本文選題：法舒地爾 + Kv7鉀離子通道　； 參考：《河北醫(yī)科大學(xué)》2014年碩士論文

【摘要】：電壓門控型Kv7（Kv7.1-7.5）鉀通道家族由KCNQ基因編碼，在調(diào)節(jié)心肌動(dòng)作電位及穩(wěn)定神經(jīng)元膜電位方面發(fā)揮重要作用。Kv7.1通道主要表達(dá)于心肌組織，并與其輔助亞單位KCNE1通道共同編碼組成延遲整流鉀通道（IKs），在調(diào)節(jié)心肌細(xì)胞動(dòng)作電位時(shí)程中發(fā)揮著重要作用，KCNQ1/KCNE1突變體構(gòu)成遺傳性心律失常的基礎(chǔ)并導(dǎo)致長(zhǎng)QT綜合癥。Kv7.2和Kv7.3通道以四聚體形式共表達(dá)產(chǎn)生的電流已經(jīng)被證實(shí)是M電流分子基礎(chǔ)。另有研究發(fā)現(xiàn)Kv7.5通道也參與M電流的形成。Kv7.2和Kv7.3通道基因突變或M通道功能失調(diào)，可引發(fā)許多中樞性疾病，如良性家族性新生兒驚厥癥（BFNC）。Kv7.4通道主要表達(dá)于內(nèi)耳的耳蝸和前庭器官以及中樞聽(tīng)覺(jué)傳導(dǎo)通路。Kv7.4通道突變被證實(shí)引發(fā)遺傳性耳聾癥（DFNA2）。近期研究發(fā)現(xiàn)Kv7.1、Kv7.4、Kv7.5通道高表達(dá)于血管平滑肌等多種平滑肌細(xì)胞。藥理學(xué)研究顯示Kv7.1對(duì)血管張力無(wú)影響，Kv7.4、Kv7.5參與血管張力的調(diào)節(jié)，Kv7.4、Kv7.5調(diào)節(jié)劑對(duì)高血壓存在潛在的治療價(jià)值。但是目前高選擇性的Kv7.4、Kv7.5調(diào)節(jié)劑尚未見(jiàn)報(bào)道。本研究發(fā)現(xiàn)Rho激酶抑制劑法舒地爾（Fasudil）可選擇性激活Kv7.4/Kv7.5通道，而對(duì)其它Kv7通道無(wú)作用。 Fasudil，又名HA1077，是一種新型異喹啉磺酰胺衍生物類Rho激酶（Rho-kinase）選擇性抑制藥，能強(qiáng)效擴(kuò)血管，可以有效緩解腦血管痙攣，臨床上主要用于改善和預(yù)防蛛網(wǎng)膜下腔出血后引起的腦血管病，腦血管痙攣及肺動(dòng)脈高壓的治療。研究認(rèn)為Fasudil的血管舒張作用與抑制Rho激酶有關(guān)，而我們認(rèn)為Fasudil的擴(kuò)血管作用還與增大Kv7鉀電流有關(guān)。此外，我們發(fā)現(xiàn)Fasudil對(duì)Kv7鉀離子通道家族的調(diào)節(jié)作用具有選擇性。 本論文以Kv7鉀離子通道家族為出發(fā)點(diǎn)，利用電生理穿孔膜片鉗技術(shù)及四通道微血管張力測(cè)定系統(tǒng)，研究Fasudil對(duì)表達(dá)于HEK293細(xì)胞的Kv7鉀離子通道、分離培養(yǎng)的乳大鼠的小直徑背根神經(jīng)節(jié)（DRG）神經(jīng)元細(xì)胞M通道的作用以及Fasudil對(duì)腸系膜阻力血管的作用。 1. Fasudil對(duì)表達(dá)于HEK293細(xì)胞的Kv7鉀離子通道的作用 目的：研究Fasudil對(duì)Kv7.1/KCNE1、Kv7.2、Kv7.2/Kv7.3、Kv7.4及Kv7.5的選擇性調(diào)節(jié)作用。 方法：利用電生理穿孔膜片鉗技術(shù)，觀察Fasudil對(duì)表達(dá)于HEK293細(xì)胞的Kv7鉀離子通道的作用。瑞替加濱（Retigabine，RTG，Kv7鉀離子通道開(kāi)放劑）為陽(yáng)性對(duì)照藥。 結(jié)果：(1)30μM Fasudil對(duì)Kv7.1/KCNE1電流無(wú)明顯作用。 (2)1μM、3μM、10μM、30μM及100μM Fasudil對(duì)Kv7.2及Kv7.2/7.3電流均無(wú)明顯作用。 (3) Fasudil可濃度依賴性地增強(qiáng)Kv7.4電流，10μM、30μM、100μMFasudil及10μM RTG分別使尾電流增加0.82、1.38、2.03及3.16倍。 (4) Fasudil可濃度依賴性地增強(qiáng)Kv7.5電流。Fasudil使電導(dǎo)-電壓（G-V）激活曲線左移，且左移的幅度隨濃度升高而增大。30μM Fasudil使G-V曲線由-53.7mV左移至-62.4mV，左移幅度為9.39±1.10mV；10μM RTG使曲線左移至-68.9mV，左移幅度為13.925±1.80mV。 結(jié)論：Fasudil對(duì)Kv7.4及Kv7.5電流有增大作用，而對(duì)Kv7.1/KCNE1、Kv7.2及Kv7.2/7.3電流無(wú)明顯作用，說(shuō)明Fasudil對(duì)Kv7鉀電流的調(diào)節(jié)作用具有選擇性。 2. Fasudil對(duì)大鼠的小直徑背根神經(jīng)節(jié)（DRG）神經(jīng)元細(xì)胞上M電流的作用 目的：研究Fasudil對(duì)分離培養(yǎng)的大鼠的DRG神經(jīng)元M電流的影響。 方法：利用電生理穿孔膜片鉗技術(shù)，觀察Fasudil對(duì)分離培養(yǎng)的大鼠DRG神經(jīng)元細(xì)胞M型鉀電流的作用。 結(jié)果：(1)1μM、3μM、10μM、30μM及100μM Fasudil對(duì)大鼠DRG神經(jīng)元上表達(dá)的M型鉀電流無(wú)明顯作用。 (2)1μM、3μM、10μM、30μM及100μM Fasudil對(duì)大鼠DRG神經(jīng)元的靜息膜電位無(wú)明顯作用。 結(jié)論：Fasudil對(duì)大鼠DRG神經(jīng)元細(xì)胞上M電流和靜息膜電位均無(wú)明顯作用，提示Fasudil對(duì)Kv7.2/Kv7.3無(wú)明顯作用。 3. Fasudil對(duì)離體大鼠腸系膜二級(jí)阻力血管的作用 目的：研究Fasudil對(duì)離體大鼠腸系膜二級(jí)阻力血管的作用及機(jī)制。 方法：利用微血管張力測(cè)定技術(shù)，觀察Fasudil對(duì)離體大鼠腸系膜二級(jí)阻力血管的作用。每次實(shí)驗(yàn)分為兩小組。Fasudil組：10μM Phe預(yù)收縮血管，待平穩(wěn)之后，依次加入不同濃度的Fasudil，記錄實(shí)驗(yàn)結(jié)果；Fasudil+XE991組：10μM Phe預(yù)收縮平穩(wěn)之后，加入10μM XE991（Kv7鉀離子通道阻斷劑）孵育15min，再依次加入不同濃度的Fasudil，記錄實(shí)驗(yàn)結(jié)果。 結(jié)果：Fasudil可濃度依賴性地舒張Phe預(yù)收縮的腸系膜二級(jí)阻力血管，EC50為0.83±0.25μM，，最大舒張率（Emax）為96.12%；Fasudil可濃度依賴性地舒張Phe+XE991預(yù)收縮的腸系膜二級(jí)阻力血管，量效曲線右移，EC50為5.04±0.96μM，Emax為96.46%。 結(jié)論：Fasudil舒張Phe+XE991預(yù)收縮的血管的量效曲線發(fā)生了右移，其機(jī)制可能是Fasudil增大了血管平滑肌細(xì)胞上Kv7.4及Kv7.5鉀電流，使血管舒張。提示Fasudil對(duì)Kv7.4及Kv7.5的選擇性調(diào)節(jié)作用是其舒張血管作用的機(jī)制之一。 以上研究結(jié)果表明，F(xiàn)asudil對(duì)Kv7鉀通道具有選擇性調(diào)節(jié)作用，為選擇性的Kv7鉀離子通道調(diào)節(jié)劑的開(kāi)發(fā)提供了新的思路；另外，F(xiàn)asudil對(duì)Kv7.4和Kv7.5鉀電流的增大作用可能是其血管調(diào)節(jié)的作用機(jī)制之一，對(duì)其臨床應(yīng)用提供了新的理論依據(jù)。
