环孢素A逆转野百合碱诱导的肺动脉高压

目的:探讨环孢素A(cyclosporine A,CsA)对野百合碱(monocrotaline,MCT)诱发肺动脉高压的影响及其作用机制.方法:36只雄性Sprague-Dawley(SD)大鼠随机分为正常对照组(n=8)、肺动脉高压模型组(n=12)、CsA低、高剂量组(0.33和1 mg·kg-1,n=8).后3组大鼠颈背部皮下一次性注射MCT 50mg·kg-1诱导肺动脉高压模型,MCT注射后d 14～d 21,CsA组灌胃给药,模型组灌胃等体积的生理氯化钠溶液(5 mL·kg-1).MCT注射后d 22,右心导管术测肺动脉压,称肺湿重(wW)、右心室自由壁(RV)重和左心室加室间隔(LV S)重,计算右心肥大指数[RVHI=RV/(LV S)],肺湿重指数(LI=wW/BW).HE染色观察肺病理改变;免疫组化方法观察肺动脉平滑肌细胞增殖细胞核抗原(PCNA)阳性表达.用Image-ProPlus 5.1软件分析肺动脉中膜相对厚度及肺动脉平滑肌PCNA阳性细胞的比值.结果:CsA低、高剂量组均能逆转MCT诱导的肺动脉高压(P<0.05或P<0.01),降低RVHI及LI(P<0.05或P<0.01),改善肺动脉重构(P<0.05或P<0.01),减轻肺部炎症,抑制肺动脉平滑肌的增殖(P<0.05或P<0.01),且高剂量组更明显.结论:CsA能明显降低MCT诱导的肺动脉高压,逆转肺动脉重构,其机制与抑制肺动脉平滑肌增殖和抑制肺部炎症有关.     

亚高原地区野百合碱诱导大鼠肺动脉高压模型的剂量研究

目的 探讨亚高原地区野百合碱(monocrotaline,MCT)诱导大鼠肺动脉高压模型的最佳剂量.方法 将从平原地区购买85只(♂)SD大鼠随机分为对照组、MCT-20 mg·kg-1组、MCT-30 mg·kg-1组、MCT-40 mg·kg-1组、MCT-50 mg·kg-1组、MCT-60 mg·kg-1组.除...     

野百合碱诱导大鼠肺动脉高压动物模型的制备

目的采用注射野百合碱(MCT)制备大鼠肺动脉高压模型,并对肺动脉压测定方法进行优化。方法通过ip MCT诱导建立大鼠肺动脉高压模型,通过测定大鼠肺血管阻力的方法来对大鼠右心室压进行测定,采用阳性药对照、血流动力学测定和组织学观察确定模型是否建立成功。结果 ip 50 mg/kg MCT 4周后大鼠右心室平均压、右心肥大指数对比对照组明显增高,观察病理组织切片,可见明显的内皮细胞损伤,分布不均,动脉管壁明显增厚,肺组织有大量的炎性细胞浸润,出现肺血管的重构,证实肺动脉高压动物模型造模成功。结论采用ip MCT可以建立稳定的大鼠肺动脉高压模型,且具有较高的存活率,同时建议采用改良的心导管测定方法测定大鼠右心室压力。     

野百合碱致肺动脉高压相关机制研究进展

吡咯里西啶类生物碱(pyrrolizidine alkaloids,PAs)分布十分广泛,3%的有花植物中含有PAs,其中含量较多的为紫草科、菊科、豆科及兰科植物[1]。含PAs的中药应用广泛,如中国药典2005年版一部即收录了佩兰(菊科)、紫草(紫草科)、款冬花(菊科)等多种含有该类生物碱的植物。野百合碱(monocrotaline,MCT)是来自于豆科猪屎豆     

地塞米松对野百合碱诱导肺动脉高压模型大鼠血管活性物质的影响

目的 探讨地塞米松早期干预对野百合碱(MCT)诱导肺动脉高压(PAH)大鼠肺血管活性物质的影响.方法 成年雄性SD大鼠30只随机均分为对照(C)组、MCT模型(M)组、MCT+地塞米松(MD)组.建立MCT诱导PAH模型,应用放射免疫法观察血浆一氧化氮(NO)和内皮素1(ET-1)水平的变化.结果 注射MCT3周后,M组大鼠肺动脉平均压(mPAP)显著高于C组和MD组(P＜0.05);与C组和MD组比较,M组血浆ET-1含量升高,NO含量降低(P＜0.05);而MD组ET-1和NO含量与C组比较无统计学差异.结论 地塞米松能抑制MCT诱导的PAH大鼠血浆中的ET-1含量升高和NO含量降低,从而改善内皮细胞功能,降低PAH.     

