本文選題：尾加壓素Ⅱ　切入點：延髓腹外側(cè)頭端　出處：《河北醫(yī)科大學(xué)》2008年碩士論文

【摘要】： 尾加壓素Ⅱ(urotensinⅡ, UⅡ)最早是從硬骨魚的脊髓尾部垂體中分離出的生長抑素樣環(huán)肽,后來證實從軟體動物到哺乳動物體內(nèi)均有存在。UⅡ及其受體GPR14(G-protein coupled receptor,GPR14)主要分布于中樞神經(jīng)系統(tǒng)、心血管系統(tǒng)、腎臟和內(nèi)分泌器官等。UⅡ與GPR14結(jié)合后使細(xì)胞內(nèi)的Ca2+濃度增加,引起一系列生物效應(yīng)。 UⅡ是迄今為止最強的縮血管活性肽,其縮血管作用是內(nèi)皮素的10倍以上,具有種屬特異性和組織特異性,且不需要內(nèi)皮介導(dǎo)。UⅡ能促進(jìn)大鼠胸主動脈攝取鈣,這種作用能被鈣通道阻斷劑維拉帕米和尼群地平阻斷,推測UⅡ通過電壓依賴性和非電壓依賴性鈣通道促進(jìn)鈣內(nèi)流。我們先前的研究表明UⅡ還可以抑制頸動脈竇壓力感受器反射,此作用是UⅡ與平滑肌上的UⅡ受體結(jié)合,通過開放L型鈣通道引起頸動脈竇區(qū)血管收縮而實現(xiàn)的。UⅡ還有舒張血管的效應(yīng),并呈內(nèi)皮依賴性。UⅡ的舒血管效應(yīng)可能與NO、前列環(huán)素等舒血管活性因子有關(guān)。UⅡ與冠心病的關(guān)系也很密切,急性冠脈綜合癥患者血漿中UⅡ的濃度明顯下降,提示UⅡmRNA表達(dá)下調(diào)。UⅡ還有促進(jìn)心肌肥大、刺激細(xì)胞外基質(zhì)生成和介導(dǎo)粥樣硬化斑塊形成等效應(yīng)。 對于UⅡ中樞效應(yīng)的研究發(fā)現(xiàn),給清醒的羊側(cè)腦室注射UⅡ,引起血漿腎上腺素和促腎上腺皮質(zhì)激素的釋放,并使心輸出量增大、血壓升高。給清醒的鱒魚腦室注射50pmol UⅡ僅引起輕度的心率增加,當(dāng)劑量達(dá)到500pmol時引起血壓顯著升高而心率不變。在正常大鼠和高血壓清醒大鼠,側(cè)腦室注射UⅡ引起血壓和心率顯著增加,高血壓大鼠尤為明顯。UⅡ的作用因給藥途徑不同而不同:靜脈注射UⅡ引起血壓下降,而側(cè)腦室注射UⅡ則因激活了交感神經(jīng)系統(tǒng)而使血壓上升。在不同腦區(qū)微量注射UⅡ,產(chǎn)生不同的心血管效應(yīng):在A1區(qū)微量注射UⅡ可引起劑量依賴性的和長時程的血壓降低及心率減慢效應(yīng);而在A2區(qū)則沒有明顯效果;在室旁核和弓狀核引起輕微但顯著的血壓升高和心動過速的效應(yīng)。以上結(jié)果不僅說明,UⅡ在不同的腦區(qū)發(fā)揮不同的心血管作用,而且支持一種假設(shè),即UⅡ在不同腦區(qū)的神經(jīng)元中發(fā)揮不同作用。我們新近的研究表明,UⅡ能夠抑制海馬CA1區(qū)神經(jīng)元、PVN神經(jīng)元的自發(fā)放電;給大鼠的側(cè)腦室注射UⅡ,20min后可在PVN神經(jīng)元發(fā)現(xiàn)c-fos蛋白mRNA水平顯著增加。 延髓腹外側(cè)頭端區(qū)(RVLM)接受來自中樞其它部位和外周傳入的多種心血管活動信息,并有下行通路直接投射到胸段脊髓灰質(zhì)中間外側(cè)柱的交感節(jié)前神經(jīng)元,從而在維持交感緊張和穩(wěn)定血壓的調(diào)節(jié)活動中具有重要意義。RVLM存在UⅡ受體GPR14的mRNA和蛋白表達(dá),表明UⅡ及其受體GPR14在RVLM內(nèi)可能具有調(diào)節(jié)心血管活動的功能。 目的:本研究旨在應(yīng)用心血管中樞RVLM區(qū)微量注射的方法觀察UⅡ?qū)τ诖笫笮难芟到y(tǒng)及腎交感神經(jīng)放電活動的影響,探討UⅡ及受體GPR14的生理作用及其信號傳導(dǎo)機制。 方法:在36只麻醉雄性SD大鼠,將UⅡ微量注入RVLM區(qū)后,應(yīng)用連接到計算機上的BL~420E+多道生物機能系統(tǒng)同步記錄大鼠血壓(BP)、心率(HR)和腎交感神經(jīng)活動(RSNA)的原始放電和積分值。 結(jié)果:(1)UⅡ(0.3, 3 and 30 nmol/L)可使大鼠BP、HR和RSNA明顯增加。與對照相比,BP(MAP)分別從86.12±4.66mmHg升高到99.42±3.85mmHg(P0.01), 86.67±4.41mmHg升高到98.92±4.20mmHg (P0.01),以及86.65±6.39mmHg升高到101.89±6.34 mmHg (P0.01);HR從322.80±9.37bpm升高到342.60±7.97bpm (P0.05), 325.33±5.27bpm升高到351.50±7.53bpm (P0.05),以及311.00±10.96bpm升高到338.33±11.56bpm (P0.01);RSNA分別興奮了141.93±6.74% (P0.01), 133.96±6.88% (P0.01)和142.78±9.94% (P0.01)。BP、HR和RSNA在給藥后15分鐘內(nèi)開始變化,在30~40分鐘達(dá)到最高點(。2)預(yù)先向大鼠RVLM區(qū)微量注射UⅡ受體GPR14的阻斷劑BIM23127 (300nmol/L),可以阻斷UⅡ的作用。(3)預(yù)先向大鼠RVLM區(qū)微量注射N型Ca2+通道阻斷劑芋螺毒素ω-conotoxin GVIA (200nmol/L),可以阻斷UⅡ的作用。(4)預(yù)先向大鼠RVLM區(qū)微量注射絲裂原活化蛋白激酶(MAPK)激酶抑制劑PD98059(25μmol/L),可以抑制UⅡ的作用。 結(jié)論:在RVLM區(qū)內(nèi)微量注射UⅡ使麻醉大鼠的血壓、心率和腎交感神經(jīng)放電活動明顯增加。其機制可能為UⅡ與其受體GPR14結(jié)合,激活N型Ca2+通道,增強Ca2+內(nèi)流進(jìn)而激活MAPK途徑而發(fā)揮作用。
[Abstract]:Urotensin II (urotensin II, U II) was first isolated from the tail of the spinal cord in the teleost pituitary somatostatin peptide that later confirmed from animal to mammals and there were software.U II and its receptor GPR14 (G-protein coupled receptor, GPR14) mainly distributed in the central nervous system and cardiovascular system. The kidney and endocrine organs such as.U II and GPR14 bind to the intracellular Ca2+ concentration increases, causing a series of biological effects.
