本文選題：電針 + 內(nèi)關(guān)穴　； 參考：《南京中醫(yī)藥大學(xué)》2014年博士論文

【摘要】：背景：氟哌利多是臨床麻醉中常用的丁酰苯類藥物,主要對中樞神經(jīng)邊緣系統(tǒng)、下丘腦、黑質(zhì)和紋狀體等部位的多巴胺受體產(chǎn)生阻斷作用,因而具有強大的神經(jīng)安定和鎮(zhèn)吐作用,可與芬太尼合用于神經(jīng)安定麻醉或小劑量單獨用于惡心嘔吐的防治。但美國食品藥品監(jiān)督管理局(Food and Drug Administration, FDA)于2001年,基于多起使用氟哌利多出現(xiàn)尖端扭轉(zhuǎn)性室速猝死的病例,對其提出黑框警告,限制了氟哌利多的臨床使用,但很多麻醉學(xué)者認為長期的臨床麻醉實踐了證實小劑量氟哌利多的安全性,其優(yōu)良的止吐效果和低廉的價格優(yōu)勢使得目前尚無最佳的可替代藥物,而FDA這一行為有失公允,在麻醉學(xué)界產(chǎn)生了廣泛的爭議。電針麻醉曾廣泛用于臨床實踐并取得良好的效果,也是現(xiàn)代麻醉學(xué)對中華傳統(tǒng)醫(yī)學(xué)的重要應(yīng)用和發(fā)展。近年來,電針廣泛用于防治麻醉相關(guān)的不良反應(yīng),如惡心嘔吐、缺血再灌注損傷和臟器功能不全等,在國際麻醉學(xué)研究中也有所報道,并越來越受重視。尤其是電針內(nèi)關(guān)穴能產(chǎn)生較好的止吐效果,有研究還提示電針內(nèi)關(guān)具有心血管保護和抗心律失常作用,而電針內(nèi)關(guān)穴是否能減輕氟哌利多誘發(fā)的QT間期延長,尚缺乏相關(guān)研究。通過研究相關(guān)機制可以為臨床麻醉使用電針提供理論支持,也有助于研究電針對相關(guān)藥物的心臟毒性保護作用并推動電針在麻醉學(xué)中的應(yīng)用,有重要的科研價值和社會意義,并有助于節(jié)約和降低醫(yī)療費用。縫隙連接蛋白是存在于相鄰心肌細胞間的一種重要的膜通道蛋白,它參與了心肌細胞的電和化學(xué)信號的傳導(dǎo),并通過調(diào)控離子交換影響心肌細胞間的電偶聯(lián)和機械收縮偶聯(lián)。縫隙連接蛋白是由兩個對稱的連接子組成,每個連接子由連接蛋白的六聚體結(jié)構(gòu)形成。心肌中最為重要的連接蛋白是縫隙連接蛋白43(connexin 43, Cx43),主要位于心肌細胞間的閏盤部位。相關(guān)文獻認為Cx43密切參與了QT間期的形成,并對QT間期延長產(chǎn)生重要影響。心肌中Cx43蛋白的數(shù)量和分布變化會改變心肌細胞的電偶聯(lián)狀態(tài),Cx43蛋白減少會降低心肌細胞電傳導(dǎo)的均質(zhì)性,心肌去極化和復(fù)極化時間延長,可能是QT間期延長的重要病理生理機制；而增加Cx43蛋白的含量和功能則可能改善心肌細胞間電傳導(dǎo)的異質(zhì)化,減弱QT間期的延長。目的：(1)觀察不同劑量的氟哌利多和電針內(nèi)關(guān)穴預(yù)處理對大鼠QT間期的影響。(2)研究不同劑量的氟哌利多和電針內(nèi)關(guān)穴預(yù)處理對大鼠Cx43mRNA和蛋白表達的影響。方法：(1)動物分組：將雌性SD大鼠隨機分成正常對照組C組(8只)、小劑量氟哌利多組DL組(8只)、大劑量氟哌利多組DH組(8只)、電針對照組EC組(8只)、小劑量氟哌利多電針預(yù)處理組EDL組(8只)和大劑量氟哌利多電針預(yù)處理組EDH組(8只)。C組經(jīng)股靜脈給予等量生理鹽水,DL組經(jīng)股靜脈給予氟哌利多0.13mg/kg, DH組經(jīng)股靜脈給予氟哌利多1.3mg/kg, EC組預(yù)先電針左側(cè)內(nèi)關(guān)穴30min后經(jīng)股靜脈給予等量生理鹽水,EDL組預(yù)先電針左側(cè)內(nèi)關(guān)穴30min后經(jīng)股靜脈給予氟哌利多0.13mg/kg,EDH組預(yù)先電針左側(cè)內(nèi)關(guān)穴30min后經(jīng)股靜脈給予氟哌利多1.3mg/kg。(2)使用Ⅱ?qū)?lián)監(jiān)測并記錄給藥前0min、給藥后5min、10min、15min、30min、60min和120min心電圖,根據(jù)Bazett's公式QTc-B=QT/(?) (RR)計算大鼠QTc值。(3)RT-PCR法檢測心室肌組織中Cx43mRNA表達情況,凝膠成像分析系統(tǒng)拍攝電泳條帶,BandScan4.3軟件進行灰度分析,將Cx43mRNA和內(nèi)參基因GAPDHmRNA的光密度比值作為Cx43mRNA的表達水平。(4)Western blotting法檢測心室肌組織中Cx43蛋白的表達,并采用放射自顯影法記錄影像,凝膠成像系統(tǒng)拍攝后,使用image Pro Plus6.0軟件進行灰度分析,計算Cx43和內(nèi)參蛋白GAPDH的光密度比值,作為Cx43蛋白的表達水平。(5)免疫組化法研究心室肌中Cx43的分布表達,心室肌組織經(jīng)固定、切片、脫蠟、抗原-抗體反應(yīng)和染色等步驟后,在光學(xué)顯微鏡40倍下觀察切片中Cx43蛋白的表達情況,取3個高表達區(qū)域400倍下拍照保存,并使用Image Pro Plus6.0軟件進行平均光密度分析。結(jié)果：(1)電針內(nèi)關(guān)穴對氟哌利多處理大鼠QTc間期的影響：①與正常對照組對比,小劑量氟哌利多組在5min、10min、15min和30min各時點QTc間期顯著延長,P0.01差異有顯著性；大劑量氟哌利多組與正常對照組對比,在5min、10min、15min、30min、60min和120min等時點QTc間期均顯著延長,P0.01差異有顯著性。②電針預(yù)處理后,EDL組在給藥后5min和15minQTc值均顯著低于DL組,P0.01差異有顯著性；10min和30min各時點的QTc間期值均顯著低于DL組,P0.05差異有統(tǒng)計學(xué)意義。③電針預(yù)處理后,EDH組在給藥后5min時QTc值顯著低于DH組,P0.05差異有統(tǒng)計學(xué)意義；30min和60min時點的QTc值均顯著低于DH組,P0.01差異有顯著性。④電針內(nèi)關(guān)穴與生理鹽水注射對照組比,QTc間期無顯著統(tǒng)計學(xué)差異。(2)電針內(nèi)關(guān)對Cx43mRNA表達影響,Cx43mRNA表達水平EC組(0.92±0.03)和C組(0.84±0.02)比較,P0.05差異有統(tǒng)計學(xué)意義；EDL組(0.91±0.03)和DL組(0.84±0.02)相比較,P0.05差異有統(tǒng)計學(xué)意義； EDH組(0.73±0.02)和DH組(0.64±0.03)相比較,P0.05差異有統(tǒng)計學(xué)意義。(3) Western blotting法檢測Cx43蛋白表達水平,EC組(1.46±0.15)和C組(1.09±0.08)比較,P0.01差異有顯著性；EDL組(1.57±0.16)和DL組(1.09±0.10)相比較,P0.01,差異有顯著性；EDH組(1.15±0.05)和DH組(0.96±0.08)相比較,P0.01差異有顯著性。(4)免疫組織化學(xué)染色法檢測心肌Cx43蛋白分布和表達：①C組Cx43陽性部分呈深棕色密集顆粒狀分布于心肌細胞交界和閏盤處；DL組與C組類似；DH組Cx43蛋白呈淡棕黃色細顆粒狀表達,呈散在點狀分布于心肌細胞交界和閏盤處；EC組中Cx43蛋白呈深棕黃色粗線狀廣泛分布于心肌細胞交界和閏盤處；EDL組Cx43呈深棕黃色顆粒狀分布于心肌細胞交界和閏盤處；EDH組心室肌中Cx43呈棕黃色顆粒狀分布于心肌細胞交界和閏盤處。②Cx43蛋白平均光密度值在EC組(0.189±0.008),C組(0.168±0.009),二者比較,P0.01差異有顯著性； Cx43蛋白平均光密度值在EDL組(0.202±0.009),DL組(0.160±0.009),二者比較,P0.01差異有顯著性； Cx43蛋白平均光密度值在EDH組(0.198±0.009),DH組(0.153±0.007),二者比較,P0.01差異有顯著性。結(jié)論：1.氟哌利多呈劑量依賴性導(dǎo)致大鼠QTc間期延長。2.電針內(nèi)關(guān)穴可減輕氟哌利多誘發(fā)的大鼠QTc間期延長。3.電針內(nèi)關(guān)穴可上調(diào)心肌Cx43mRNA和蛋白的表達,從而減少氟哌利多造成的心肌細胞復(fù)極過程中動作電位的異質(zhì)性,這可能是電針改善氟哌利多誘發(fā)QTc間期延長的機制之一。
