川芎嗪防治大鼠慢性缺氧性肺动脉高压的作用

本文研究了川芎嗪对大鼠慢性缺氧性肺动脉高压的预防及治疗效果。结果显示,川芎嗪经口服(100mg/kg)和腹腔注射(80mg/kg),每日二次,均可防止慢性缺氧性肺动脉高压及右心室肥大的发生。在已患慢性肺动脉高压的大鼠,静脉注射川芎嗪(80mg/kg)显著增加心输出量,降低肺血管阻力及肺动脉压力,其降压作用比正常及急性缺氧性肺动脉高压时更为明显。这提示川嗪芎可用于预防及治疗慢性缺氧性肺动脉高压及肺压病。     

缺氧性肺动脉高压大鼠肺毛细血管超微结构变化

目的研究缺氧对肺毛细血管结构的影响及其在缺氧性肺动脉高压(HPH)发展过程中的作用。方法本实验模拟海拔5km高原连续缺氧 ,制备HPH大鼠动物模型 ,应用电镜观察缺氧后10、20和30d肺毛细血管超微结构变化 ,探讨变化机制及其意义。结果缺氧10d,可见毛细血管内充满红细胞 ,红细胞呈缗钱状 ,相互挤压或套叠 ;内皮细胞 (EC)肿胀 ,胞质呈节段性增厚。缺氧20d与30d病变基本一致 ,但比10d更为明显。可见较多毛细血管充血 ,中性粒细胞 (PMN)滞留、嵌塞 ,有的PMN与EC黏附。毛细血管内易见血小板聚集 ,阻塞管腔。有的毛细血管高度扩张。EC肿账 ,可见胞质电子密度降低 ,饮泡增多 ,连接增宽 ,有的EC胞质形成较多微绒毛突入管腔 ,有的EC胞核核膜增厚 ,呈多边形或乳头状 ,核染色质凝集边移 ,基底膜节段性增厚。毛细血管周围水肿 ,可见大小不一的水肿空泡。结论缺氧可引起肺毛细血管充血、淤血 ,EC肿胀、基底膜增厚使毛细血管管腔狭窄 ,PMN滞留、血小板聚集 ,微循环发生障碍 ,致肺血流阻力增加 ,从而促使HPH的发生和发展目的研究缺氧对肺毛细血管结构的影响及其在缺氧性肺动脉高压(HPH)发展过程中的作用。方法本实验模拟海拔5km高原连续缺氧 ,制备HPH大鼠动物模型 ,应用电镜观察缺氧后10、20和30d肺毛细血管超微结构变化     

前列腺素与白三烯对慢性吸烟大鼠缺氧性肺血管收缩反应的作用

Wistar大鼠每天“吸烟”1小时,“吸烟”30天后,肺动脉平均压(Ppa)和肺循环阻力(PVR)与对照组无显著差异,但缺氧(吸10%氧)性肺血管收缩反应(HPV)显著降低(P<0.01)。缺氧前吸烟组和对照组动脉血浆6-酮-前列腺素F_(1α)(6-Keto-PGF_(1α))、血栓素B_2(TXB_2)及6-Keto-PGF_(1α)/TXB_2均无差异,缺氧时吸烟组血浆6-Keto-PGF_(1α)和6-Keto-PGF_(1α)/TXB_2高于缺氧前(P<0.05),而TXB_2无显著差异,对照组缺氧前后此二物质均无明显变化。消炎痛可部分逆转吸烟所致HPV降低。缺氧前吸烟组血浆中白三烯(LTs)浓度与对照组无显著差异,而在缺氧时的增值明显低于对照组的增值(P<0.05)。结果提示:慢性吸烟可使大鼠的HPV降低,其机制可能与PGI_2生成增加和LTs生成减少有关。     

L-精氨酸对缺氧性肺动脉高压大鼠内皮素释放的影响

目的：探讨Ｌ－精氨酸（Ｌ－Ａｒｇ）对缺氧性肺动脉高压（ＨＰＨ）大鼠血浆内皮素－１（ＥＴ－１）释放的影响。方法：将Ｗｉｓｔａｒ大鼠４０只分为：对照组,缺氧组,缺氧＋Ｎ＾ω－硝基－Ｌ－精氨酸甲脂（Ｌ－ＮＡＭＥ）组和缺氧Ｌ－Ａｒｇ组。结果：缺氧组的肺动脉平均压（ｍＰＡＰ）显著高于对照组（Ｐ〈０．０５）,缺氧组＋Ｌ－Ａｒｇ组的ｍＰＡＰ显著低于缺氧组（Ｐ〈０．０５）及缺氧＋Ｌ－ＮＡＭＥ组（Ｐ〈０．０１）,缺     

