發(fā)布時間：2019-03-12 19:07

【摘要】：Bupivacaine(布比卡因)被列為目前最強力有效的I型局麻藥之一,但潛在的嚴重毒性反應(yīng)在一定程度上限制了其在臨床上的應(yīng)用。布比卡因的毒性主要歸因于對電壓門控鈉通道(VGSCs)功能的嚴重阻滯。然而,這些疏水性分子與靶通道受體位點結(jié)合的細胞與分子機制仍模棱兩可。Nav1.5是一種在心肌細胞中豐富表達的電壓門控鈉通道亞型,其功能紊亂被認為是導(dǎo)致心律失常的主要原因。本課題研究目的接近臨床濃度范圍內(nèi)布比卡因作用靶通道Nav1.5的細胞與分子機制理解。本論文工作首先將Nav1.5 m RNA異源表達在爪蟾卵母宿主細胞中,經(jīng)電生理記錄,結(jié)果表明,布比卡因可抑制Nav1.5的峰電流,且抑制藥效呈濃度依賴性和電壓依賴性,半抑制劑量(IC50)為4.51μM。與其他局麻藥一致,布比卡因?qū)av1.5的阻滯具有使用依賴性。上述結(jié)果提示,布比卡因既可劑量依賴性地影響Nav1.5門控動力學(xué)參數(shù),也可助推Nav1.5通道開放態(tài)(open-state)的慢失活進程。本項研究有助于拓展臨床用藥布比卡因的靶向選擇性及其機制的醫(yī)學(xué)基礎(chǔ)知識,并為臨床局麻藥的安全用藥提供參考。
[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.
【學(xué)位授予單位】：上海大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R614

【相似文獻】

相關(guān)期刊論文 前5條

1 何艷,李長平,張文杰,孫小霞,鐘國贛;人外周血淋巴細胞電壓依賴性鉀通道電流的記錄及其特性[J];白求恩醫(yī)科大學(xué)學(xué)報;1999年02期

2 吳新生,何淑舫;G蛋白對神經(jīng)細胞電壓依賴性離子通道的直接調(diào)制作用[J];生理科學(xué)進展;1997年01期

3 曹文,孫勝利,凌樹森,王自正,戴德哉;L-甲狀腺素誘導(dǎo)心肌肥厚模型下電壓依賴性K~+通道m(xù)RNA的表達[J];醫(yī)學(xué)研究生學(xué)報;2000年04期

4 許長慶,張宗明,吳才宏,周培愛;谷氨酸對大鼠海馬CA_1區(qū)錐體細胞電壓依賴性Na~+電流的影響[J];基礎(chǔ)醫(yī)學(xué)與臨床;2000年02期

5 ;[J];;年期

相關(guān)會議論文 前2條

1 李俊英;;決定鈣離子通道電壓依賴性激活的分子結(jié)構(gòu)域的研究[A];天津市生物醫(yī)學(xué)工程學(xué)會2004年年會論文集[C];2005年

2 高青華;黃世錚;趙美瞇;郭鳳;郝麗英;;壬基苯酚對GH3細胞電壓依賴性鉀離子通道電流的影響及作用機制[A];中國生理學(xué)會第23屆全國會員代表大會暨生理學(xué)學(xué)術(shù)大會論文摘要文集[C];2010年

相關(guān)碩士學(xué)位論文 前3條

1 張恒;Bupivacaine對異源表達的心肌型Na_v1.5電壓依賴性的阻滯[D];上海大學(xué);2015年

2 劉俊;胞外鎂離子電壓依賴性抑制Kir2.2通道內(nèi)向鉀離子流分子機制的研究[D];河北工業(yè)大學(xué);2014年

3 范超;SLC26A家族的電壓依賴性[D];南方醫(yī)科大學(xué);2014年

，

本文編號：2439069