Molecular determinants of local anesthetic action of beta-blocking drugs: Implications for therapeutic management of long QT syndrome variant 3.
Molecular determinants of local anesthetic action of beta-blocking drugs: Implications for therapeutic management of long QT syndrome variant 3.
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DOI：
10.1016/j.yjmcc.2009.05.012
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发表时间：
2010-01
影响因子：
5
通讯作者：
Kass, Robert S.
中科院分区：
文献类型：
--
作者：
Bankston, John R.;Kass, Robert S.
先天性长QT综合征（LQTS）是一种遗传性心律失常，其中编码离子通道或离子通道相关蛋白的基因突变延迟心室复极，并使突变携带者处于严重或致命性心律失常的风险中。LQTS心律失常的触发和治疗管理已被证明是不同的方式，显着依赖于基因突变。此外，β受体阻滞剂对LQT-1的治疗有效，但由于伴随心率减慢，肾上腺素能活性降低，因此认为β受体阻滞剂在LQT-3的治疗中具有潜在的促肾上腺素释放作用。在这里，我们报告了β受体阻滞剂普萘洛尔与野生型（WT）和LQT-3突变型Na+通道的相互作用，其作用方式类似于局部麻醉药物。我们证明，普萘洛尔块钠离子通道的使用依赖性的方式，普萘洛尔的疗效是依赖于通道的失活状态，普萘洛尔块晚期非失活电流比峰值钠电流更有效，和突变的局部麻醉剂结合位点大大降低普萘洛尔块的峰值和晚期钠离子通道电流的疗效。此外，我们的研究结果表明，这种活性，如局部麻醉药物，不同的药物结构和生物物理变化的Na+通道功能所造成的特定LQT-3突变。
The congenital long QT syndrome (LQTS) is a heritable arrhythmia in which mutations in genes coding for ion channels or ion channel associated proteins delay ventricular repolarization and place mutation carriers at risk for serious or fatal arrhythmias. Triggers and therapeutic management of LQTS arrhythmias have been shown to differ in a manner that depends strikingly on the gene that is mutated. Additionally, beta-blockers, effective in the management of LQT-1, have been thought to be potentially proarrhythmic in the treatment of LQT-3 because of concomitant slowing of heart rate that accompanies decreased adrenergic activity. Here we report that the beta-blocker propranolol interacts with wild type (WT) and LQT-3 mutant Na+ channels in a manner that resembles the actions of local anesthetic drugs. We demonstrate that propranolol blocks Na+ channels in a use-dependent manner; that propranolol efficacy is dependent on the inactivated state of the channel; that propranolol blocks late non-inactivating current more effectively than peak sodium current; and that mutation of the local anesthetic binding site greatly reduces the efficacy of propranolol block of peak and late Na+ channel current. Furthermore our results indicate that this activity, like that of local anesthetic drugs, differs both with drug structure and the biophysical changes in Na+ channel function caused by specific LQT-3 mutations.
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影响因子：
120.7
作者：
Napolitano, C;Priori, SG;Leonardi, S
通讯作者：
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影响因子：
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作者：
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DOI：
10.1111/j.1742-7843.2005.pto960206.x
发表时间：
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作者：
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通讯作者：
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