Bupivacaine对异源表达的心肌型Na_v1.5电压依赖性的阻滞
发布时间：2019-03-12 19:07
【摘要】：Bupivacaine(布比卡因)被列为目前最强力有效的I型局麻药之一,但潜在的严重毒性反应在一定程度上限制了其在临床上的应用。布比卡因的毒性主要归因于对电压门控钠通道(VGSCs)功能的严重阻滞。然而,这些疏水性分子与靶通道受体位点结合的细胞与分子机制仍模棱两可。Nav1.5是一种在心肌细胞中丰富表达的电压门控钠通道亚型,其功能紊乱被认为是导致心律失常的主要原因。本课题研究目的接近临床浓度范围内布比卡因作用靶通道Nav1.5的细胞与分子机制理解。本论文工作首先将Nav1.5 m RNA异源表达在爪蟾卵母宿主细胞中,经电生理记录,结果表明,布比卡因可抑制Nav1.5的峰电流,且抑制药效呈浓度依赖性和电压依赖性,半抑制剂量(IC50)为4.51μM。与其他局麻药一致,布比卡因对Nav1.5的阻滞具有使用依赖性。上述结果提示,布比卡因既可剂量依赖性地影响Nav1.5门控动力学参数,也可助推Nav1.5通道开放态(open-state)的慢失活进程。本项研究有助于拓展临床用药布比卡因的靶向选择性及其机制的医学基础知识,并为临床局麻药的安全用药提供参考。
[Abstract]:Bupivacaine (bupivacaine) is listed as one of the most powerful and effective local anesthetic of type I at present, but its clinical application is limited to some extent because of its potential severe toxic reaction. The toxicity of bupivacaine is mainly due to the severe blockage of voltage-gated sodium channel (VGSCs) function. However, the cellular and molecular mechanisms of these hydrophobic molecules binding to target channel receptor sites remain ambiguous. Nav1.5 is a voltage-gated sodium channel subtype that is abundant in cardiomyocytes. Its dysfunction is considered to be the main cause of arrhythmias. The purpose of this study is to understand the cellular and molecular mechanisms of bupivacaine acting on target channel Nav1.5 in a range close to clinical concentration. In this work, Nav1.5 m RNA was first expressed in Xenopus oocytes. The results showed that bupivacaine could inhibit the peak current of Nav1.5 in a concentration dependent and voltage dependent manner, and the inhibitory effect of bupivacaine was in a concentration dependent and voltage dependent manner. The half inhibitory dose (IC50) was 4.51 渭 M. Consistent with other local anesthetics, bupivacaine was used to block Nav1.5 in a dose-dependent manner. These results suggest that bupivacaine can not only influence the Nav1.5 gating kinetic parameters in a dose-dependent manner, but also promote the slow inactivation of Nav1.5 channel open state (open-state). This study is helpful to expand the medical basic knowledge of targeted selectivity and its mechanism of bupivacaine in clinical use and provide reference for safe use of local anesthetic in clinic.
【学位授予单位】：上海大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R614
本文编号：2439069
[Abstract]:Bupivacaine (bupivacaine) is listed as one of the most powerful and effective local anesthetic of type I at present, but its clinical application is limited to some extent because of its potential severe toxic reaction. The toxicity of bupivacaine is mainly due to the severe blockage of voltage-gated sodium channel (VGSCs) function. However, the cellular and molecular mechanisms of these hydrophobic molecules binding to target channel receptor sites remain ambiguous. Nav1.5 is a voltage-gated sodium channel subtype that is abundant in cardiomyocytes. Its dysfunction is considered to be the main cause of arrhythmias. The purpose of this study is to understand the cellular and molecular mechanisms of bupivacaine acting on target channel Nav1.5 in a range close to clinical concentration. In this work, Nav1.5 m RNA was first expressed in Xenopus oocytes. The results showed that bupivacaine could inhibit the peak current of Nav1.5 in a concentration dependent and voltage dependent manner, and the inhibitory effect of bupivacaine was in a concentration dependent and voltage dependent manner. The half inhibitory dose (IC50) was 4.51 渭 M. Consistent with other local anesthetics, bupivacaine was used to block Nav1.5 in a dose-dependent manner. These results suggest that bupivacaine can not only influence the Nav1.5 gating kinetic parameters in a dose-dependent manner, but also promote the slow inactivation of Nav1.5 channel open state (open-state). This study is helpful to expand the medical basic knowledge of targeted selectivity and its mechanism of bupivacaine in clinical use and provide reference for safe use of local anesthetic in clinic.
【学位授予单位】：上海大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R614
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