肺心合剂对野百合碱诱发大鼠肺动脉高压肺血管重建的影响

背景：肺的功能和结构改变致肺动脉高压是导致肺心病的先决条件，中药肺心合剂能够有效降低肺动脉高压，但其机制尚未完全阐明。目的：比较不同剂量中药肺心合剂与硝苯地平对肺动脉高压大鼠肺血管重建的逆转效应。设计：以实验动物为研究对象的随机对照实验研究。单位：一所医科大学附属医院护理系、一所医学院附属医院、一所省级医院中医科。方法：利用野百合碱(50mg／kg)复制大鼠肺心病模型。雄性Wister大鼠60只，随机分为6组：正常对照组、模型组、肺心合剂低、中、高剂量组及硝苯地平组，每组lO只。分别于制模后14d灌胃相应药物，连续用药8d。处死动物后，利用特殊染色结合病理图象分析方法，测定肺小动脉病理及其形态计量学改变。主要观察指标：①光镜观察及肺小动脉图象分析。②各组肺小动脉管壁中膜厚度．管壁中膜厚度与血管外径比值、管壁面积与血管总面积比值、管腔面积与血管总面积比值。结果：肺心合剂及硝苯地平均能明显减轻模型大鼠的肺血管重构(P&;lt;0．01)。以肺心合剂高剂量组效果最好。但治疗组各指标仍未完全恢复到正常对照组水平。结论：肺心合剂能部分逆转肺血管结构重建，有效降低肺动脉高压。     

硝苯地平对野百合碱所致大鼠肺动脉高压的影响

目的探讨硝苯地平 (Nif)对野百合碱 (MCT)诱发慢性炎性肺动脉高压的防治作用。方法 3 3只雄性Wistar大鼠随机分为正常对照组、肺动脉高压模型组、Nif治疗组 ,每组 11只。予MCT (5 0mg/kg)制做大鼠肺动脉高压模型后 ,分别给Nif组及模型组大鼠连续灌胃Nif(2 0mg/kg·d)和等量生理盐水 2 1d。采用改良右心导管术测定肺血流动力学参数 ;处死大鼠后 ,称量肺湿重 (wW )、右心室自由壁 (RV)和左心室加室间隔 (LV S)重 ,计算右心肥厚指数 (RV/LV S)。结果Nif能明显降低肺动脉高压模型大鼠的平均肺动脉压及RV/LV S(P <0 0 1) ,但对wW无明显影响 (P >0 0 5 )。结论长期使用Nif能有效防治MCT所致肺动脉高压 ,改善心功能。     

肺心合剂对肺动脉高压大鼠肺血管重建的影响

目的:探讨肺心合剂对野百合碱诱发肺动脉高压大鼠肺血管重建的影响.方法:利用野百合碱(50 mg/kg)复制大鼠肺心病模型.60只雄性Wistar大鼠随机分为正常对照组,模型组,肺心合剂低、中、高剂量组及硝苯地平组6组,每组10只.分别于制模后14 d灌胃相应药物,连续用药8 d.处死动物后,利用特殊染色结合病理图像分析方法测定肺小动脉病理(光镜下观察和弹力纤维染色切片)及其形态计量学(指标为与终末细支气管伴行的肺小动脉管壁中膜厚度、外径、管壁面积、室管腔面积以及与血管外径的比值).结果:肺心合剂及硝苯地平均能明显减轻模型大鼠的肺血管重构(P均<0.01),以肺心合剂高剂量组效果最好;但治疗组各指标仍未完全恢复到正常对照组水平.结论:肺心合剂能部分逆转肺血管结构重建,有效降低肺动脉高压.     

