Effect of SR-140333,a neurokinin-1 receptor antagonist,on airway reactivity to methacholine in sedated rats

目的：探讨神经激肽对乙酰甲胆碱（ＭＣ）气道反应性的作用．方法：观察非肽类ＮＫ１受体拮抗剂ＳＲ１４０３３３对镇静大鼠的ＭＣ气道反应性和离体气管条的收缩反应．结果：ＳＲ１４０３３３抑制ＭＣ气雾（１０－１０００μｍｏｌ／ｍ３）引起的呼吸频率增快，抑制ＭＣ气雾（１ｍｍｏｌ／ｍ３）反应的ＩＤ５０为４９（１４－１７２μｇ·ｋｇ－１）；ＳＲ１４０３３３１μｍｏｌ·Ｌ－１对乙酰甲胆碱引起的气管平滑肌收缩无抑制作用．阿托品可阻断ＭＣ的在体和离体反应．结论：内源性速激肽参与在体ＭＣ气道反应，至少部分由ＮＫ１受体介导．     

神经激肽—1受体拮抗剂SR—140333对镇静大鼠乙酰甲胆碱气道反应…

目的：探讨神经激肽对乙酰甲胆碱（ＭＣ）气道反应性的作用。方法：观察非肽类ＮＫ－１受体拮抗剂ＳＲ－１４０３３３对镇静大鼠的ＭＣ气道反应性和离体气管条的收缩反应结果：ＳＲ－１４０３３３抑制ＭＣ气雾（１０－１０００μｍｏｌ／ｍ＾３）引起的呼吸频率增快，抑制ＭＣ气雾（１ｍｍｏｌ／ｍ＾３）反应的ＩＤ５０为４．９（１．４－１７．２μｇ．ｋｇ＾－１）；ＳＲ－１４０３３３１μｍｏｌ．Ｌ＾－１对乙酰甲胆碱引起的气管     

速激肽受体拮抗剂对豚鼠组胺反应的影响

目的：探讨速激肽与组胺（Ｈｉｓ）反应的关系。方法：观察速激肽受体拮抗剂对豚鼠Ｈｉｓ的整体和离体的呼吸道和心血管效应。结果：单用或合用速激肽ＮＫ－１受体拮抗剂ＣＰ－９６３４５（１ｍｇ·ｋｇ－１，ｉｐ）及ＮＫ－２受体拮抗剂ＳＲ－４８９６８（１ｍｇ·ｋｇ－１，ｉｐ）均可显著降低清醒豚鼠吸入Ｈｉｓ气雾的气道反应性。ＣＰ－９６３４５（１ｍｇ·ｋｇ－１，ｉｖ）可显著降低静脉注射Ｈｉｓ引起麻醉豚鼠支气管和心房的伊文思蓝渗出，ＳＲ－４８９６８（１ｍｇ·ｋｇ－１，ｉｖ）则对肺内压升高有较弱的抑制作用，两药对平均动脉压降低无明显作用。在豚鼠的离体气管和支气管平滑肌标本，ＣＰ－９６３４５（１μｍｏｌ·Ｌ－１）及ＳＲ－４８９６８（１μｍｏｌ·Ｌ－１）对Ｈｉｓ的Ｅｍａｘ及ｐＤ２无明显作用。结论：速激肽部分参与了豚鼠的Ｈｉｓ炎症反应，速激肽受体拮抗剂有抗炎作用。     

速激肽NK-1受体拮抗剂SR-140333对抗原引起致敏大鼠气道高反应性的影响

为观察速激肽NK-1受体拮抗剂SR-140333对抗原攻击引起的致敏大鼠气道高反应性的影响,测定了致敏大鼠在抗原攻击前后的基础呼吸频率,对MCh的反应性及支气管-肺泡灌洗液中的白细胞数量。实验结果显示,致敏大鼠吸入OA后6h基础呼吸频率增加,并显著增加乙酰甲胆碱(MCh)的反应性、MCh的-logPC₃₀值和支气管-肺泡灌洗液中的白细胞数量。ip速激肽NK-1受体拮抗剂SR-140333(0.1mg·kg^-1)或地塞米松(0.5mg·kg^-1),可明显抑制上述反应,小剂量SR-140333(0.01mg·kg^-1)仅有部分抑制作用。结果提示抗原攻击可引起致敏大鼠气道高反应性和气道炎症,速激肽NK-1受体拮抗剂可抑制这些反应。     

Effects of dl-3-n-butylphthalide on region al cerebral blood flow in right middle cerebral artery occlusion rats