不同食用油对大鼠肺血管反应性和慢性低氧性肺动脉高压的影响

本研究观察了豆油和猪油对大鼠肺血管反应性和慢性低氧性肺动脉高压的影响。大鼠进高脂饮食2月后,常压缺氧14天。缺氧时吸入气O_2浓度为10±0.5%,每天缺氧8小时。结果喂含15%豆油的高脂饮食的大鼠的平均肺动脉压<(?)pa,肺血管阻力(PVR)和肺血管对急性缺氧的反应性(△PVR%)均显著高于缺氧对照组,右心室肥大也较缺氧对照组严重。喂含15%猪油的高脂饮食或含7.5%豆油加7.5%猪油的高脂饮食的大鼠的Ppa,PVR,△PVR%以及右心室肥大程度与缺氧对照组大鼠无明显差别。血粘度和红细胞压积在慢性常压缺氧后均增高,但不同的高脂饮食对其影响不大。实验结果提示,富含豆油的高脂饮食增强大鼠的低氧性肺血管收缩反应,加重慢性低氧性肺动脉高压和右心室肥大。     

西拉普利对大鼠缺氧性肺动脉高压血管内皮保护作用的研究

目的：观察西拉普利对大鼠缺氧性肺动脉高压血管内皮的保护作用。方法：运用血液动力学方法、观察循环内皮细胞及血管紧张素转化酶、丙二醛的测定。结果：缺氧性肺动脉高压时右室压、肺动脉平均压升高（P＜0．01）,循环内皮细胞数量增加（P＜0．01）,丙二醛升高（P＜0．01）,西拉普利治疗后各值下降（P＜0．01）;缺氧时血管紧张素转化酶下降（P＜0．01）,西拉普利治疗后有上升（P＜0．01）。结论：西拉普利能降低肺动脉压,清除氧自由基,减少血CEC,对血管内皮细胞有保护作用。     

用肺组织条作缺氧性肺血管收缩反应研究的探索

目的: 探索由急性缺氧所致肺组织条张力变化与肺动脉和气管张力变化的关系,以探讨用肺组织条研究缺氧性肺血管反应的可行性。方法:因为肺组织条中可收缩的部分主要是血管和气管,所以分别做肺组织条、肺动脉、气管的张力实验。纵向剪取Wistar大鼠肺组织条以及肺动脉环(肺动脉三级分支制成的肺动脉环)和肺内段气管条悬挂于张力传感器上,记录张力变化。结果:急性缺氧使肺组织条及肺动脉环张力增加,而气管条张力下降,在加入吲哚美辛阻断前列腺素生成后,肺组织条缺氧性收缩反应增强,肺血管环缺氧反应也增加,而对肺内气管条的缺氧反应无明显影响;在加入L-NAME阻断一氧化氮生成后,肺组织条和肺血管环缺氧性收缩反应均增强,而对肺内气管条的缺氧反应无明显影响;在加入4-AP阻断电压门控钾通道后,肺组织条与肺血管环缺氧性收缩反应均下降,而气管缺氧性舒张反应则减弱。 结论:必要时可用肺组织条作缺氧性肺血管反应性研究。     

肾上腺髓质素缓解大鼠低氧性肺动脉高压

目的探讨肾上腺髓质素(ADM)对大鼠低氧性肺动脉高压的防治作用及机制。方法雄性Wistar大鼠18只,分为对照组、低氧组和低氧 ADM组,每组6只。持续皮下注射ADM1-50后,测定平均肺动脉压(mPAP)、右心室肥大指数RV/(LV S)、肺小动脉病理及形态计量学和体循环平均压(mSBP),放免法测定肺动脉血浆ADM水平,原位杂交测定肺动脉ADMR mRNA的表达。结果①低氧组大鼠mPAP,RV/(LV S),管壁厚度与血管外径比值(MT%)及管壁面积与血管面积比值(MA%)均显著升高(P<0.01);ADM组显著缓解以上变化(P<0.01)。②低氧组与低氧 ADM组肺动脉血浆ADM浓度均高于对照组,且低氧 ADM组较低氧组ADM浓度低(P<0.05)。③低氧组与低氧 ADM组的ADMR mRNA表达较对照组增强(P<0.01)。结论持续皮下注射ADM对慢性低氧所致的肺动脉高压及肺血管重塑有预防和部分逆转作用。     