野百合碱诱导大鼠肺动脉高压模型的建立

背景：目前尚缺乏简单易行、实用、操作性强的肺动脉高压动物模型。目的：建立一种实用的注射野百合碱诱导的肺动脉高压动物模型。方法：采用一次性皮下注射野百合碱60mg/kg的方法制备SD大鼠肺动脉高压模型。结果与结论：野百合碱注射后第1,2,3,4周,大鼠平均肺动脉压明显升高,右心室肥厚明显。光镜下可见肺小血管肌化程度增强,相对中膜厚度增加,肺血管密度减少,以上症状均随野百合碱注射时间的延长逐渐加重。证实此方法建立的大鼠肺动脉高压模型造模成功。     

肺心合剂对肺动脉高压模型大鼠的影响

目的：探讨肺心合剂对野百合碱(MCT)诱发肺动脉高压模型大鼠的治疗作用。方法：利用MCT制备大鼠肺动脉高压模型。雄性Wistar大鼠60只，随机分为正常对照组、模型组、硝苯吡淀组以及肺心合刑高、中、低剂量组，每组10只。分别于制模后14d灌胃相应药物，连续用药8d。采用有心导管术测定肺血流动力学参数，计算平均肺动脉压(mPAP)；处死动物后取肺脏称取肺湿质量，计算肺渗出指数和有心肥厚指数。结果：肺心合剂和硝苯吡淀都能明显降低肺动脉高压大鼠的mPAP、肺渗出指数和有心肥厚指数(P＜0．05或P＜0．01)，以肺心合剂大剂量组效果最好。结论：肺心合剂能有效降低肺动脉高压，改善心功能。     

野百合碱诱导大鼠肺动脉高压模型的建立

背景:目前尚缺乏简单易行、实用、操作性强的肺动脉高压动物模型.目的:建立一种实用的注射野百合碱诱导的肺动脉高压动物模型.方法:采用一次性皮下注射野百合碱60 mg/kg的方法制备SD大鼠肺动脉高压模型.结果与结论:野百合碱注射后第1,2,3,4周,大鼠平均肺动脉压明显升高,右心室肥厚明显.光镜下可见肺小血管肌化程度增强,相对中膜厚度增加,肺血管密度减少,以上症状均随野百合碱注射时间的延长逐渐加重.证实此方法建立的大鼠肺动脉高压模型造模成功.     

缬沙坦对野百合碱诱导肺动脉高压模型大鼠肺动脉重构的影响

目的:观察缬沙坦(valsartan)对野百合碱(monocrotaline)所致肺动脉高压大鼠肺血管重构的影响.方法:将健康雄性Wistar 大鼠随机分为3 组:M 组(肺动脉高压模型组)一次性项背部注射野百合碱(60 mg / kg)后自由摄食、饮水;V 组(缬沙坦干预组),同M 组注射野百合碱并同等条件饲养,4 周后开始用缬沙坦20 mg / (kg·d)灌胃,持续4 周达实验终点;C 组(正常对照组)一次性项背部注射等量生理盐水后与实验组同等条件饲养.然后经微导管介入测定大鼠肺动脉平均压(mPAP);计算右室肥大指数[RV/ (LV + S)];分别采用HE 染色、弹力纤维染色及VG 染色观察肺动脉结构的改变,计算肺动脉管壁厚度和管腔面积,评价缬沙坦对肺动脉重构的影响.结果:缬沙坦可有效降低野百合碱所致肺动脉高压大鼠模型肺动脉管壁的厚度,增大管腔面积(P ＜ 0.01).结论:缬沙坦可有效抑制肺动脉高压大鼠肺动脉重构,作用机制可能与其抑制AngⅡ介导的增殖效应有关.     

野百合碱处理大鼠肺动脉高压模型的塑造

肺动脉高压尤其是特发性肺动脉高压（Idiopathic Pulrnonary Artery Hypertension, IPAH）是一种预后极差的疾病，其发病机制不明，治疗棘手。野百合碱（Monocrotatine，MCY）属于豆科植物野百合属，它所引起的肺动脉高压（Pulmonry Artery Hypertersion，PAH）大鼠是一种较为理想的肺动脉高压动物模型，在MCI-PAH动物模型大鼠血清中已发现内皮素-1（ET-1）、心钠素（ANP）及血栓素2（rXB2）明显升高，     