[Abstract]:The voltage gated Kv7 (Kv7.1-7.5) potassium channel family is encoded by the KCNQ gene and plays an important role in regulating the cardiac action potential and stabilizing the neuron membrane potential. The.Kv7.1 channel is mainly expressed in the myocardial tissue, and the delayed rectifier potassium channel (IKs) is composed of its auxiliary subunit KCNE1 channel, and the action potential is adjusted to regulate the action potential of the cardiac myocytes. The process plays an important role. KCNQ1/KCNE1 mutants form the basis of hereditary arrhythmia and lead to the current produced by the co expression of the long QT syndrome.Kv7.2 and Kv7.3 channels in the form of four polymer, which has been confirmed as the molecular basis of the M current. Further studies have found that Kv7.5 channels are also involved in the formation of.Kv7.2 and Kv7.3 channel gene mutations or M of the M current. Dysfunction of the channel can cause many central diseases, such as the benign familial neonatal convulsion (BFNC).Kv7.4 channel is mainly expressed in the inner ear cochlea and vestibule organs, and the.Kv7.4 channel mutation in the central auditory pathway is confirmed to cause hereditary deafness (DFNA2). Recent studies have found that Kv7.1, Kv7.4, Kv7.5 channels are highly expressed in blood vessels. A variety of smooth muscle cells such as smooth muscle cells. Pharmacological studies have shown that Kv7.1 has no effect on vascular tension, Kv7.4, Kv7.5 participates in the regulation of vascular tension, Kv7.4, Kv7.5 regulator has potential therapeutic value for hypertension. However, the high selective Kv7.4, Kv7.5 regulator has not yet been reported. This study found that the Rho kinase inhibitor FDD (Fasudi) L) selectively activates the Kv7.4/Kv7.5 channel, but has no effect on other Kv7 channels.
Fasudil, also known as HA1077, is a new type of ISO quinoline sulfonamide derivative, Rho kinase (Rho-kinase) selective inhibitor, which can effectively expand blood vessels and effectively relieve cerebral vasospasm. It is mainly used to improve and prevent cerebrovascular disease, cerebral vasospasm and pulmonary hypertension after subarachnoid hemorrhage. The study thinks Fas The vasodilatation of udil is associated with the inhibition of Rho kinase, and we believe that the vasodilatation of Fasudil is also related to the increase of the Kv7 potassium current. Furthermore, we found that Fasudil has a selective role in the regulation of the Kv7 potassium channel family.
In this paper, using the Kv7 potassium channel family as the starting point, using the electrophysiological perforation patch clamp technique and the four channel microvascular tension measurement system, the effect of Fasudil on the Kv7 potassium channel expressed in HEK293 cells, the role of the M channel of the small diameter dorsal root ganglion (DRG) of the rat's small diameter dorsal root ganglion (DRG) and the mesenteric resistance to the mesenteric obstruction were studied. The role of force and blood vessel.
Effect of 1. Fasudil on Kv7 potassium channels expressed in HEK293 cells
Objective: To study the selective regulation of Fasudil on Kv7.1/KCNE1, Kv7.2, Kv7.2/Kv7.3, Kv7.4 and Kv7.5.
Methods: the effect of Fasudil on the Kv7 potassium channel expressed in HEK293 cells was observed by electrophysiological perforation patch clamp technique. Retegine (Retigabine, RTG, Kv7 potassium channel opener) was a positive control drug.
Results: (1) 30 M Fasudil had no significant effect on Kv7.1/KCNE1 current.