Endothelium-derived mediators and hypoxic pulmonary vasoconstriction

The vascular endothelium synthesises, metabolises or converts a multitude of vasoactive mediators, and plays a vital role in the regulation of pulmonary vascular resistance. Its role in hypoxic pulmonary vasoconstriction (HPV) is however controversial. Although HPV has been demonstrated in both pulmonary arteries where the endothelium has been removed and isolated pulmonary artery smooth muscle cells, many reports have shown either partial or complete dependence on an intact endothelium for sustained HPV (> approximately 20 min). However, despite many years of study no known endothelium-derived mediator has yet been unequivocally shown to be essential for HPV, although several may either facilitate the response or act as physiological brakes to limit the extent of HPV. In this article we review the evidence for and against the role of specific endothelium-derived mediators in HPV. We make the case for a facilitatory or permissive function of the endothelium, that in conjunction with a rise in smooth muscle intracellular Ca(2+) initiated by a mechanism intrinsic to smooth muscle, allows the development of sustained HPV. In particular, we propose that in response to hypoxia the pulmonary vascular endothelium releases an as yet unidentified agent that causes Ca(2+) sensitisation in the smooth muscle.     

Effect of fasudil on hypoxic pulmonary hypertension and right ventricular hypertrophy in rats

Objective: To investigate whether right ventricular hypertrophy in hypoxic pulmonary hypertension (HPH) rats could be prevented by treatment with Rho kinase inhibitor fasudil. Methods: The rat model of pulmonary hypertension was established by exposing rats to normobaric intermitent hypoxia [(10±0.5)% O₂]. Twenty-four Spraque-Dawley male rats were randomly divided into control group, hypoxic model group and hypoxia with fasudil groups (n=8 each). The mean pulmonary arterial pressure (mPAP), and right ventricle hypertrophy index (RVHI) were measured. Ultrastructure of the right ventricular myocardial cells was observed under transmission electron microscope (TEM). –Results: The level of mPAP (31.38±1.98) mmHg and RVHI (0.47±0.03) were significantly higher in the hypoxic model group than (15.25±0.91) mmHg and (0.25±0.02) in control group respectively (P<0.01). Transmission electron microscope (TEM) revealed the model group right ventricular mitochondria increased significantly, swelling, cristae blurred, lost, heart muscle Siming dark band was not clear. The level of mPAP (16.63±1.53) mmHg and RVHI (0.27±0.02) were significantly lower in fasudil treatment group than in model group respectively (P<0.01). After the intervention of fasudil right ventricular myocardial injury was significantly reduced. Conclusions: Fasudil may partly prevent and reverse the development of pulmonary hypertension and right ventricular hypertrophy and myocardial cell injury.     

牛磺酸对大鼠慢性缺氧性肺动脉高压的预防作用

目的：进一步研究牛磺酸对慢性缺氧性肺动脉高压的防治作用。方法：复制大鼠间断缺氧４周模型,采用透射电镜、放射免疫和生化技术研究牛磺酸对肺动脉高压的治疗效果。结果：缺氧４周大鼠肺动脉压力升高,右心肥大,血中ＥＴ－１、ＡＣＥ水平升高,ＮＯ－２／ＮＯ－３和ＳＯＤ水平降低;ＭＰＡＰ与ＥＴ－１呈正相关,与ＮＯ－２／ＮＯ－３呈负相关;牛磺酸可抑制缺氧大鼠ＥＴ－１和ＡＣＥ分泌,增加ＮＯ和ＳＯＤ水平,降低肺动脉压力;透射电镜观察表明牛磺酸能对抗缺氧大鼠的心肺组织损伤。结论：牛磺酸通过减轻缺氧所致细胞损伤,调节血管舒缩物质的平衡,对缺氧性肺高压有一定防治作用。     

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction,pulmonary arterial remodelling and pulmonary hypertension

