本文選題：血壓波動(dòng)性 + 血小板　； 參考：《泰山醫(yī)學(xué)院》2014年碩士論文

【摘要】：目的 研究血壓波動(dòng)性(BPV)增高對(duì)阿司匹林(Asp)抗血小板作用的影響及機(jī)制。 方法 實(shí)驗(yàn)分為在體實(shí)驗(yàn)和體外實(shí)驗(yàn)兩部分。 1.在體實(shí)驗(yàn)將Sprague-Dawley(SD)大鼠行去竇弓神經(jīng)(SAD)或假手術(shù)(Sham)，隨機(jī)分為8組：Sham組、SAD組、Sham+Asp低劑量組(5mg/kg)、SAD+Asp低劑量組(5mg/kg)、Sham+Asp中劑量組(15mg/kg)、SAD+Asp中劑量組(15mg/kg)、Sham+Asp高劑量組(45mg/kg)、SAD+Asp高劑量組(45mg/kg)，n=6。術(shù)后四周，在清醒自由活動(dòng)狀態(tài)下，檢測(cè)血壓(BP)、BPV和壓力感受性反射敏感性(BRS)的變化。Asp每日灌胃給藥，Sham組和SAD組大鼠灌胃等體積的溶媒，連續(xù)7天后，處死大鼠心臟取血，取肝素抗凝血，利用比濁法測(cè)定二磷酸腺苷(ADP)、膠原、凝血酶、花生四烯酸(AA)誘導(dǎo)的血小板聚集率；應(yīng)用小室灌流技術(shù)檢測(cè)在高切變率(1200s-1)和低切變率(300s-1)下血小板對(duì)膠原的黏附率；采用流式細(xì)胞技術(shù)測(cè)定血小板表面P-選擇素表達(dá)、活性氧(ROS)、一氧化氮(NO)以及鈣離子(Ca2+)平均熒光強(qiáng)度；取EDTA-消炎痛抗凝血，放免法檢測(cè)血漿TXB2含量，AA誘導(dǎo)下測(cè)定血小板環(huán)氧化酶(COX)活性。 2.體外實(shí)驗(yàn)取SD大鼠肝素抗凝血，隨機(jī)分為8組：非波動(dòng)組、波動(dòng)組、非波動(dòng)+Asp低濃度組(10μg/ml)、波動(dòng)+Asp低濃度組(10μg/ml)、非波動(dòng)+Asp中濃度組(30μg/ml)、波動(dòng)+Asp中濃度組(30μg/ml)、非波動(dòng)+Asp高濃度組(100μg/ml)、波動(dòng)+Asp高濃度組(100μg/ml)，n=5。Asp(非波動(dòng)組、波動(dòng)組應(yīng)用等體積溶媒)和血液在37℃孵育15min后，進(jìn)入體外壓力波動(dòng)模型5min，利用流式細(xì)胞技術(shù)檢測(cè)血小板微聚集率和上述相應(yīng)指標(biāo)，應(yīng)用小室灌流技術(shù)測(cè)定血小板黏附率。 結(jié)果 1.在體實(shí)驗(yàn)結(jié)果 1.1SAD大鼠血流動(dòng)力學(xué)和BRS變化與Sham組比較，SAD組大鼠SBP、DBP和MBP無(wú)明顯差異，但是SBPV、DBPV和MBPV均顯著增高，BRS顯著降低，表明SAD大鼠呈單純性BPV增高狀態(tài)，且動(dòng)脈壓力感受性反射功能明顯受損。 1.2血壓波動(dòng)性增高對(duì)Asp抗血小板作用的影響①與相應(yīng)Sham組比較，，SAD(Asp0、5、15mg/kg)組大鼠血小板聚集率、黏附率、血小板表面P-選擇素陽(yáng)性表達(dá)率、血漿TXB2含量及COX活性均顯著升高；②與Sham+Asp(45mg/kg)組比較，SAD+Asp(45mg/kg)組大鼠血小板聚集率、黏附率、血小板表面P-選擇素陽(yáng)性表達(dá)率、COX活性、血漿中TXB2含量均無(wú)顯著差異；③與SAD+Asp(0mg/kg)組比較，SAD+Asp (45mg/kg)組大鼠上述指標(biāo)均顯著降低。 1.3血小板COX活性及ROS、NO、Ca2+水平變化①與相應(yīng)Sham組比較，SAD(Asp0、5、15mg/kg)組大鼠血小板COX活性升高，血小板ROS、Ca2+平均熒光強(qiáng)度增高，NO平均熒光強(qiáng)度降低。②與相應(yīng)Sham+Asp(45mg/kg)組比較，SAD+Asp(45mg/kg)組大鼠血小板COX活性以及ROS、Ca2+、NO平均熒光強(qiáng)度無(wú)顯著差異；③與SAD+Asp(0mg/kg)組比較，SAD+Asp(45mg/kg)組大鼠血小板COX活性以及ROS、Ca2+平均熒光強(qiáng)度降低，NO平均熒光強(qiáng)度升高。 2.體外實(shí)驗(yàn)結(jié)果 2.1壓力和壓力波動(dòng)性變化與非波動(dòng)組比較，波動(dòng)組的SBP、DBP和MBP無(wú)明顯差異，但SBPV、DBPV和MBPV均顯著增高。表明模擬SAD大鼠BPV增高的體外模型是成功的。 