(2) 1 M, 3 M, 10 M, 30 M and 100 M Fasudil had no obvious effect on Kv7.2 and Kv7.2/7.3 currents.
(3) Fasudil can enhance Kv7.4 currents in a concentration dependent manner. The 10 M, 30 M, 100 MFasudil and 10 M RTG respectively increase the tail current by 0.82,1.38,2.03 and 3.16 times.
(4) Fasudil can enhance the Kv7.5 current.Fasudil to make the conductance voltage (G-V) activation curve move left, and the amplitude of the left shift increases with the concentration of.30 mu M Fasudil to move the G-V curve from -53.7mV left to -62.4mV, and the left shift is 9.39 + 1.10mV, and the 10 mu M makes the left shift to 13.925 +.
Conclusion: Fasudil has an increasing effect on the current of Kv7.4 and Kv7.5, but has no obvious effect on the current of Kv7.1/KCNE1, Kv7.2 and Kv7.2/7.3, indicating that Fasudil has a selective effect on the regulation of the potassium current of Kv7.
Effect of 2. Fasudil on M currents in rat small diameter dorsal root ganglion (DRG) neurons
Objective: To study the effect of Fasudil on the M currents of DRG neurons isolated from rats.
Methods: electrophysiological perforation patch clamp technique was used to observe the effect of Fasudil on M type potassium currents in cultured rat DRG neurons.
Results: (1) 1 mu M, 3 M, 10 M, 30 M and 100 M Fasudil had no significant effect on M potassium currents in rat DRG neurons.
(2) 1 mu M, 3 M, 10 M, 30 M and 100 M Fasudil had no significant effect on resting membrane potential of DRG neurons in rats.
Conclusion: Fasudil has no significant effect on M current and resting membrane potential of DRG neurons in rats, suggesting that Fasudil has no significant effect on Kv7.2/Kv7.3.
Effect of 3. Fasudil on isolated rat mesenteric two grade resistance vessels
Objective: To study the effect and mechanism of Fasudil on isolated rat mesenteric two grade resistance vessels.
Methods: the effect of Fasudil on the two level resistance vessels of rat mesentery in vitro was observed by microvascular tension measurement. Each experiment was divided into two groups of.Fasudil groups: 10 u M Phe preconstricted blood vessels. After the stabilization, the experimental results were added to different concentrations of Fasudil in order, and the Fasudil+XE991 group: after the pre contraction of 10 mu M Phe was stationary, add The 15min was incubated with 10 M XE991 (Kv7 potassium channel blocker), and then the Fasudil was added in order to record the experimental results.
Results: Fasudil had a concentration dependent relaxation of Phe precontracted mesenteric two resistance vessels, EC50 was 0.83 + 0.25 mu M, and the maximum diastolic rate (Emax) was 96.12%; Fasudil could be concentrated on Phe+XE991 precontracted mesenteric two resistance vessels, the volume effect curve was shifted rightward, EC50 was 5.04 + 0.96 micron, Emax was 96.46%.
Conclusion: the volume effect curve of Fasudil diastolic Phe+XE991 precontracted blood vessels has a right shift. The mechanism may be that Fasudil increases the Kv7.4 and Kv7.5 potassium currents on vascular smooth muscle cells and makes the vasodilatation. The selective regulation of Fasudil on Kv7.4 and Kv7.5 is one of the mechanisms of vasodilatation.
The above results show that Fasudil can selectively regulate the potassium channel of Kv7 and provide a new idea for the development of selective Kv7 potassium channel regulator. In addition, the effect of Fasudil on the potassium current of Kv7.4 and Kv7.5 may be one of the mechanisms of its vascular regulation, and provides a new theoretical basis for its clinical application.