Hypoxic pulmonary vasoconstriction (HPV) serves to optimize ventilation–perfusion matching in focal hypoxia and thereby enhances pulmonary gas exchange. During global hypoxia, however, HPV induces general pulmonary vasoconstriction, which may lead to pulmonary hypertension (PH), impaired exercise capacity, right‐heart failure and pulmonary oedema at high altitude. In chronic hypoxia, generalized HPV together with hypoxic pulmonary arterial remodelling, contribute to the development of PH. The present article reviews the principal pathways in the in vivo modulation of HPV, hypoxic pulmonary arterial remodelling and PH with primary focus on the endothelin‐1, nitric oxide, cyclooxygenase and adenine nucleotide pathways. In summary, endothelin‐1 and thromboxane A₂ may enhance, whereas nitric oxide and prostacyclin may moderate, HPV as well as hypoxic pulmonary arterial remodelling and PH. The production of prostacyclin seems to be coupled primarily to cyclooxygenase‐1 in acute hypoxia, but to cyclooxygenase‐2 in chronic hypoxia. The potential role of adenine nucleotides in modulating HPV is unclear, but warrants further study. Additional modulators of the pulmonary vascular responses to hypoxia may include angiotensin II, histamine, serotonin/5‐hydroxytryptamine, leukotrienes and epoxyeicosatrienoic acids. Drugs targeting these pathways may reduce acute and/or chronic hypoxic PH. Endothelin receptor antagonists and phosphodiesterase‐5 inhibitors may additionally improve exercise capacity in hypoxia. Importantly, the modulation of the pulmonary vascular responses to hypoxia varies between species and individuals, with hypoxic duration and age. The review also define how drugs targeting the endothelin‐1, nitric oxide, cyclooxygenase and adenine nucleotide pathways may improve pulmonary haemodynamics, but also impair pulmonary gas exchange by interference with HPV in chronic lung diseases.     

Carbonic anhydrase inhibitors and hypoxic pulmonary vasoconstriction

Acetazolamide and other related carbonic anhydrase (CA) inhibitors have had a long history of effectiveness in prevention and treatment of acute mountain sickness (AMS) and remain the standard of care for this indication. Despite many decades of CA inhibitor use for AMS, the possibility has never been seriously entertained that these drugs might also afford protection against high altitude pulmonary edema (HAPE). In this paper, I will present our evidence and supporting data of others, that acetazolamide has inhibitory effects on the hypoxic response of the pulmonary circulation that may be useful in HAPE. Data from pulmonary artery smooth muscle cells, isolated perfused lungs, and live unanethetized animals all point to a potent reduction in hypoxic pulmonary vasoconstriction (HPV) by acetazolamide that may have clinical utility in HAPE and possibly other pulmonary hypertensive disorders. Astonishingly, the efficacy of acetazolamide as a HPV inhibitor does not appear to be related to carbonic anhydrase inhibition, since other potent CA inhibitors have no effect on HPV either in the conscious dog or on hypoxic calcium (Ca(2+)) signalling in rat pulmonary artery smooth muscle cells, despite enzyme presence in these cells. Although we have not yet determined the mechanism of action for acetazolamide in HPV, we have ruled out actions on membrane L-type Ca(2+) channels, normoxic and hypoxic membrane potential and rho-kinase activation. Based upon these negative findings in isolated pulmonary artery smooth muscle cells and preliminary data in Ca(2+) free media we propose that acetazolamide may act at the level of Ca(2+) release from the sarcoplasmic reticulum, a process which initiates and amplifies cell membrane Ca(2+) channel opening. In further work, we have developed and will use a methylated analog of acetazolamide to yield a molecule lacking CA inhibiting activity, but which in most other respects (size, pK(a), heterocyclic ring structure, electrostatic charge distribution) is equivalent to acetazolamide.     

红景天苷通过抑制氧化应激防治大鼠低氧性肺动脉高压

目的:观察低氧性肺动脉高压大鼠肺组织及血清中氧化/抗氧化相关指标的变化,研究红景天苷(Sal)能否通过恢复氧化/抗氧化系统平衡防治低氧性肺动脉高压。方法:将32只SD大鼠随机分为4组:常氧(normoxia,N)组、低氧4周(hypoxia for 4 weeks,H_4)组、Sal低剂量(hypoxia for 4 weeks and treatment with Sal at 16mg/kg,H_4S16)组和Sal高剂量(hypoxia for 4 weeks and treatment with Sal at 32 mg/kg,H_4S32)组。造模完成后测定平均肺动脉压(m PAP)、右心室/(左心室+室间隔)[RV/(LV+S)]和血管壁面积/血管总面积(WA/TA);测量肺组织和血清中丙二醛(MDA)和8-异构前列腺素F_(2α)(8-iso-PGF_(2α))含量,并测量血清中超氧化物歧化酶(SOD)活性及肺组织中NADPH氧化酶(NOX4)和SOD1的相对表达量。结果:与N组相比,H_4组的NOX4相对表达量及MDA和8-iso-PGF_(2α)含量均显著升高(P0.05);而与H4组相比,Sal低、高剂量组除m PAP、RV/(LV+S)和WA/TA明显减低外,NOX4的相对表达量及MDA和8-iso-PGF_(2α)含量亦明显减低(P0.05)。与N组相比,H_4组的SOD1相对表达量和SOD活性显著下降,而Sal低、高剂量组的SOD1相对表达量和SOD活性均显著升高并呈剂量依赖性。结论:红景天苷可能通过减轻低氧引起的肺组织氧化应激损伤、恢复氧化/抗氧化系统平衡而起到改善肺动脉高压的作用。     