2.2壓力波動(dòng)性增高對(duì)阿司匹林抗血小板作用的影響①與相應(yīng)非波動(dòng)組比較，波動(dòng)組(Asp0、10、30μg/ml)血小板表面P-選擇素陽(yáng)性表達(dá)率、微聚集率和黏附率均顯著升高；②與非波動(dòng)+Asp(100μg/ml)組比較，波動(dòng)+Asp(100μg/ml)組血小板表面P-選擇素陽(yáng)性表達(dá)率、微聚集率和黏附率均無(wú)顯著差異；③與波動(dòng)+Asp(0μg/ml)組比較，波動(dòng)+Asp(100μg/ml)組血小板表面P-選擇素陽(yáng)性表達(dá)率、微聚集率和黏附率均顯著降低。 2.3血小板ROS、NO、Ca2+探針熒光強(qiáng)度的變化①與相應(yīng)非波動(dòng)組比較，波動(dòng)組(Asp0、10、30μg/ml)血小板ROS、Ca2+平均熒光強(qiáng)度增高，NO的平均熒光強(qiáng)度降低；②與非波動(dòng)+Asp(100μg/ml)組比較，波動(dòng)+Asp(100μg/ml)組血小板ROS、Ca2+、NO平均熒光強(qiáng)度無(wú)顯著差異；③與波動(dòng)+Asp(0μg/ml)組比較，波動(dòng)+Asp(100μg/ml)組血小板ROS、Ca2+平均熒光強(qiáng)度顯著降低，NO平均熒光強(qiáng)度明顯升高。 結(jié)論 血壓波動(dòng)性增高能夠降低阿司匹林對(duì)血小板活化的抑制作用，機(jī)制與血小板COX活性增高、氧化應(yīng)激和NO、Ca2+信號(hào)變化有關(guān)。增加阿司匹林的劑量可以對(duì)抗血壓波動(dòng)性增高的這種作用。
[Abstract]:objective
Objective to study the effect and mechanism of increased blood pressure (BPV) on antiplatelet action of aspirin (Asp).
Method
The experiment is divided into two parts: in vivo experiment and in vitro experiment.
1. Sprague-Dawley (SD) rats were randomly divided into 8 groups: Sham group, SAD group, SAD group, Sham+Asp low dose group (5mg/kg), SAD+Asp low dose group (5mg/kg), Sham+Asp medium dose group (15mg/kg), high dose group, high dose group. In the latter four weeks, the changes of blood pressure (BP), BPV, and pressure receptive reflex sensitivity (BRS) were measured in the wake of conscious and free activity..Asp was administered daily to the gastric administration, the Sham group and the SAD group were given the volume of the solvent. After 7 days, the rat heart was killed and the heparin anticoagulant blood was taken, and the ADP, collagen, thrombin and flower were measured by turbidimetry. The platelet aggregation rate induced by four enoic acid (AA); the adhesion rate of platelets to collagen at high shear rate (1200s-1) and low shear rate (300s-1) was detected by small ventricular perfusion technique. Flow cytometry was used to determine the expression of P- selectin on the surface of platelets, reactive oxygen species (ROS), nitric oxide (NO) and calcium ion (Ca2+) average fluorescence intensity, and E DTA- indomethacin anticoagulant, radioimmunoassay was used to detect plasma TXB2 content, and AA was used to determine platelet activity of COX.
