兰州大学机构库 >第二临床医学院
血管紧张素II受体-脑啡肽酶双重阻滞对雌性高血压大鼠生殖道一氧化氮合酶以及纤维化的影响
Alternative TitleEffects of dual inhibition of angiotensin II receptor- neprilysin on nitric oxide synthase and fibrosis in the genital tract of female spontaneous hypertensive rats
喻晓荣
Thesis Advisor余静
2019-05-01
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name硕士
Degree Discipline内科学
Keyword高血压 雌性 沙库巴曲缬沙坦 氧化应激 纤维化
Abstract研究背景及目的:高血压是常见的慢性非传染性疾病,也是心血管病最主要 的危险因素。高血压相关的器官损害(HMOD)通常是指心、脑、肾脏和外周血 管损害。同时高血压还易导致全身小动脉痉挛,血管内皮损伤,炎症,氧化应激, 纤维化和重塑。女性生殖道血管丰富,类似的损害会引起该处相应的病理生理损 害。我们课题组前期的研究表明,女性高血压患者和血压正常的女性相比,更容 易发生性功能障碍(FSD),女性生殖道也可以作为 HMOD 之一。临床上的 5 大 类降压药物包括钙通道阻滞剂(CCB)、血管紧张素转换酶抑制剂(ACE-I)、血 管紧张素受体拮抗剂(ARB)、利尿剂和 β 受体阻滞剂。既往已有这些药物对高 血压女性性功能影响的研究。血管紧张素 II-脑啡肽酶抑制剂既能阻断 AT1 受体, 抑制血管收缩、交感神经兴奋、抑制醛固酮分泌、抑制炎症和氧化应激的发生, 又能提高利钠肽水平,使血管舒张、血压降低、同时具有抗组织增殖、抗纤维化 的作用,理论上应该较 ACE-I 或 ARB 相应的器官保护作用更强。本研究探讨 AT1 受体和脑啡肽酶双重阻滞剂沙库巴曲缬沙坦对雌性高血压大鼠生殖道氧化应激 以及纤维化指标的影响,旨在从动物实验上初步探讨沙库巴曲缬沙坦是否具有改 善 FSD 的病理生理基础的作用。 方法:16 周龄的 SPF 级别的自发性高血压大鼠(SHR),随机被分为沙库巴 曲缬沙坦组、缬沙坦组、氯噻酮组、SHR 组、正常对照组(为 WKY 大鼠),每 组 10 只。进行为期三个月的给药,药物通过灌胃的方式给予。通过鼠尾动脉压 的测量来获得大鼠收缩压(SBP)和舒张压(DBP)和平均动脉压(MBP)。12 周 过后,我们对所有的大鼠在无菌的操作间进行手术取材,取其阴道组织用于实验 研究,Western 印迹法测其氧化应激指标(eNOS、nNOS 蛋白表达),通过 HE 染 色,Masson 染色观察阴道组织纤维化程度。 结果:1. 大鼠血压的改变:和 SHR 相比,沙库巴曲缬沙坦组、缬沙坦组和 氯噻酮组均能明显的降低血压,包括 SBP、DBP 和 MBP;且和缬沙坦、氯噻酮 相比,沙库巴曲缬沙坦组降低 SBP 更显著。2.Western 印迹法结果:与 WKY 组 比较,SHR 组大鼠阴道组织 eNOS、nNOS 蛋白相对表达量显著降低,差异有统 计学意义(P<0.01);和 SHR 相比,沙库巴曲缬沙坦组和缬沙坦组 eNOS、nNOS 蛋白相对表达量明显上调(P<0.01),氯噻酮组没有统计学意义(P>0.05)。3. HE 染色结果:WKY 组(正常对照组)结果显示阴道上皮层形态基本正常,胶原纤 维没有增加,排列整齐,没有发生明显病理改变,阴道血管肌层形态大致正常; SHR 组大鼠阴道上皮层显著增厚,角化明显,胶原纤维明显增加,排列紊乱,病 理改变明显,阴道血管肌层呈管壁增厚,管腔狭窄等病理性改变;沙库巴曲缬沙 坦组和缬沙坦组均能降低阴道上皮增生,阴道胶原纤维增加,但程度有稍许差别, 沙库巴曲缬沙坦组和缬沙坦组相比,阴道上皮增加稍有减轻,胶原纤维增加有所 减少,纤维化程度有所减轻;而氯噻酮组对降低阴道纤维化程度不明显。4. Masson 染色结果:和 SHR 大鼠相比,沙库巴曲缬沙坦组大鼠阴道胶原纤维含量显著减 少(P<0.05),缬沙坦组胶原纤维含量明显减少(P<0.05),而氯噻酮组和 SHR 组 相比,胶原纤维含量并没有发生明显改变(P>0.05)。 结论:SHR 雌性大鼠生殖道发生纤维化的原因与氧化应激有关,沙库巴曲缬 沙坦在一定程度上可以抑制氧化应激的发生,改善生殖道血管内皮损伤,降低纤 维化程度,从而改善 SHR 雌性大鼠生殖道重塑。
Other AbstractObjective: Hypertension is the common chronic non-communicable disease and the most important risk factor for cardiovascular disease. Hypertension-mediated organ damage (HMOD) usually refers to damage to the heart, brain, kidney and peripheral blood vessels. Hypertension also causes spasms of small arteries, vascular endothelial damage, inflammation, oxidative stress, fibrosis and remodeling, the female genital tract is rich in blood vessels, similar damage will cause the corresponding pathophysiological damage. Our previous study proved that female hypertensive patients are more likely to develop sexual dysfunction than women with normal blood pressure, female genital tract can also be used as one of HMOD. The five major clinical categories of antihypertensive drugs include calcium channel blockers (CCB), angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor antagonists (ARB), diuretics and beta blockers. Previous studies of the effects of these drugs on sexual function in hypertensive women have been conducted. Angiotensin II-neprilysin inhibitor (Sacubitril/valsartan) is a first-in-class drug, it can not only block AT1 receptor, inhibit vasoconstriction, sympathetic excitation, inhibit aldosterone secretion, inhibit inflammation and oxidative stress, but also increase the level of natriuretic peptide, dilate blood vessels, reduce blood pressure, at the same time, it had the function of anti-tissue proliferation and anti-fibrosis, in theory, it should be stronger than the corresponding organ protection of ACE-I or ARB. Therefore, in this study, we investigated the effects of AT1 receptor and neprilysin double blocker (Sacubitril/valsartan) on oxidative stress and fibrosis indexin female hypertensive genital tract, the aim of this study