Altered pulmonary vascular smooth muscle responsiveness in monocrotaline-induced pulmonary hypertension

Studies were conducted to determine whether experimental pulmonary hypertension is associated with alterations in pulmonary vascular smooth muscle responsiveness. Adult male rats were given a single s.c. injection of monocrotaline (105 mg/kg) or saline and were sacrificed 4, 7 or 14 days later. Segments of the main trunk and right extrapulmonary artery and an intrapulmonary artery were isolated for determination of vascular reactivity to contractile and relaxant agonists. Monocrotaline treatment caused changes in mechanical properties of pulmonary arteries in that vessels isolated from rats 14 days after monocrotaline administration required greater passive loads to achieve maximal active force development. Cumulative concentration-response curves were generated to potassium chloride, angiotensin II, norepinephrine, isoproterenol and acetylcholine. Vascular contractility was enhanced in main pulmonary artery 4 days after monocrotaline injection but no differences in responsiveness between control and monocrotaline exposed vessels were observed 7 days post-treatment. In contrast, significant decreases in contractility with a specific loss in the response to angiotensin II were observed in pulmonary arteries isolated from rats 14 days after monocrotaline administration. These vessels also were less responsive to the relaxant effects of isoproterenol and acetylcholine when compared to control vessels. These results demonstrate that changes in pulmonary vascular smooth muscle responsiveness occur during evolution of pulmonary hypertension induced by monocrotaline. Enhanced contractility may contribute to inappropriate vasoconstriction early in the development of hypertensive pulmonary vascular disease but does not appear to be involved in sustained elevations in pulmonary artery pressure. Diminished relaxation observed after pulmonary hypertension was well established may contribute to the loss in efficacy of vasodilators in the long-term management of pulmonary hypertension.     

Arctigenin prevents monocrotaline-induced pulmonary arterial hypertension in rats

The hallmark features of the development of pulmonary arterial hypertension (PAH) include the proliferation of pulmonary vascular smooth muscle cells, oxidative stress, inflammation, and pulmonary artery remodeling. Arctigenin is a bioactive component of Arctium lappa that exerts anti-inflammatory and antiproliferative effects in several diseases; however, its effects on pulmonary arteries are still unclear. This study aimed to investigate the efficacy of arctigenin to prevent PAH. Rats injected with monocrotaline (MCT) progressively developed PAH. Arctigenin treatment (50 mg per kg per day, intra-peritoneally) ameliorated right ventricular systolic pressure and pulmonary arterial remodeling, decreased the expression of inflammatory cytokines, and limited the proliferation of pulmonary vascular smooth muscle cells in lungs. Mechanistically, arctigenin effectively inhibited the MCT-induced elevation of NLRP3, caspase-1, and interleukin 1-beta expression in the lungs. These results indicate that arctigenin ameliorates MCT-induced PAH, at least in part, through exerting its anti-inflammatory, antioxidant, and antiproliferative effects, which inhibit the NLRP3 inflammasome signal pathway in rats.

Arctigenin ameliorates monocrotaline-induced pulmonary arterial hypertension, at least in part, through exerting its anti-inflammatory, antioxidant, and antiproliferative effects, which inhibit the NLRP3 inflammasome signal pathway in rats.     

Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer limits monocrotaline-induced pulmonary vascular remodeling in rats