[Abstract]:Background: droperidol is a common butanyl drug in clinical anesthesia. It is mainly used to block the dopamine receptors in the central nervous system, the hypothalamus, the substantia nigra, and the striatum, and thus has a strong neurostability and antiemetic effect. It can be combined with fentanyl in neurodiazepam anesthesia or small dose alone for nausea nausea. The prevention and treatment of spitting. But in 2001, the Food and Drug Administration (FDA), based on multiple use of droperidol's case of sudden sudden ventricular tachycardia death, proposed a black frame warning, limiting the clinical use of droperidol, but many anesthesiologists believe that long-term clinical anesthesia has proven small doses. The safety of droperidol, its excellent antiemetic effect and low price advantage make no best alternative drugs at present, and the behavior of FDA is unfair and has produced widespread controversy in the anesthesiology. Electroacupuncture anesthesia has been widely used in clinical practice and has achieved good results. It is also a modern anesthesiology for Chinese traditional medicine. Important applications and development. In recent years, electroacupuncture has been widely used to prevent and cure anaesthesia related adverse reactions, such as nausea, vomiting, ischemia reperfusion injury and organ dysfunction. It has also been reported in international Anesthesiology, and is becoming more and more important. Especially, electroacupuncture Neiguan acupoints can produce better antiemetic effect. It has the effect of cardiovascular protection and antiarrhythmia, and whether the electroacupuncture Neiguan acupoint can relieve the prolonged QT interval induced by droperidol is still lack of related research. The application of drunken learning has important scientific and social significance and helps to save and reduce medical costs. Gap junctional protein is an important membrane channel protein that exists between adjacent myocardial cells. It participates in the conduction of electrical and chemical signals of cardiac myocytes and through regulating ion exchange to influence the coupling of electric couples among cardiac myocytes. The connexin is composed of two symmetrical connexions, each of which is formed by the six polymer structure of the connexin. The most important connexin in the myocardium is the gap connexin 43 (connexin 43, Cx43), mainly located in the intercalated disc between the cardiac myocytes. The relevant literature considers that Cx43 is closely involved in the QT interval. The formation of QT has an important effect on the prolongation of the interval of interphase. The changes in the number and distribution of Cx43 protein in the myocardium will change the electric couple state of the cardiac myocytes. The decrease of Cx43 protein will reduce the homogeneity of the electrical conduction of the cardiac myocytes, the depolarization and repolarization time of the myocardium, which may be the important pathophysiological mechanism of the prolongation of the interphase of QT; and the increase of Cx43 The protein content and function