【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R96

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10 李寶馨;楊寶峰;;基于HERG鉀通道,靶向性研究心律失常發(fā)生及藥物干預(yù)的機(jī)制[A];中國(guó)化學(xué)會(huì)第八屆天然有機(jī)化學(xué)學(xué)術(shù)研討會(huì)論文集[C];2010年

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2 呂工;ATP敏感鉀通道及其相關(guān)藥物研究[N];中國(guó)醫(yī)藥報(bào);2002年

3 周勇;北大醫(yī)學(xué)部揭示鉀通道結(jié)構(gòu)基礎(chǔ)和分子機(jī)制[N];中國(guó)醫(yī)藥報(bào);2007年

4 衣曉峰 陳英云;哈醫(yī)大鉀通道藥理學(xué)研究獲系列進(jìn)展[N];中國(guó)醫(yī)藥報(bào);2007年

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6 成銀霞;外周鎮(zhèn)痛藥作用新機(jī)制：激活精氨酸/NO/cGMP/蛋白激酶G/ATP敏感性鉀通道 Analgesics:Stimrlators of the NO-cGMP-PKG-K+ ATP Channel[N];中國(guó)醫(yī)藥報(bào);2006年

7 呂工 編譯 林;心有靈藥一點(diǎn)通[N];醫(yī)藥經(jīng)濟(jì)報(bào);2002年

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10 石金山;缺氧/藥物后處理對(duì)大鼠心肌細(xì)胞ATP敏感性鉀通道亞基的影響[D];遵義醫(yī)學(xué)院;2010年

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