Extracellular matrix dysregulation is key to the development of pulmonary hypertension (PH), suggesting a pivotal role for the proteases that control matrix remodeling. Both hypoxia- and monocrotaline-induced PH are associated with increased protease activity in the distal and proximal pulmonary arteries. However, the role of proteases is not completely understood. In hypoxic PH, matrix metalloproteinase (MMP) inhibition increased pulmonary vascular remodeling, whereas in monocrotaline PH, serine elastase inhibition reversed pulmonary vascular remodeling. These conflicting effects of protease inhibition may be ascribable to differences across experimental models in either the mechanisms underlying PH or the methods used to inhibit protease activity. In the present study, we investigated the effects of specific MMP inhibition on monocrotaline PH development. To inhibit lung MMP in rats exposed to monocrotaline (60 mg/kg as a single subcutaneous injection), we used intratracheal instillation of the adenovirus-mediated human TIMP-1 gene (Ad.hTIMP-1, 10(8) plaque-forming units) as in our previous study on hypoxic PH. MMP inhibition in lungs was evaluated by in situ zymography. Rats treated with Ad.hTIMP-1 had less severe pulmonary vascular remodeling evidenced by a decreased right ventricular hypertrophy, with decreased muscularization of peripheral pulmonary arteries and increased lung-cell apoptosis compared to controls. No periadventitial collagen accumulation was observed in distal pulmonary arteries, whereas elastin content was significantly increased in Ad.hTIMP-1-treated rats. These data support a deleterious role for proteases in toxic and inflammatory PH and indicate that MMPs may have opposite effects in different PH models.     

Magnesium aspartate hydrochloride attenuates monocrotaline-induced pulmonary artery hypertension in rats

1. The effect of oral magnesium aspartate hydrochloride on monocrotaline (MCT)-induced pulmonary arterial hypertension was evaluated in rats. 2. A single subcutaneous injection of MCT, a pyrrolizidine alkaloid of plant origin, induces significant morphological changes in pulmonary vessels, pulmonary arterial hypertension and right ventricular hypertrophy in rats by 3 weeks. 3. Two groups of rats (Mg2+ control and Mg2+ + MCT) were started on oral Mg2+ (15.4 g/l magnesium aspartate hydrochloride dissolved in deionized water) 2 weeks before the MCT injection. The rest were given deionized water. At the start of the experiment, the control groups (deionized water and Mg2+) were given normal saline subcutaneously; the other groups (deionized water and Mg2+) were given MCT (60 mg/kg) subcutaneously. 4. Pulmonary artery pressure, right ventricular hypertrophy, lung pathology, organ weights and serum electrolytes were assessed 3 weeks after a single subcutaneous injection of MCT. Seventy-five per cent of the rats treated with MCT and oral Mg2+ (12 out of 16) showed significant reduction in pulmonary arterial hypertension, arterial pathology and right ventricular hypertrophy. 5. Our data indicate that Mg2+ attenuates experimentally induced pulmonary hypertension, possibly either by modulating the intracellular Ca2+ level and/or by directly affecting the pulmonary endothelial cell-smooth muscle cell complex involved in metabolism and maintenance of pulmonary vascular resistance.     

Pimobendan improves right ventricular myocardial contraction and attenuates pulmonary arterial hypertension in rats with monocrotaline-induced pulmonary arterial hypertension

Purpose

The present study aimed to evaluate the therapeutic effect of pimobendan treatment for pulmonary hypertension (PH) in rats administered monocrotaline (MCT).

Methods

Fifty-four 12-week-old male Sprague–Dawley rats were injected with monocrotaline or saline solution. Serial echocardiography and right ventricular systolic pressure (RVSP) measurement via a cardiac catheter were performed. After injection of MCT, rats received oral pimobendan (MCT/pimobendan group) or no treatment (MCT group) until undergoing echocardiography and cardiac catheter insertion.

Results

Right ventricular systolic pressure in the MCT/pimobendan group was lower than that in the MCT group at 6 weeks. Right ventricle free wall (RVFW) myocardial systolic velocity (Sm) in the MCT group showed a reduction compared with the saline group at 2 weeks. RVFW Sm in the MCT/pimobendan group was preserved as compared with the saline group at 2 weeks. RVFW Tei index in the MCT/pimobendan group showed a reduction compared with the saline group and the MCT group at 2 weeks. Echocardiography in the MCT/pimobendan group showed improvement compared with MCT rats.

Conclusions

Both a reduction in RVSP and improvement in myocardial contraction were demonstrated with administration of pimobendan in rats with PH induced by MCT. Echocardiography evaluation of systolic function seems to be useful for monitoring excess administration of pimobendan.     