酚妥拉明对野百合碱引起的大鼠肺动脉高压的影响

本文研究结果表明:野百合碱是一个有效的引起Wistar大鼠肺动脉高压模型的药物;酚妥拉明(0.2mg·kg~(-1)0.4mg·kg~(-1))im.每天2次.连续用药21d后.可降低野百合碱引起的肺动脉高压.但对股动脉血压无明显影响。酚妥拉明(0·52mg·kg~(_1))iv一次即可明显降低野百合碱引起的大鼠肺动脉高压和股动脉压。     

野百合碱诱导的肺动脉高压大鼠肺血管5-HT转载体表达增强

目的　研究野百合碱诱导的大鼠肺动脉高压与5 HT转载体基因表达的关系。方法　应用MCT诱导的慢性肺动脉高压大鼠模型,建立离体动脉环5 HT浓度反应曲线;HE染色观察肺动脉构型重建,应用RT PCR检测大鼠肺动脉5 HT转载体mRNA表达。结果　MCT大鼠肺血管对5 HT收缩反应增强,肺肌型小动脉中膜增厚,MCT诱导的肺动脉高压大鼠肺血管5 HT转载体mRNA表达明显增多。5 HT转载体基因表达与肺肌型小动脉中膜增厚有明显相关性。结论　MCT诱导的肺动脉高压大鼠肺血管构型重建及5 HT引起收缩反应增强,伴有5 HT转载体mRNA表达增多;同时5 HT转载体mRNA表达与肺肌型小动脉中膜增厚有明显相关性,提示5 HT转载体可能在肺动脉高压中起重要作用。     

黄芪多糖对野百合碱诱导大鼠肺动脉高压的减缓作用及其机制研究

目的研究黄芪多糖对野百合碱诱导大鼠肺动脉高压的减缓作用及可能机制。方法将100只SD雄性大鼠随机分为正常对照组、野百合碱组、黄芪多糖低剂量组和黄芪多糖高剂量组。除正常对照组外,其余组大鼠按60 mg/kg单次腹腔注射野百合碱。黄芪多糖低剂量组及高剂量组大鼠在给药后的第2~28天分别按200 mg/kg及400 mg/kg腹腔注射黄芪多糖,每日1次。每组25只大鼠各取15只进行研究,检测各组大鼠平均肺动脉压(mPAP)、右心肥厚指数(RVHI),观察其肺动脉及心肌细胞形态变化,检测其肺组织中白细胞介素17(IL-17)mRNA及蛋白的表达水平。结果与正常对照组比较,野百合碱组及黄芪多糖各剂量组大鼠mPAP、RVHI均显著升高(P<0.01),肺组织中IL-17的mRNA和蛋白表达水平均显著升高(P<0.01),肺动脉及心肌细胞有明显病理改变;与野百合碱组比较,黄芪多糖各剂量组大鼠mPAP、RVHI均显著降低(P<0.01),肺组织中IL-17的mRNA和蛋白表达水平均显著降低(P<0.01),肺动脉及心肌细胞病理变化有改善;与黄芪多糖低剂量组比较,黄芪多糖高剂量组大鼠上述指标水平及病理改变的改善更明显。结论黄芪多糖能降低野百合碱诱导大鼠的肺动脉高压,并改善肺动脉结构及心肌病理改变,推测其机制可能与下调大鼠肺组织中IL-17的表达有关。     

不同剂量银杏叶提取物对野百合碱所致肺动脉高压的作用效果研究

目的 研究针对野百合碱所致的肺动脉高压在不同剂量银杏叶提取物(GBE)作用下的效果,测定肺组织血管活性物质内皮素-1(ET-1)、一氧化氮合成酶(eNOS)的表达.方法 依随机数字表将50只雄性SD大鼠分为五组:正常对照组(C组)、肺动脉高压模型组(M组)、GBE低剂量治疗组(G1组,40 mg/kg)、GBE中剂量治...     