腺苷A2a受体在红景天苷调节大鼠低氧性肺动脉高压中的作用

 目的：探讨腺苷A_2a受体（A_2aAR）对低氧性肺动脉高压大鼠的保护作用及红景天苷对大鼠低氧性肺动脉高压的调控作用及其机制。方法：将SD大鼠60只随机分为6组：正常组、低氧组、低氧+红景天苷低剂量组、低氧+红景天苷中剂量组、低氧+红景天苷高剂量组、低氧+A_2aAR激动剂（CGS-21680）组。测定各组大鼠平均肺动脉压（mPAP）、平均颈动脉压（mCAP）和右心室(RV)/（左心室+室间隔）(LV+S),观察各组肺细小动脉显微结构变化;用免疫组化法和原位杂交法测定肺细小动脉管壁A_2aAR含量的变化;用实时荧光定量PCR法和Western blotting法测定肺组织匀浆A_2aAR mRNA和蛋白含量的变化。结果：（1）低氧组大鼠mPAP明显高于正常对照组,A_2aAR激动剂组和红景天苷高剂量组可以明显降低mPAP,红景天苷中、低剂量组mPAP虽有下降趋势,但差异无统计学意义。（2）低氧组大鼠RV/(LV+S)显著高于正常组,A_2aAR激动剂组和红景天苷中、高剂量组RV/(LV+S)显著低于低氧组,红景天苷低剂量组较低氧组有减低趋势,但差异无统计学意义。（3）低氧组大鼠肺细小动脉重构显著, A_2aAR激动剂组及红景天苷低、中、高剂量组肺血管重构较低氧组明显减轻。（4）低氧组肺血管和肺组织A_2aAR mRNA和蛋白表达均明显高于正常组,A_2aAR激动剂组和红景天苷高剂量组肺血管和肺组织A_2aAR mRNA和蛋白水平均较低氧组进一步升高。结论：A_2aAR对低氧性肺动脉高压大鼠具有保护作用;红景天苷能够上调低氧性肺动脉高压大鼠肺血管和肺组织A_2aAR的表达,该通路可能是其减轻低氧性肺动脉高压和肺血管重建的重要机制。     

L-精氨酸和牛磺酸联合抗缺氧损伤及防治缺氧性肺动脉高压的研究

目的研究L-精氨酸、牛磺酸联合应用的抗缺氧损伤以及对缺氧性肺动脉高压(HPH)的防治效果。方法雄性W istar大鼠40只,制作缺氧性HPH模型,随机分为平原对照组(C)、单纯缺氧组(H)、缺氧 L-精氨酸组(Arg)、缺氧 牛磺酸组(Tau)、缺氧 牛磺酸 L-精氨酸组(TA),测定各组的肺动脉压(mPAP)、右心室肥大指数(RVH I)、血浆乳酸脱氢酶(LDH)、脂质过氧化产物丙二醛(MDA)、肺匀浆NO含量的变化。结果H组与C组相比,mPAP高出约25 mmHg(P<0.01),RVH I增加1.56倍(P<0.01),血浆LDH活性增高10.1倍(P<0.01),血浆MDA含量增加1.64(P<0.01),而肺匀浆NO含量降低68%(P<0.01)。各治疗组与H组相比,mPAP均显著降低5 mmHg(P<0.05),RVH I均显著降低20%(P<0.01),血浆LDH活性显著降低(P<0.01),其中TA组与Arg组比较有显著差异(P<0.01),血浆MDA含量显著降低(P<0.01),但各治疗组之间无显著性差异。肺匀浆NO含量在Tau组无显著性变化,在Arg和TA组显著回升(P<0.01)。结论L-精氨酸和牛磺酸具有抗缺氧损伤及防治肺动脉高压的效果,两者联用可进一步增加NO产生,减少乳酸脱氢酶的漏出,加强细胞保护作用。