U II is by far the strongest vasoactive peptide, the vasoconstrictive effect is 10 times more than in the endothelium, species-specific and tissue-specific, and does not need the endothelium mediated.U II can promote rat aortic calcium intake, and this effect can be calcium channel blocker nitrendipine block and Vera Pammy presumably, U II through voltage dependent and voltage dependent calcium channels to promote calcium influx. Our previous studies have shown that U II can also inhibit the carotid sinus baroreceptor reflex, this role is combined with U II and U II receptor on smooth muscle, caused by carotid sinus vasoconstriction achieved by open type L calcium channel.U II vasodilatation and effect, and is NO and endothelium-dependent vasodilation effects of.U II, the relationship between prostacyclin and other vasoactive factors associated with coronary heart disease.U II is also very close, in patients with acute coronary syndrome The concentration of U II decreased significantly, suggesting that U II mRNA expression was down regulated..U II also promoted myocardial hypertrophy, stimulated extracellular matrix production and mediate atherosclerotic plaque formation.
For the study of U II central effects found for sheep intracerebroventricular injection of U II awake, caused by plasma adrenaline and ACTH release, and increased cardiac output, increased blood pressure. To clear the trout intraventricular injection of 50pmol U II caused only slight increase in heart rate, when the dosage of 500pmol was caused by blood pressure increased heart rate unchanged. Awake rats in normal rats and hypertension, intracerebroventricular injection of U II induced blood pressure and heart rate increased significantly, especially in hypertensive rats.U II effect due to different routes of administration of intravenous injection of U II induced decrease in blood pressure, and intracerebroventricular injection of U II due to activation of the sympathetic the nervous system and blood pressure to rise. In different brain regions of microinjection of U II, produced varying cardiovascular effects in A1 microinjection of U II can induce dose dependent and duration to reduce blood pressure and heart rate effect; and There is no obvious effect in the A2 region; in the paraventricular and arcuate nuclei caused a slight but significant increase in blood pressure and tachycardia effect. These results not only illustrate that U II play different cardiovascular effects in different brain regions, but also support a hypothesis that U II in different brain regions of neurons we play a different role. Recent studies show that U II can inhibit hippocampal CA1 neurons, the spontaneous discharge of PVN neurons; to the intracerebroventricular injection of U of rats, after 20min PVN neurons found c-fos protein level of mRNA was significantly increased.
The rostral ventrolateral medulla (RVLM) from other parts of the central and peripheral afferent cardiovascular activities of various kinds of information, and the descending pathway directly onto the thoracic spinal cord intermediolateral column of sympathetic preganglionic neurons, which has the important significance of.RVLM mRNA and protein expression of U II receptor GPR14 in regulating sympathetic nervous activity to maintain the blood pressure and stability, show that U II and its receptor GPR14 may regulate the function of cardiovascular activity in RVLM.
Objective: the aim of this study is to observe the effects of U II on the cardiovascular system and renal sympathetic nerve activity in rats, and to explore the physiological function and signal transduction mechanism of U II and GPR14 receptor by using microinjection in the central area of RVLM.
Methods: in 36 anesthetized male SD rats, after injecting U II into RVLM area, we recorded the blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) of the original discharge and integral value by BL~420E+ multichannel biological function system connected to the computer.
緇撴灉:(1)U鈪，

本文編號：1657899