辛伐他汀对野百合碱诱导的肺动脉高压大鼠IL-6和IL-8表达的影响

目的观察辛伐他汀对野百合碱（MCT）诱导的肺动脉高压大鼠炎症细胞因子IL-6和IL-8表达的影响,探讨辛伐他汀作用于肺动脉高压的机制。方法将30只健康雄性SD大鼠随机平均分为正常对照组、MCT诱导的肺动脉高压组（模型对照组）、辛伐他汀干预治疗组（治疗组）。模型对照组和治疗组注射野百合碱造模。治疗21 d后,采用右心导管法检测大鼠平均肺动脉压（mPAP）;称量RV和LV＋S,计算右心肥大指数（RVHI）。采用RT-PCR检测大鼠肺组织中IL-6和IL-8 mRNA的表达,采用ELISA法检测大鼠血清中IL-6和IL-8水平。结果模型对照组mPAP和RVHI值显著高于治疗组和正常对照组,治疗组和正常对照组mPAP和RVHI值比较无显著性差异。模型对照组大鼠肺组织中IL-6和IL-8 mRNA的表达和血清中IL-6和IL-8水平显著高于正常对照组和治疗组,而治疗组大鼠肺组织中IL-6和IL-8 mRNA的表达和血清中IL-6水平与正常对照组比较无显著性差异,但治疗组大鼠血清IL-8水平高于正常对照组（P〈0.05）。结论辛伐他汀可通过抑制MCT诱导大鼠肺动脉高压模型大鼠肺组织中炎性细胞因子的表达、下调大鼠炎性细胞因子的分泌,达到对肺动脉高压的治疗作用。     

Effects of inorganic nitrate in a rat model of monocrotaline‐induced pulmonary arterial hypertension

The nitrate‐nitrite‐nitric oxide (NO) pathway represents an alternative source of NO generation, which is independent of NO synthase and potentiated by hypoxia. Augmentation of this pathway by dietary nitrate has proven favourable effects in several cardiovascular disease models. However, less is known regarding its potential value in pulmonary arterial hypertension (PAH). The aim of this study was to assess the effects of oral inorganic nitrate administration in monocrotaline (MCT)‐induced PAH. Male 12‐week‐old Wistar rats were injected subcutaneously with monocrotaline (MCT, 60 mg/kg). Nitrate treatment (0.3 or 1 mmol/kg/d; drinking water) commenced on day 12 following the MCT injection and continued for 16 days. Nitrate administration did not attenuate right ventricular (RV) hypertrophy, increased lung weight and up‐regulated mRNA expression of brain natriuretic peptide. Plasma nitrate and nitrite levels were significantly increased as well as lung nitrate level, whereas nitrite lung level was decreased following nitrate treatment (1 mmol/kg/d). MCT‐induced PAH resulted in an increased MnSOD protein level, which was not observed following nitrate treatment. MCT‐associated up‐regulation of nNOS in the lung appeared to be dose‐dependently prevented by nitrate treatment. Western blot analysis did not reveal any differences in eNOS, iNOS, XO or gp91phox expression in the lungs among the groups. In conclusion, nitrate treatment did not significantly attenuate pathological RV and lung remodelling in the rat MCT model of PAH. The suppression of MnSOD and nNOS expression by nitrate could be interpreted as reduced demand of endogenous antioxidant defence in this model.     

Tetrandrine prevents monocrotaline-induced pulmonary hypertension in rats

In this study, the effects of chronic administration of tetrandrine (TET) on monocrotaline (MCT) induced pulmonary hypertension were investigated. The results showed that MCT induced marked pulmonary hypertension and right ventricular hypertrophy; TET 50 mg kg⁻¹ and 100 mg kg⁻¹ significantly decreased pulmonary artery pressure (Ppa, from 5.2 ± 0.48 kPa to 4.35 ± 0.69 kPa, P < 0.05 and to 3.79 ± 0.84 kPa, P < 0.05, respectively) without marked influence on systemic arterial pressure (Psa). TET restored right ventricular hypertrophy (right ventricular index significantly decreased from 0.41 to 0.37 and 0.32, respectively). Histological findings showed that TET restored MCT-induced lung tissues and vascular lesion and pulmonary arteries media hypertrophy. We conclude that chronic administration of TET does have selective effects on pulmonary hypertension produced by MCT. Drug Dev. Res. 39:158–160. © 1997 Wiley-Liss, Inc.     

The promising effect of barberry (Zereshk) extract against experimental pulmonary microvascular remodeling and hypertension: A comparison with sildenafil

Context: Despite the beneficial effects of barberry (Berberis integerrima Berberidaceae) on decreasing systemic hypertension, its influence has not been investigated on pulmonary hypertension.

Objective: The objective of this study is to examine the effect of barberry fruit, on monocrotaline-induced pulmonary hypertension.

Materials and methods: Nine groups were arranged as follows: the control group, the monocrotaline (M) group, the barberry groups with doses of 50, 100, and 200 (mg/kg), the M plus barberry groups, and the M plus sildenafil group. Two weeks after a single injection of monocrotaline (60?mg/kg, s.c.), barberry water extracts or sildenafil (30?mg/kg/d) were gavaged daily for 2 weeks. At the end of the 4th week, hemodynamic, biochemical, and histopathological parameters were assessed.

