【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在一定程度上限制了其在臨床上的應用。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,布比卡因對Nav1.5的阻滯具有使用依賴性。上述結果提示,布比卡因既可劑量依賴性地影響Nav1.5門控動力學參數(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)學基礎知識,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.
【學位授予單位】：上海大學
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R614

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