ANTIARRYHTHMIC DRUG ACTION ON VMAX OF CARDIAC CELLS

抗心律失常药物对心肌细胞Vmax的作用

• 批准号: 3350505
• 负责人: LUC M HONDEGHEM
• 金额: $ 19.96万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-07-01 至 1989-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3350505
• 关键词: action potentials; antiarrhythmic agent; cardiotonic agents; cardiovascular disorder chemotherapy; chemical structure function; chlorpromazine; computer simulation; electrophysiology; heart conduction system; heart function; heart pharmacology; heart rate; lidocaine; mathematical model; membrane potentials; myocardial infarction; phenytoin; physical chemical interaction; procainamide; quinidine

The objectives of the present investigation are: (1) To further test the modulated receptor hypothesis for the action of antiarrhythmic drugs on cardiac sodium channels. (2) To develop a faster and more complete search method for analysis of the experimental results, including upper and lower limits for the estimates. (3) To characterize the structure-activity relationship for lidocaine procainamide, aprindine and amiodarone derivatives. (4) To continue the development of a preparation that can be voltage clamped. (5) To study drug interactions in terms of modulated receptor hypothesis. It is hoped that this research will further improve our understanding of the action of antiarrhythmic drugs; that the elucidation of the QSAR will promote the development of better and safer antiarrhythmic drugs; that the drug interactions will provide better use of the currently available drugs. Guinea pig papillary muscles and single isolated cardiocytes will be voltage clamped. The sodium current or Vmax will be measured and these data will be used to estimate the drug blocked channels. By clamping the preparations to various potentials and different durations it is possible to determine the affinity and the kinetics of the interaction of antiarrhythmic drugs with sodium channels. The modulated receptor constants and the biophysical properties of the drugs will be correlated using cluster analysis techniques to unravel the structure activity relationship in a quantitative fashion (QSAR). The results of QSAR will be used to improve existing antiarrhythmic drugs and to design new ones.

本研究的目的是：（1）进一步检验 抗肿瘤药物作用的受体调节假说 心脏钠离子通道 (2)开发一个更快更全面的搜索 方法分析的实验结果，包括上，下 估计的限度。 (3)为了表征结构活性， 利多卡因、普鲁卡因胺、阿普林定和胺碘酮之间的关系 衍生物. (4)继续研制一种制剂， 电压箝位。 (5)为了研究药物相互作用， 受体假说 希望这项研究能够进一步完善 我们对抗疟疾药物作用的理解; QSAR的阐明将促进更好、更安全的 药物相互作用将提供更好的使用 目前可用的药物。 豚鼠乳头肌和单个分离的心肌细胞将 电压箝位。 将测量钠电流或Vmax，这些 数据将用于估计药物阻塞的通道。 夹闭 准备各种电位和不同的持续时间，这是可能的 以确定亲和力和相互作用的动力学， 钠离子通道的抗心律失常药物。 调节受体常数和生物物理性质的 药物将使用聚类分析技术进行关联， 定量构效关系（QSAR）。 定量构效关系的研究结果将用于改进现有的抗肿瘤药物 and to design设计new新ones.