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

心脏钾通道基因表达的抗心律失常药物作用机制研究

• 批准号: 07670774
• 负责人: KAMIYA Kaichiro
• 金额: $ 1.41万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670774/
• 关键词: amiodarone; ion channels; heart; antiarrhythmic drugs; thyroid hormone; mRNA; potassium channels; dntiarrhythmic drugs; アミオダロン; 甲状腺ホルモン; イオンチャネル; 活動電位; 遺伝子; カリウム電流

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.

在本研究中，我们研究了对氨二酮或甲状腺激素水平的长期治疗对心脏离子通道的影响，尤其是重复使钾通道的影响。我们还测试了基因表达调制在这些变化上的可能作用。首先，在从新生大鼠中分离出的培养的心室心肌细胞中观察到氨二酮和甲状腺激素在心脏钾通道上的相互作用。在存在T3的情况下，1 Mum处的胺碘酮在3天培养物中降低了ITO和IK的两个钾电流。另一方面，在没有T3的情况下，这些对ITO和IK的抑制作用3天，这些抑制作用3天 - 废除文化。其次，在甲状腺素水平的各种水平下测量的克隆K通道亚基，KV 1.4和KV 1.5的mRNA水平在甲状腺功能下的甲状腺素水平下测量，甲状腺功能低下的mRNA水平降低，甲状腺功能亢进症的mRNA水平降低。另一方面，KV 1.4的mRNA水平表现出相反的方向，并且在甲状腺功能减退症状态下增加，并且不受甲状腺功能亢进症的影响。这些结果表明，慢性胺碘酮对ITO和IK的抑制作用取决于甲状腺激素的水平，并且还表明，由于在细胞离电基水平离子心脏肌细胞上相互作用而导致的甲状腺激素通过抵消甲状腺激素而发挥抗心律失常作用。

项目成果

GUO Weinong, KAMIYA Kaichiro CHENG Jianhua, TOYAMA Junji: "Changes in action potentials and ion currents in long-term cultured neonatal rat ventricular cells." American Journal of Physiology (Cell). 271. C93-C102 (1996)

郭伟农、神谷佳一郎、程建华、远山润二：“长期培养的新生大鼠心室细胞动作电位和离子电流的变化”。

IWATA Hirokazu,KODAMA Itsuo SUZUKI Ryoko,KAMIYA Kaichiro TOYAMA Junji: "Effects of Long-term oral administration of amiodarone on the ventricular repolarization of rabbit hearts." Japanese Circulation Journal. 60. 662-672 (1996)

岩田博和、小玉五雄铃木良子、神谷凯一郎富山润二：“长期口服胺碘酮对兔心心室复极的影响”。

NISHIYAMA A,KAMBE F,KAMIYA K,KUROKOUCHI K,KANDA K,MURATA Y,TOYAMA J,SEO H: "Effects of stress on Kv 1.5K^+ channel gene expression in the left ventricule of rat hearts." Environmental Medicine. 39. 141-143 (1995)

NISHIYAMA A、KAMBE F、KAMIYA K、KUROKOUCHI K、KANDA K、MURATA Y、TOYAMA J、SEO H：“应激对大鼠左心室 Kv 1.5K^ 通道基因表达的影响。”

GHENG Jianhua, KAMIYA Kaichiro, KODAMA Itsuo and TOYAMA Junji: "Differential effects of MS-551 and E-4031 on action potentials and the delayd-rectifier K+ current in rabbit ventricular myocytes." Cardiovasclar Research. 31. 963-974 (1996)

GHENGjianhua、KAMIYA Kaichiro、KODAMA Ituo 和 TOYAMA Junji：“MS-551 和 E-4031 对兔心室肌细胞动作电位和延迟整流 K 电流的不同影响。”

CHENG J,KAMIYA K,KODAMA I,TOYAMA J: "Differential blocking properties of the new class-III antiarrhythmic agents,MS-551 and E-4031 on the cardiac delayed rectifier K^+ current." Environmental Medicine. 39. 137-140 (1995)

CHENG J、KAMIYA K、KODAMA I、TOYAMA J：“新型 III 类抗心律失常药物 MS-551 和 E-4031 对心脏延迟整流 K^ 电流的不同阻断特性。”