A study on the mechanisms of antiarrhythmic agents through gene expression of cardiac potassium channels

在本研究中，我们研究了胺碘酮或不同水平甲状腺激素长期治疗对心脏离子通道，特别是复极化钾通道的影响。我们还测试了基因表达调节对这些变化的可能作用。首先，在体外培养的乳鼠心室肌细胞上观察了胺碘酮和甲状腺激素对心肌钾通道的相互作用。在T_3存在的情况下，1 μ M的胺碘酮在培养3天内使Ito和Ik的钾电流均降低约30%，而在T_3不存在的情况下，胺碘酮对Ito和Ik的抑制作用在培养3天内被消除。其次，在不同甲状腺素水平下，测定克隆的K通道亚基Kv1.4和Kv1.5mRNA的水平，Kv1.5mRNA的水平在甲状腺功能低下时降低，在甲状腺功能亢进时升高。另一方面，Kv 1.4的mRNA水平表现出相反的方向，并在甲状腺功能减退的条件下增加，而不受甲状腺功能亢进的条件。这些结果表明，胺碘酮对Ito和Ik的抑制作用依赖于甲状腺激素的水平，也表明胺碘酮通过在细胞水平上与心肌细胞中的T3相互作用而抵消甲状腺激素而发挥抗心律失常作用。

In our present study, we investigated the effects of long-term treatment of amiodarone or varying levels of thyroid hormone on cardiac ion channels, especially repolarizing potassium channels. We also tested possible role of modulation of gene expression on these changes. Firstly, the interaction of amiodarone and thyroid hormone on the cardiac potassium channels were observed in cultured ventricular myocytes isolated from neonatal rat. In the presence of T3, amiodarone at 1 muM decreased both potassium currents of Ito and Ik about 30% within 3-days culture.On the other hand, in the absence of T3, these inhibitory effects on Ito and Ik by amiodarone for 3 days-culture were abolished. Secondly, mRNA levels of cloned K channel subunit, Kv 1.4 and Kv 1.5, were, measured under the various levels of thyroxine, Levels of mRNA of Kv 1.5 was decreased in the hypothyroid condition and increased in hyperthyroid ones. On the other hand, mRNA levels of Kv 1.4 exhibited opposite direction and increased in hypothyroid condition and not affected by hyperthyroid conditions. These result indicate that the inhibitory actions of chronic amiodarone on Ito and Ik were dependent on the levels of thyroid hormones and also suggest that amiodarone exert antiarrhythmic action by counteracting the thyroid hormones due to the interaction to T3 at the cellular levels ion cardiac myocytes.