Results: In comparison with the M group, barberry (200?mg/kg) or sildenafil significantly reduced the right ventricular systolic pressure (RVSP) (22.95?±?1.78?mm Hg and 30.71?±?1.64?mm Hg, versus 41.28?±?1.5?mm Hg), right ventricular hypertrophy (RVH) (0.39?±?0.03 and 0.42?±?0.02, versus 0.57?±?0.02), and the medial wall thickness (MWT) (4.56?±?0.15?µm and 5.97?±?0.19?µm, versus 7.02?±?0.43?µm). Barberry or sildenafil had no significant effect on the plasma level of endothelin-1, glutathione peroxidase, and the malondialdehide of lung.

Conclusion: 200?mg/kg of barberry has an improving effect on the monocrotaline-induced pulmonary hypertension. This effect was stronger than that of the sildenafil's and may have been mediated through mechanisms other than the modulation of the endothelin-1 or redox system.     

Riociguat for pulmonary hypertension

Pulmonary hypertension, an elevation of the mean pulmonary artery pressure ≥25 mmHg, ultimately leads to premature death due to right ventricular dysfunction. Ten treatments from three classes of drugs are licensed for the management of pulmonary arterial hypertension. These treatments have improved exercise capacity but median survival is still poor. Additionally there are no licensed therapies for the other groups of pulmonary hypertension. Riociguat is a novel drug that stimulates soluble guanylate cyclase independently of nitric oxide and in synergy with nitric oxide. This review summarises the available evidence for riociguat in the treatment across all groups of pulmonary hypertension with a focus on pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.     

Emerging therapies for pulmonary arterial hypertension

Pulmonary arterial hypertension is characterised by increased pulmonary vascular resistance due to increased vascular tone and structural remodelling of pulmonary vessels. The therapies that are in use so far have been developed to correct endothelial dysfunction and reduce vasomotor tone. These treatments have a limited effect on the remodelling process and, increasingly, the focus is turning to potent strategies for inhibiting vascular proliferation and promoting vascular apoptosis. Multiple novel targets have been uncovered over the last 5 years and several are now in early clinical trials. At present, it is clear that there is no single treatment for the condition. Although this is the case, studies are investigating the role of combining therapies that are already established.     

伊洛前列素治疗肺动脉高压的疗效

目的：观察吸入伊洛前列素治疗重症肺动脉高压的效果。方法：采用病例分析和文献复习方法。3例重症肺动脉高压女性患者,其中2例为特发性肺动脉高压,1例为系统性红斑狼疮合并肺动脉高压。3例患者均在常规治疗基础上吸入伊洛前列素10μg,每次吸入约10～15 min,每隔3 h一次,共6次。观察吸入前后体动脉压、心率、6 min步行距离和超声心动图各项指标的变化以及患者的不适反应。结果：3例患者6 min步行距离和肺动脉压力均有明显改善。结论：吸入伊洛前列素可以显著提高重症肺动脉高压患者活动耐力和降低肺动脉压力。     

尼群地平对大鼠野百合碱性肺动脉高压的防治作用

目的：利用野百合碱（ＭＣＴ）引起的大鼠肺动脉高压（ＰＨ）模型，探讨尼群地平（ＮＩＴ）对ＭＣＴ性ＰＨ的防治作用。方法：给ＭＣＴ或ＭＣＴ＋ＮＩＴ（１０ｍｇ·ｋｇ－１ｉｐ，每日一次）４ｗｋ，测定肺血流动力学参数和静脉血浆及肺组织匀浆中内皮素样免疫反应物（ｉｒ－ＥＴ）、一氧化氮（ＮＯ）、超氧化物歧化酶（ＳＯＤ）和丙二醛（ＭＤＡ）的含量。结果：ＮＩＴ能有效地降低ＭＣＴ模型大鼠的肺动脉压（从４．５±０．９降至３．６±０．５ｋＰａ）和肺血管阻力（从１１８±１７降至７９±１８ｋＰａ·ｍｉｎ·Ｌ－１），能抑制ＭＣＴ引起的肺小动脉中膜增厚；ＮＩＴ能显著抑制ＭＣＴ模型大鼠的肺组织匀浆中ＮＯ含量的减少和血浆中ＳＯＤ活性的降低（Ｐ＜０．０５），明显阻止肺匀浆中ＭＤＡ的升高（Ｐ＜０．０１）。结论：长期使用ＮＩＴ可有效防治ＭＣＴ性ＰＨ，其作用可能与其Ｃａ２＋拮抗作用及保护ＳＯＤ活性和增加ＮＯ含量有关。