木犀草素增強亞劑量卡托普利降壓作用并減少咳嗽的研究
發(fā)布時間：2019-05-15 22:11
【摘要】：背景和目的:血管緊張素轉(zhuǎn)化酶抑制劑(ACEI)在抗高血壓和保護靶器官方面的效應已得到公認,但其缺點是引起刺激性干咳的發(fā)生率高,因此,降低ACEI類藥物咳嗽發(fā)生率具有重要的臨床意義。鑒于木犀草素不但具有降壓作用,而且還具有較強的抗炎作用,能降低氣道高反應性等藥理活性,本研究擬評估木犀草素能否增強亞劑量卡托普利降壓作用并減少其咳嗽的不良反應,并探討相互作用機制。實驗方法:1)構(gòu)建腎性高血壓大鼠模型,檢測大鼠尾動脈血壓變化。2)二氧化硫引咳法研究對小鼠咳嗽的影響。3)霧化吸入卵白蛋白建立氣道高反應性小鼠模型,ELISA法測定支氣管肺泡灌洗液(BALF)中IL-4、IL-5及IFN-γ的含量。4)MTT法檢測小鼠巨噬細胞代謝活力。5)ELISA法和NO檢測試劑盒檢測藥物對巨噬細胞分泌IL-1 β、IL-10、TNF-a和NO的影響。6)激光共聚焦掃描顯微鏡檢測藥物對LPS誘導小鼠巨噬細胞內(nèi)Ca2+濃度和pH變化的影響。實驗結(jié)果:1)高血壓大鼠分組給藥并檢測血壓,結(jié)果顯示,從第7天開始,給予卡托普利和木犀草素的動物血壓明顯下降。第14天,亞劑量卡托普利和木犀草素聯(lián)用時降壓效果基本達到常劑量卡托普利的效果。2)小鼠咳嗽隨卡托普利用量增加而增加,聯(lián)用木犀草素可以降低小鼠咳嗽發(fā)生率。3)木犀草素明顯降低高氣道反應性小鼠模型BALF中IL-4和IL-5水平,卡托普利無明顯抑制作用。兩者亞劑量聯(lián)用能抑制IL-4和IL-5分泌,升高IFN-γ水平。4)木犀草素明顯抑制巨噬細胞代謝活力,降低TNF-a,IL-1β和IL-10分泌水平,而卡托普利在高濃度時有明顯抑制作用,低濃度卡托普利則無明顯抑制作用。兩者聯(lián)用能抑制TNF-a,IL-1β和IL-10的分泌,無協(xié)同效應,但有一定相加效應。另外卡托普利和木犀草素均能抑制NO的分泌,但也無協(xié)同效應。5)木犀草素和卡托普利明顯降低胞內(nèi)Ca2+濃度,升高胞內(nèi)pH,但兩者聯(lián)用對胞內(nèi)Ca2+濃度和pH變化無明顯協(xié)同效應。結(jié)論:1)亞劑量木犀草素和亞劑量卡托普利聯(lián)用基本能達到常劑量卡托普利的降壓效果。2)亞劑量卡托普利和木犀草素聯(lián)用能減少前者導致的小鼠咳嗽發(fā)生率,其機制可能與卡托普利劑量下降以及木犀草素能抑制IL-4、IL-5分泌,增加IFN-丫水平,調(diào)節(jié)TH1和TH2細胞比例有關(guān)。3)體外卡托普利和木犀草素聯(lián)用雖無明顯協(xié)同抗炎作用,但有一定相加效應,木犀草素的抗炎作用對減少卡托普利咳嗽發(fā)生頻率可能有幫助,其抗炎機制可能通過降低細胞內(nèi)Ca2+濃度、升高pH值、抑制巨噬細胞分泌促炎細胞因子等功能有關(guān)。
[Abstract]:Background & objective: the effect of angiotensin converting enzyme inhibitor (ACEI) on antihypertension and protection of target organs has been recognized, but its disadvantage is that the incidence of irritating dry cough is high, so, It is of great clinical significance to reduce the incidence of cough with ACEI drugs. In view of the fact that luteolin not only has antihypertensive effect, but also has strong anti-inflammatory effect, which can reduce airway hyperresponsiveness and other pharmacological activities. The purpose of this study was to evaluate whether luteolin can enhance the antihypertensive effect of subdose captopril and reduce the adverse reactions of cough, and to explore the mechanism of interaction. Methods: 1) the rat model of renal hypertension was established, and the changes of blood pressure in tail artery of rats were detected. 2) the effect of sulfur dioxide on cough in mice was studied. 3) the model of airway hyperresponsiveness was established by atomization inhalation of ovalbumin. The contents of IL-4,IL-5 and IFN- 緯 in (BALF) of bronchoalveolar lavage fluid were determined by ELISA. 4) the metabolic activity of mouse macrophages was detected by MTT. 5) ELISA assay and NO kit were used to detect the secretion of IL-1 尾 by macrophages. The effects of IL-10,TNF-a and NO were detected by confocal laser scanning microscope. 6) the effects of drugs on the concentration of Ca2 and the change of pH in mouse macrophages induced by LPS were detected by laser confocal scanning microscope. The results were as follows: 1) Hypertension rats were divided into groups and blood pressure was measured. The results showed that the blood pressure of animals given captopril and rhinocerol decreased significantly from the 7th day. On the 14th day, the antihypertensive effect of subdose captopril combined with luteolin basically reached the effect of constant dose captopril. 2) the cough of mice increased with the increase of captopril dosage. Combined with lignogenin could reduce the incidence of cough in mice. 3) luteolin significantly decreased the levels of IL-4 and IL-5 in BALF model of hyperairway reactive mice, but captopril had no significant inhibitory effect. The combination of the two subdoses could inhibit the secretion of IL-4 and IL-5 and increase the level of IFN- 緯. 4) the metabolic activity of macrophages and the secretion of TNF-a,IL-1 尾 and IL-10 were significantly decreased by luteolin. Captopril had obvious inhibitory effect at high concentration, but no significant inhibitory effect at low concentration of captopril. The combination of them could inhibit the secretion of TNF-a,IL-1 尾 and IL-10 without synergistic effect, but had a certain additive effect. In addition, captopril and luteolin could inhibit the secretion of NO, but there was no synergistic effect. 5) luteolin and captopril significantly decreased intracellular Ca2 concentration and increased intracellular pH,. However, there was no significant synergistic effect on intracellular Ca2 concentration and pH. Conclusion: 1) the combination of subdose luteolin and subdose captopril can basically achieve the antihypertensive effect of constant dose captopril. 2) the combination of subdose captopril and luteolin can reduce the incidence of cough in mice caused by the former. The mechanism may be related to the decrease of captopril dose and the inhibition of IL-4,IL-5 secretion and the increase of IFN- level. Regulating the proportion of TH1 and TH2 cells is related. 3) although the combination of captopril and luteolin in vitro has no obvious synergistic anti-inflammatory effect, it has a certain additive effect. The anti-inflammatory effect of luteolin may be helpful to reduce the frequency of captopril cough. The anti-inflammatory mechanism may be related to the decrease of intracellular Ca2 concentration, the increase of pH value and the inhibition of macrophage secretion of pro-inflammatory cytokines.