2. the heparin anticoagulant of SD rats was randomly divided into 8 groups: non wave group, wave group, non wave +Asp low concentration group (10 u g/ml), fluctuating +Asp low concentration group (10 mu g/ml), non fluctuating +Asp concentration group (30 mu g/ml), undulating +Asp concentration group (30 u g/ml), non wave +Asp high concentration group (100 mu g/ml), undulant +Asp high concentration group (100 mu), 100 (non wave group, wave group and other volume solvent) and blood were incubated at 37 centigrade for 15min to enter the pressure wave model 5min in vitro. The platelet aggregation rate and the corresponding index were detected by flow cytometry, and the platelet adhesion rate was measured by small chamber perfusion technique.
Result
1. in vivo experiment results
The changes of hemodynamics and BRS in 1.1SAD rats were compared with that of group Sham. There was no significant difference in SBP, DBP and MBP in group SAD, but SBPV, DBPV and MBPV were all significantly increased, BRS significantly decreased, indicating that SAD rats showed a state of pure increase, and the arterial pressure receptive reflex was significantly impaired.
1.2 the effect of high fluctuation of blood pressure on the antiplatelet effect of Asp (1) compared with the corresponding Sham group, the platelet aggregation rate, adhesion rate, the positive expression of P- selectin on the platelet surface, the plasma TXB2 content and the COX activity were significantly increased in the SAD (Asp0,5,15mg/kg) group, and the platelet aggregation in the SAD+Asp (45mg/kg) group was compared with the Sham+Asp (45mg/kg) group. There was no significant difference in the rate of collection, adhesion, the positive expression of P- selectin on the platelet surface, the activity of COX, and the content of TXB2 in the plasma. (3) compared with the SAD+Asp (0mg/kg) group, the above indexes in the SAD+Asp (45mg/kg) group were significantly reduced.
1.3 the activity of platelet COX and the changes of ROS, NO, Ca2+ level 1. Compared with the corresponding Sham group, the activity of platelet COX in the SAD (Asp0,5,15mg/kg) group increased, the platelet ROS, the average fluorescence intensity of Ca2+ increased, and the NO average fluorescence intensity decreased. There was no significant difference in the average fluorescence intensity. Compared with the SAD+Asp (0mg/kg) group, the COX activity of platelets in the rats of SAD+Asp (45mg/kg) group and the average fluorescence intensity of Ca2+ decreased and the average fluorescence intensity of NO increased.
2. in vitro experimental results
2.1 there was no significant difference in SBP, DBP and MBP in the fluctuation group, but the SBPV, DBPV and MBPV were all significantly higher than those in the non wave group, indicating that the model in vitro of the increased BPV in the simulated SAD rats was successful.
2.2 the effect of increased pressure fluctuation on the antiplatelet action of aspirin (1) compared with the non wave group, the positive expression rate of P- selectin on the platelet surface, the rate of micro aggregation and adhesion of the platelet surface in the wave group (Asp0,10,30 mu g/ml) were all significantly increased. 2. Compared with the non wave +Asp (100 mu g/ml) group, the platelet surface P- selectin in the group of +Asp (100 mu g/ml) group was fluctuated. There was no significant difference in positive expression rate, micro aggregation rate and adhesion rate. Compared with the wave +Asp (0 mu g/ml) group, the positive expression rate of P- selectin on the platelets on the fluctuating +Asp (100 g/ml) group decreased significantly.
2.3 the changes in the fluorescence intensity of the platelet ROS, NO, and Ca2+ probe (1) compared with the non wave group, the platelet ROS in the wave group (Asp0,10,30 mu g/ml), the average fluorescence intensity of Ca2+ increased and the average fluorescence intensity of NO decreased, and there was no significant difference in the average fluorescence intensity of the fluctuation +Asp (100 micron g/ml) group compared with the non undulation +Asp (100 micron g/ml) group. (3) compared with the fluctuating +Asp (0 g/ml) group, the mean fluorescence intensity of platelet ROS and Ca2+ decreased significantly in the fluctuating +Asp (100 g/ml) group, and the average fluorescence intensity of NO increased significantly.
conclusion
High blood pressure fluctuation can reduce the inhibitory effect of aspirin on platelet activation. The mechanism is associated with increased platelet COX activity, oxidative stress and changes in NO and Ca2+ signals. The increase of aspirin dose can antagonism the effect of high blood pressure fluctuation.

【學(xué)位授予單位】：泰山醫(yī)學(xué)院
【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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