硫化氢可通过改善肺动脉内皮间质转化减轻野百合碱诱导的大鼠肺动脉高压

目的：探讨硫化氢（H2S）对野百合碱（MCT）诱导的大鼠肺动脉高压（PAH）的影响，以及内皮间质转化（EndMT）在其中发挥的作用。方法：选择40只雄性SD大鼠，将其随机分为对照组、模型组、硫氢化钠（NaHS）组和炔丙基甘氨（PAG，H2S合成抑制剂）组。模型组、NaHS组和PAG组大鼠予以一次性腹腔注射MCT（60mg/kg）制备PAH模型，7d后，分别给予腹腔注射0.9%氯化钠溶液、NaHS（1mg·kg-1·d-1）、PAG（10mg·kg-1·d-1）干预14d。MCT注射21d后，通过右心导管检测各组大鼠肺动脉压力，随后处死大鼠，评估肺动脉重构和肺动脉EndMT情况。另将人肺动脉内皮细胞（HPAECs）予以0.9%氯化钠溶液或NaHS（50、100、200μmol/L）预处理2h，然后予以转化生长因子-β1（TGF-β1，10ng/mL）刺激1h、3d、10d，分别观察Snail的表达、EndMT情况及细胞形态学变化。结果：与对照组相比较，模型组大鼠的肺动脉收缩压（PASP）、平均肺动脉压（mPAP）、右心室肥厚指数（RVHI）、肺小动脉管壁厚度、肺组织α平滑肌肌动蛋白（α-SMA）、肺组织Snail水平均升高（P<0.05），血管内皮钙黏蛋白（VE-cadherin）表达水平降低（P<0.05）。予以NaHS干预后，这一趋势被逆转；而予以PAG干预后，相关指标则进一步恶化（P<0.05）。体外实验结果显示，TGF-β1刺激后，HPAECs梭形细胞增加，α-SMA、Snail表达升高（P<0.05），VE-cadherin表达减少（P<0.05）；NaHS预处理可剂量依赖性地抑制TGF-β1诱导的HPAECs形态学变化及α-SMA、VE-cadherin和Snail表达水平变化。结论：H2S可减轻MCT诱导的PAH，其机制可能与其抑制肺动脉EndMT有关。     

Pulmonary vascular remodeling: a target for therapeutic intervention in pulmonary hypertension.

Pulmonary vascular remodelling is an important pathological feature of pulmonary hypertension, leading to increased pulmonary vascular resistance and reduced compliance. It involves thickening of all three layers of the blood vessel wall (due to hypertrophy and/or hyperplasia of the predominant cell type within each layer), as well as extracellular matrix deposition. Neomuscularisation of non-muscular arteries and formation of plexiform and neointimal lesions also occur. Stimuli responsible for remodelling involve transmural pressure, stretch, shear stress, hypoxia, various mediators [angiotensin II, endothelin (ET)-1, 5-hydroxytryptamine, growth factors, and inflammatory cytokines], increased serine elastase activity, and tenascin-C. In addition, there are reductions in the endothelium-derived antimitogenic substances, nitric oxide, and prostacyclin. Intracellular signalling mechanisms involved in pulmonary vascular remodelling include elevations in intracellular Ca2+ and activation of the phosphatidylinositol pathway, protein kinase C, and mitogen-activated protein kinase. In animal models of pulmonary hypertension, various drugs have been shown to attenuate pulmonary vascular remodelling. These include angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, ET receptor antagonists, ET-converting enzyme inhibitors, nitric oxide, phosphodiesterase 5 inhibitors, prostacyclin, Ca2+ -channel antagonists, heparin, and serine elastase inhibitors. Inhibition of remodelling is generally accompanied by reductions in pulmonary artery pressure. The efficacy of some of the drugs varies, depending on the animal model of the disease. In view of the complexity of the remodelling process and the diverse aetiology of pulmonary hypertension in humans, it is to be anticipated that successful anti-remodelling therapy in the clinic will require a range of different drug options.