坎地沙坦以电压依赖性方式阻断Kv4.3通道（+50毫伏时为22.2±3.5%），且不改变Kv4.3通道失活的电压依赖性。坎地沙坦在所有驱动频率下均略微延长了豚鼠乳头肌记录的动作电位持续时间。依普罗沙坦在0.1至1赫兹驱动的肌肉中延长了动作电位持续时间，但在更快频率（2 - 3赫兹）下缩短了该参数。所有这些结果表明，坎地沙坦和依普罗沙坦对参与人类心脏复极化的Kv1.5、HERG、KvLQT1+minK以及Kv4.3电流具有直接影响。
