Molecular mechanisms and its prevention of drug-induced long QT syndrome

药物性长QT综合征的分子机制及其预防

• 批准号: 14370222
• 负责人: KAMIYA Kaichiro
• 金额: $ 8.83万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370222/
• 关键词: Long QT syndrome; Arrhythmias; K+ channel; Sudden Cardiac Death; genes; 突然死

Acquired long QT syndrome is most caused by block of cardiac HERG K+ channels by commonly used medications. It is unclear why so many structurally diverse compounds block HERG channels, but this undesirable side effect now is recognized as a major hurdle in the development of new and safe drugs. To determine the structural basis for high-affinity drug block of HERG channels, determined the important residues for drug binding of class III antiarrhythmic agents ; vesnarinone (cardiotonic agent), E-4031, dofetilide and dl-sotalol(a methanesulfonanilide antiarrhythmic drug), nifekalant (a non-methanesulfonanilide antiarrhythmic drug), bepridil and amiodarone (multi-channel blockers). We mutated to alanine individual residues of S6 (L646-Y667) and the few residues of the pore helix (L622-V625) predicted to line the channel cavity and inner pore regions based on homology with the solved crystal structure of the KcsA channel (Doyle et al.,1998). Vesnarinone bound to six specific residues within the channel cavity. This result was published in Molecular Pharmacology (Kamiya et al.,2001). In addition, acute application of amiodarone, an antiarrhythmic agent, was found to inhibit HERG current, whereas long-term treatment of amiodarone decreased IKs (Kamiya et al., Circulation 001). Dofetilide caused less block in six channels with Ala missense mutations located in the pore helix (T623A, S624A and V625A) and the S6 domain (G648A, F656A and V659A). These six residues are identical to those reported on MK-499. In addition to these mutants, Nifekalnt caused less block on 1655A. Bepridil did not block any of S6 mutants except F656A. These results suggest that 1)methanesulfonanilide drugs have common and identical binding sites except sotalol, 2)class III drugs binds to different residues of HERG channels, thereby producing different, pharmacological effects.

获得性长QT综合征主要由常用药物阻断心脏HERG - K+通道引起。目前尚不清楚为什么如此多结构多样的化合物会阻断HERG通道，但这种不良副作用现在被认为是开发新型安全药物的主要障碍。确定HERG通道高亲和力药物阻滞的结构基础，确定III类抗心律失常药物结合的重要残基；vesnarinone（强心剂）、E-4031、do非利特和l-sotalol（一种甲磺酰苯胺类抗心律失常药物）、nifekalant（一种非甲磺酰苯胺类抗心律失常药物）、bepridil和胺碘酮（多通道阻滞剂）。我们突变了S6的丙氨酸残基（L646-Y667）和孔螺旋的少数残基（L622-V625），基于与KcsA通道的已解晶体结构的同源性，预测它们将排列在通道腔和内孔区域（Doyle et al.,1998）。Vesnarinone与通道腔内的六个特定残基结合。这一结果发表在《分子药理学》（Kamiya et al.,2001）上。此外，研究发现急性应用胺碘酮（一种抗心律失常药物）可抑制HERG电流，而长期使用胺碘酮可降低IKs （Kamiya等人，Circulation 001）。多非利特在6个通道中造成较少的阻滞，位于孔螺旋（T623A、S624A和V625A）和S6结构域（G648A、F656A和V659A）的Ala错义突变。这6个残基与MK-499上报道的相同。除了这些突变外，Nifekalnt对1655A的阻滞较小。Bepridil没有阻断除F656A外的任何S6突变体。这些结果表明：1)甲磺酰苯胺类药物除索他洛尔外具有共同且相同的结合位点；2)III类药物与HERG通道的不同残基结合，从而产生不同的药理作用。

项目成果

TSUJI Yukiomi, et al.: "Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block."Circulation. 106. 2012-2018 (2002)

TSUJI Yukiomi 等人：“慢性完全性房室传导阻滞兔子获得性 QT 间期延长和尖端扭转型室速的离子机制。”循环。

HONJO Haruo, et al.: "Sarcoplasmic reticulum Ca^<2+> is not a dominating factor in sinoatrial node pacemaker activity."Circulation Research. 92. e41-e44 (2003)

HONJO Haruo 等人：“肌浆网 Ca^2 不是窦房结起搏器活动的主导因素。”循环研究。

HONJO Haruo, et al.: "Sarcoplasmic reticulum Ca^<2+> release is not a dominating factor in sinoatrial node pacemaker activity."Circulation Research. 92. e41-e44 (2003)

HONJO Haruo 等人：“肌浆网 Ca^2 释放不是窦房结起搏器活动的主导因素。”循环研究。

MAEKAWA Atsuo, et al.: "Overexpression of calpastatin by gene transfer prevents troponin I degradation and ameliorates contractile dysfunction in rat hearts subjected to ischemia/reperfusion."Journal of Molecular and Cellular Cardiology. 35. 1277-1284 (20

MAEKAWA Atsuo 等人：“通过基因转移过度表达钙蛋白酶抑制剂可防止肌钙蛋白 I 降解并改善缺血/再灌注大鼠心脏的收缩功能障碍。”分子与细胞心脏病学杂志。

神谷香一郎: "薬物誘発性QT延長症候群の分子構造機序"循環器専門医. 10. 237-243 (2002)

Koichiro Kamiya：“药物引起的长 QT 综合征的分子结构机制”心脏病学家。10. 237-243 (2002)