may improve the heterogeneity of the intercellular electrical conduction and the prolongation of the QT interval. Objective: (1) observe the effect of different doses of droperidol and electroacupuncture Neiguan point on the QT interval in rats. (2) the expression of Cx43mRNA and protein in rats with different doses of droperidol and Electroacupuncture Neiguan point preconditioning Methods: (1) animal groups: the female SD rats were randomly divided into the normal control group C group (8 rats), the small dose droperidol group DL group (8), the large dose droperidol group DH group (8 rats), the electroacupuncture control group EC group (8), the small dose droperidol Electroacupuncture group EDL group (8 rats) and the large dose droperidol electroacupuncture pretreatment group EDH group (8).C group. The same amount of physiological saline was given via femoral vein, group DL was given droperidol 0.13mg/kg through femoral vein, group DH was given droperidol 1.3mg/kg through femoral vein, group EC was given to the left Neiguan point 30min after 30min in group EC, and EDL group was given left Neiguan point after 30min to be given droperidol 0.13mg/kg in the femoral vein, and the EDH group was beforehand. The electroacupuncture at the left Neiguan point 30min was given to droperidol 1.3mg/kg. (2) via the femoral vein to monitor and record 0min before administration by the lead II. 5min, 10min, 15min, 30min, 60min and 120min electrocardiogram were calculated after the administration. (3) the expression of the rat ventricular muscle was detected by the Bazett's formula QTc-B=QT/ (RR). The system photographed electrophoresis strip, BandScan4.3 software carried out gray analysis, and the ratio of light density of Cx43mRNA and internal reference gene GAPDHmRNA was used as the expression level of Cx43mRNA. (4) Western blotting method was used to detect the expression of Cx43 protein in ventricular muscle, and the autoradiography was recorded by autoradiography, and image Pro Pl was used after the gel imaging system was taken. Us6.0 software was used for gray analysis to calculate the light density ratio of Cx43 and GAPDH as the expression level of Cx43 protein. (5) the distribution and expression of Cx43 in ventricular muscle were studied by immunohistochemistry. After fixed, slicing, dewaxing, antigen antibody reaction and staining, the Cx43 protein in the slice was observed under the optical microscope at 40 times of the optical microscope. The expression of 3 high expression regions was taken at 400 times, and the average light density analysis was performed using Image Pro Plus6.0 software. The results were as follows: (1) the effect of the electroacupuncture Neiguan point on the QTc interval of droperidol treatment in rats: (1) the QTc interval of the small dose of droperidol group was significant at 5min, 10min, 15min and 30min at each time point. The difference in P0.01 was significant, and the time points of QTc interval in 5min, 10min, 15min, 30min, 60min and 120min were significantly longer in the large dose droperidol group than in the normal control group, and the difference of P0.01 was significant. 