Probucol and the cholesterol synthesis inhibitors simvastatin and triparanol regulate Iks channel function differently
Probucol and the cholesterol synthesis inhibitors simvastatin and triparanol regulate Iks channel function differently
复制标题
DOI：
10.1177/0960327112474848
复制
发表时间：
2013-10-01
影响因子：
2.8
通讯作者：
Sawada, Kohei
中科院分区：
文献类型：
--
作者：
Hihara, Taro;Taniguchi, Tomohiko;Sawada, Kohei
负责缓慢激活延迟整流钾电流（I-Ks）的通道由KCNQ 1和KCNE 1亚基组成，这些通道在心脏动作电位的复极中起作用。最近，我们发现，抗高血压药物普罗布考，诱导QT间期延长，降低I-Ks后24小时的治疗。在本研究中，我们研究了三种降胆固醇药物（普罗布考，一种胆固醇流出的增强剂;辛伐他汀，一种3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂;和triparanol，一种3-羟基甾醇-24-还原酶抑制剂）对胆固醇合成、KCNQ 1电流（I-KCNQ 1）和I-Ks的影响，以澄清这些药物对I-Ks的作用模式的差异。普罗布考不抑制胆固醇合成，对I-KCNQ 1没有影响，而I-Ks在治疗24小时后下降。辛伐他汀抑制胆固醇合成，降低I-KCNQ 1和I-Ks。此外，与对照I-Ks相比，I-Ks的激活动力学变得更快。Triparanol抑制胆固醇合成，但不减少I-KCNQ 1和I-Ks。然而，I-Ks的活化动力学变得更快。我们的数据表明普罗布考抑制I-Ks的机制不是通过抑制胆固醇合成介导的，而是依赖于与KCNQ 1/KCNE 1复合物的相互作用。同时，辛伐他汀和曲帕醇降低胆固醇是影响I-ks动力学的机制之一。
Channels responsible for slowly activating delayed-rectifier potassium current (I-Ks) are composed of KCNQ1 and KCNE1 subunits, and these channels play a role in the repolarization of cardiac action potentials. Recently, we showed that the antihyperlipidemic drug probucol, which induces QT prolongation, decreases the I-Ks after 24-h treatment. In the present study, we investigated the effects of three cholesterol-lowering agents (probucol, an enhancer of cholesterol efflux; simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor; and triparanol, a 3-hydroxysterol-24-reductase inhibitor) on cholesterol synthesis, the KCNQ1 current (I-KCNQ1), and the I-Ks to clarify the differences in the modes of action of these agents on the I-Ks. Probucol did not inhibit cholesterol synthesis and had no effect on I-KCNQ1, while I-Ks decreased after 24-h treatment. Simvastatin inhibited cholesterol synthesis and decreased I-KCNQ1 and I-Ks. Additionally, the activation kinetics of I-Ks became faster, compared with that of control I-Ks. Triparanol inhibited cholesterol synthesis but did not reduce I-KCNQ1 and I-Ks. However, the activation kinetics of I-Ks became faster. Our data indicated that the mechanism by which probucol inhibits I-Ks was not mediated by the inhibition of cholesterol synthesis but depended on an interaction with the KCNQ1/KCNE1 complex. Meanwhile, the reduction in cholesterol induced by simvastatin and triparanol is one of the mechanisms that affects the kinetics of I-ks.