was to explore whether it can improve the pathophysiology of genital tracts in female spontaneous hypertensive rats (SHR). Methods:16-week-old SPF-grade SHR were randomly divided into sacubitril / valsartan group, valsartan group, chlorothiazone groupand SHR group, and a normal control group (WKY group) with 10 rats in each group. During the three months period of administration, the drugs were given by gavage.The systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood pressure (MBP) were obtained by measuring rat tail artery pressure.After 12 weeks, all rats were operated on in aseptic operation, and their vaginal tissues were taken for the later experimental study. The oxidative stress index (eNOS, nNOS protein expression) was measured by Western blotting, and the degree of vaginal fibrosis was observed by HE staining and Masson staining. Results: 1. Changes of blood pressure in female SHR rats: Compared with SHR, both sacubitril/valsartan, valsartan and chlorothiazonegroups could significantly reduce blood pressure, including SBP, DBP and MBP, and compared with valsartan and chlorothiazone groups, the decrease of SBP insacubitril/valsartan group was more significant. 2. Western blotting results: Compared with WKY group, the relative expression of eNOS, nNOS protein in vaginal tissue of SHR group was significantly lower than that of the control group, and there was significant difference between the two groups (P<0.01). Compared with SHR, the relative expression of eNOS, nNOS protein in sacubitril/valsartan group and valsartan group was significantly up-regulated (P<0.01), but there was no statistical significance in chlorothiazone group(P>0. 05). 3. HE staining results: The results of WKY group showed that the morphology of vaginal epithelium was basically normal, collagen fibers did not increase, and arranged neatly, no obvious pathological changes occurred, and the shape of vaginal vascular muscular layer was approximately normal. In SHR group, the thickness of vaginal epithelium was significantly increased, the keratinization was obvious, collagen fibers increased significantly, and arranged disorder, pathological changes were obvious. Vaginal vascular muscular layer presented pathological changes, such as vascular wall was thickened and lumen was stenosis. Both sacubitril/valsartangroup and valsartan group could reduce vaginal epithelial hyperplasia, cut down the increase of collagen fibers, but the degree was slightly different. Compared with valsartan group, sacubitril/valsartan group could significantly alleviate the increase of vaginal epithelium, collagen fiber and the degree of fibrosis. However, the effect of chlorthiazone on the reduction of vaginal fibrosis is not obvious. 4. Masson staining results: Compared with SHR, the vaginal fiber content insacubitril/valsartan group decreased significantly (P < 0.05), and that in valsartan group decreased significantly (P < 0.05). Though the fiber content in chlorthiazone group was not significantly different from that in SHR group (P > 0.05). Conclusion: The causes of gentital tract fibrosis in female SHR rats are related to oxidative stress. Sacubitril/valsartan can inhibit oxidative stress and inflammation to some extent, improve vascular endothelial injury of gentital tract, reduce the degree of fibrosis, and thus ameliorate gentital tract remodeling in female SHR rats.
Pages47
URL查看原文
Language中文
Document Type学位论文
Identifierhttp://ir.lzu.edu.cn/handle/262010/338617
Collection第二临床医学院
Affiliation第二临床医学院
First Author AffilicationSecond Clinical School
Recommended Citation
GB/T 7714
喻晓荣. 血管紧张素II受体-脑啡肽酶双重阻滞对雌性高血压大鼠生殖道一氧化氮合酶以及纤维化的影响[D]. 兰州. 兰州大学,2019.
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