2. After the electroacupuncture treatment, the 5min and 15minQTc values of the EDL group were significantly lower than those in the group. The QTc interval values of each time point were significantly lower than that of the DL group, and the difference in P0.05 was statistically significant. After the electroacupuncture treatment, the QTc value of the EDH group was significantly lower than that of the DH group after 5min, and the P0.05 difference was statistically significant. The QTc values of 30min and 60min points were significantly lower than those of the DH group. There was no significant difference in QTc interval. (2) the effect of electroacupuncture Neiguan on Cx43mRNA expression, the level of Cx43mRNA expression in EC group (0.92 + 0.03) and C group (0.84 + 0.02), the difference between P0.05 and EDL group (0.91 + 0.03) and DL group (0.84 + 0.02) was statistically significant; EDH group (0.73 + 0.02) and DH group (0.64 + 0.03) were compared. The difference of P0.05 was statistically significant. (3) the expression level of Cx43 protein was detected by Western blotting method, the difference in P0.01 was significant in EC group (1.46 + 0.15) and C group (1.09 + 0.08), and in EDL group (1.57 + 0.16) and DL group (1.09 + 0.10), P0.01, the difference was significant; EDH group (1.15 + 0.05) was compared with DH group (0.96 + 0.08). (4) immunohistochemical staining was used to detect the distribution and expression of Cx43 protein in myocardium: (1) the Cx43 positive part of group C was distributed in the junction of cardiac myocytes and intercalated discs; the DL group was similar to that in the C group; the Cx43 protein in the DH group was pale brown and fine granular, distributed in the point like distribution at the junction of cardiac myocytes and intercalated discs, and in EC group. The Cx43 protein was widely distributed in the junction of cardiac myocytes and intercalated discs at the junction of cardiac myocytes and intercalated discs. In group EDL, Cx43 was distributed in the junction of cardiac myocytes and intercalated discs, and in group EDH, Cx43 was brown and yellow granules distributed at the junction of cardiac myocytes and intercalated discs. The mean optical density of Cx43 egg white was in group EC (0.189 + 0.008), C Group (0.168 + 0.009), compared with the two, the difference in P0.01 was significant, the mean light density of Cx43 protein was in group EDL (0.202 + 0.009), DL group (0.160 + 0.009), and the difference of P0.01 was significant in the two group; the average optical density of Cx43 protein was in group EDH (0.198 + 0.009), DH group (0.153 + 0.007), and P0.01 difference was significant. Conclusion: fluoro piperli Dose dependence can lead to prolongation of.2. electroacupuncture Neiguan point in QTc interval in rats. The prolongation of droperidol induced QTc interval in rats by prolonging.3. electroacupuncture Neiguan point can increase the expression of Cx43mRNA and protein in myocardium, thus reducing the heterogeneity of action potential during the repolarization process of droperidol. This may be the improvement of droperidol by electroacupuncture. One of the mechanisms that induce the prolongation of QTc interval.
【學(xué)位授予單位】：南京中醫(yī)藥大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2014
【分類號】：R614

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3 王國亮;王金福;冰;吳艷鳳;;氟哌利多用于減少肛腸術(shù)后鎮(zhèn)痛不良反應(yīng)的臨床觀察[A];中國(第七屆)腫瘤微創(chuàng)治療學(xué)術(shù)大會暨世界影像導(dǎo)引下腫瘤微創(chuàng)治療學(xué)會成立籌備大會論文匯編[C];2011年

4 田文華;;氟哌利多用于PCA防治嗎啡惡心、嘔吐的臨床觀察[A];中華醫(yī)學(xué)會疼痛學(xué)分會第六屆年會論文摘要[C];2005年

5 寧連成;谷爽;寧力;;嗎啡、羅哌卡因、氟哌利多、芬太尼應(yīng)用于86例晚期癌痛病人臨床觀察[A];山東省第十六次麻醉學(xué)學(xué)術(shù)會議論文匯編[C];2013年

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