Slowing of the Inactivation of Cardiac Voltage-Dependent Sodium Channels by the Amiodarone Derivative 2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015)
Slowing of the Inactivation of Cardiac Voltage-Dependent Sodium Channels by the Amiodarone Derivative 2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015)
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胺碘酮衍生物 2-甲基-3-(3,5-二碘-4-羧甲氧基苄基)苯并呋喃 (KB130015) 减缓心脏电压依赖性钠通道失活
DOI：
10.1124/jpet.102.042218
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发表时间：
2003
影响因子：
3.5
通讯作者：
K. Mubagwa
中科院分区：
文献类型：
--
作者：
R. Mačianskienė;S. Viappiani;K. Sipido;K. Mubagwa
2-甲基-3-（3，5-二碘-4-羧基甲氧基苄基）苯并呋喃（KB 130015或KB）是一种新药，结构上与胺碘酮和甲状腺激素相关。用全细胞（[Na+]i = [Na+]o = 10 mM）和细胞贴附式膜片钳技术研究了22°C时，它对猪单个心室肌细胞电压依赖性Na+电流（INa）的影响。KB显著减慢Na失活，这是由于以正常的快失活成分（τ快<2-3 ms）为代价产生了慢失活成分（τ慢<50 ms）。该效应具有浓度依赖性，半最大有效浓度（K 0.5）为2.1 μM。KB还减缓了失活的恢复，并将电压依赖性失活（ΔV 0.5 = −15 mV;K 0.5 ≥ 6.9 μM）和活化转移到更负的电位。用10 μM KB进行细胞内细胞透析对灭活作用的影响很小或没有影响，并且不能阻止细胞外应用药物的作用。在细胞贴附的补丁，细胞外KB延长Na+通道开放。胺碘酮（10 μM）和10 μM 3，5-二碘-l-甲状腺丙酸对灭活无影响，也不能防止KB效应。3，3 ′，5-三碘甲腺原氨酸（T3）对失活也没有影响，但在10 μM时，它增加了I Na的幅度，并部分阻止了KB对失活的减慢。这些数据表明，存在的KB和T3的结合位点的Na+通道。
2-Methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran (KB130015 or KB) is a new drug, structurally related to amiodarone and to thyroid hormones. Its effects on cardiac voltage-dependent Na+current (I Na) were studied in pig single ventricular myocytes at 22°C using the whole-cell (with [Na+]i = [Na+]o = 10 mM) and cell-attached patch-clamp techniques. KB markedly slowedI Na inactivation, due to the development of a slow-inactivating component (τslow ≈ 50 ms) at the expense of the normal, fast-inactivating component (τfast ≈ 2–3 ms). The effect was concentration-dependent, with a half-maximally effective concentration (K 0.5) of 2.1 μM. KB also slowed the recovery from inactivation and shifted the voltage-dependent inactivation (ΔV 0.5 = −15 mV;K 0.5 ≥ 6.9 μM) and activation to more negative potentials. Intracellular cell dialysis with 10 μM KB had marginal or no effect on inactivation and did not prevent the effect of extracellularly applied drug. In cell-attached patches, extracellular KB prolonged Na+ channel opening. Amiodarone (10 μM) and 10 μM 3,5,-diiodo-l-thyropropionic acid had no effect on inactivation and did not prevent KB effects. 3,3′,5-Triodo-l-thyronine (T3) also had no effect on inactivation, but at 10 μM it increasedI Na amplitude and partially prevented the slowing of inactivation by KB. These data suggest the existence of a binding site for KB and T3 on Na+ channels.
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遗传性钠通道病：新的治疗和致心律失常分子机制。
DOI：
10.1016/s1050-1738(01)00116-5
发表时间：
2001
期刊：
Trends in cardiovascular medicine.
影响因子：
--
作者：
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通讯作者：
Balser,JR
影响因子：
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作者：
Maltsev, VA;Sabbah, HN;Undrovinas, AI
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Undrovinas, AI
DOI：
--
发表时间：
1994-08
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
H. Tatebayashi;T. Narahashi
通讯作者：
H. Tatebayashi;T. Narahashi
胺碘酮诱导分离心肌细胞钠电流阻断。
DOI：
--
发表时间：
1987
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Follmer,CH;Aomine,M;Yeh,JZ;Singer,DH
通讯作者：
Singer,DH