【學位授予單位】：南方醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R544.1
本文編號：2477801
[Abstract]:Background & objective: the effect of angiotensin converting enzyme inhibitor (ACEI) on antihypertension and protection of target organs has been recognized, but its disadvantage is that the incidence of irritating dry cough is high, so, It is of great clinical significance to reduce the incidence of cough with ACEI drugs. In view of the fact that luteolin not only has antihypertensive effect, but also has strong anti-inflammatory effect, which can reduce airway hyperresponsiveness and other pharmacological activities. The purpose of this study was to evaluate whether luteolin can enhance the antihypertensive effect of subdose captopril and reduce the adverse reactions of cough, and to explore the mechanism of interaction. Methods: 1) the rat model of renal hypertension was established, and the changes of blood pressure in tail artery of rats were detected. 2) the effect of sulfur dioxide on cough in mice was studied. 3) the model of airway hyperresponsiveness was established by atomization inhalation of ovalbumin. The contents of IL-4,IL-5 and IFN- 緯 in (BALF) of bronchoalveolar lavage fluid were determined by ELISA. 4) the metabolic activity of mouse macrophages was detected by MTT. 5) ELISA assay and NO kit were used to detect the secretion of IL-1 尾 by macrophages. The effects of IL-10,TNF-a and NO were detected by confocal laser scanning microscope. 6) the effects of drugs on the concentration of Ca2 and the change of pH in mouse macrophages induced by LPS were detected by laser confocal scanning microscope. The results were as follows: 1) Hypertension rats were divided into groups and blood pressure was measured. The results showed that the blood pressure of animals given captopril and rhinocerol decreased significantly from the 7th day. On the 14th day, the antihypertensive effect of subdose captopril combined with luteolin basically reached the effect of constant dose captopril. 2) the cough of mice increased with the increase of captopril dosage. Combined with lignogenin could reduce the incidence of cough in mice. 3) luteolin significantly decreased the levels of IL-4 and IL-5 in BALF model of hyperairway reactive mice, but captopril had no significant inhibitory effect. The combination of the two subdoses could inhibit the secretion of IL-4 and IL-5 and increase the level of IFN- 緯. 4) the metabolic activity of macrophages and the secretion of TNF-a,IL-1 尾 and IL-10 were significantly decreased by luteolin. Captopril had obvious inhibitory effect at high concentration, but no significant inhibitory effect at low concentration of captopril. The combination of them could inhibit the secretion of TNF-a,IL-1 尾 and IL-10 without synergistic effect, but had a certain additive effect. In addition, captopril and luteolin could inhibit the secretion of NO, but there was no synergistic effect. 5) luteolin and captopril significantly decreased intracellular Ca2 concentration and increased intracellular pH,. However, there was no significant synergistic effect on intracellular Ca2 concentration and pH. Conclusion: 1) the combination of subdose luteolin and subdose captopril can basically achieve the antihypertensive effect of constant dose captopril. 2) the combination of subdose captopril and luteolin can reduce the incidence of cough in mice caused by the former. The mechanism may be related to the decrease of captopril dose and the inhibition of IL-4,IL-5 secretion and the increase of IFN- level. Regulating the proportion of TH1 and TH2 cells is related. 3) although the combination of captopril and luteolin in vitro has no obvious synergistic anti-inflammatory effect, it has a certain additive effect. The anti-inflammatory effect of luteolin may be helpful to reduce the frequency of captopril cough. The anti-inflammatory mechanism may be related to the decrease of intracellular Ca2 concentration, the increase of pH value and the inhibition of macrophage secretion of pro-inflammatory cytokines.
【學位授予單位】：南方醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R544.1
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