目的：观察ｄｌ３ｎ丁基苯酞（ＮＢＰ）对右大脑右中动脉阻断（ＲＭＣＡＯ）大鼠缺血区局部脑血流（ｒＣＢＦ）的影响．方法：氢清除法动态监测ＲＭＣＡＯ大鼠ｒＣＢＦ变化．结果：ＲＭＣＡＯ后１０ｍｉｎｉｐＮＢＰ（５，１０，２０ｍｇ·ｋｇ－１）可明显增加ｒＣＢＦ（与溶剂对照组相比Ｐ＜００１），４０ｍｉｎ给药有类似作用但作用较弱（与给药前相比Ｐ＜００５），６０ｍｉｎ给药不能增加ｒＣＢＦ（与给药前相比Ｐ＞００５）．此外，ＲＭＣＡＯ前４０ｍｉｎｉｐＮＢＰ也可使ＲＭＣＡＯ后不同时间点ｒＣＢＦ明显增加．尼莫地平（０５ｍｇ·ｋｇ－１，ｉｐ）与ＮＢＰ（１０ｍｇ·ｋｇ－１，ｉｐ）具有相似的作用．结论：ＮＢＰ预防给药或治疗给药能使ＲＭＣＡＯ后减少的ｒＣＢＦ明显增加．     

Effects of clonidine on myocardial β-adrenergic receptor-adenyl cyclase-cAMP system after scalds in rats

研究可乐定（Ｃｌｏ）对大鼠烫伤后心脏β肾上腺素受体（βＡＲ）腺苷酸环化酶（ＡＣ）环腺苷一磷酸（ｃＡＭＰ）系统的作用．方法：大鼠于９５℃水浴中烫９ｓ，造成背部３０％皮肤全层烫伤．用放射受体分析、间接方法、酶放射化学分析、放射免疫分析分别测定βＡＲ密度和亲和力，ＡＣ和磷酸二酯酶（ＰＤＨ）活性及ｃＡＭＰ生成量．结果：Ｃｌｏ（０３、１０和３０ｍｇ·ｋｇ－１）增加烫伤后１２ｈ心肌βＡＲ密度、ＡＣ活性及ｃＡＭＰ生成量（Ｐ＜００５或００１）；但Ｃｌｏ对烫伤大鼠心肌βＡＲ亲和力、ＰＤＨ活性及正常大鼠上述各项指标均无影响（Ｐ＞００５）．育亨宾００５ｍｇ·ｋｇ－１，部分逆转Ｃｌｏ对βＡＲ密度、ＡＣ活性和ｃＡＭＰ生成的作用；哌唑嗪００３ｍｇ·ｋｇ－１，对Ｃｌｏ的作用无明显影响．结论：Ｃｌｏ抑制烫伤后大鼠心肌βＡＲＡＣｃＡＭＰ系统的变化．     

Pharmacokinetics of flutamide and its metabolite 2-hydroxyflutamidein normal and hepatic injury rats

目的：建立一新的高压液相色谱法用来研究氟他胺（Ｆｌｕ）及其活性代谢产物２羟基氟他胺（ＨＦ）的药物动力学．方法：正常及肝损伤大鼠灌胃Ｆｌｕ５０ｍｇ·ｋｇ－１．采用反相高压液相色谱法，以甲基睾丸素为内标，流动相为甲醇∶乙腈∶水∶乙醚＝４０∶２０∶３５∶１（体积比），检测波长为２３４ｎｍ．结果：Ｆｌｕ的Ｋ与Ｃｌ分别由０６２±０１６ｈ－１及６０±１０Ｌ·ｋｇ－１·ｈ－１减小到０１６±００３ｈ－１及０６３±０２９Ｌ·ｋｇ－１·ｈ－１（Ｐ＜００１），ＡＵＣ与Ｃｍａｘ分别由８６±１３ｍｇ·Ｌ－１·ｈ及２４±０７ｍｇ·Ｌ－１增加到１００±４４ｍｇ·ｋｇ－１·ｈ及６７±２８ｍｇ·Ｌ－１（Ｐ＜００１）．ＨＦ的Ｋ（ｍ）由００７±００１ｈ－１减小到００５±００１ｈ－１（Ｐ＜００１）．结论：在肝损伤大鼠，Ｆｌｕ与ＨＦ消除受到显著抑制．     

Characterization of subtype of α_1-adrenoceptor mediating vasoconstriction in perfused rat mesenteric vascular bed

目的：研究去甲肾上腺素（ＮＥ）介导大鼠肠系膜血管床（ＭＶＢ）收缩的α１肾上腺素受体（α１ＡＲ）亚型．方法：用灌流大鼠ＭＶＢ标本收缩功能实验和克隆细胞放射配体结合实验测定α１ＡＲ亚型选择性拮抗剂ｐＡ２和ｐＫｉ,并作相关分析．结果：α１ＡＡＲ选择性拮抗剂ＲＳ１７０５３、ＷＢ４１０１、５ＭＵ及α１ＤＡＲ选择性拮抗剂ＢＭＹ７３７８的ｐＡ２分别为８９８±０２８,９１６±０２０,８．６９±００２和６０３±０２６,Ｓｃｈｉｌｄ作图斜率值与１０差别无显著性．其ｐＡ２值与α１ＡＡＲ的ｐＫｉ相关系数为０９７,与α１Ｂ和α１ＤＡＲ的相关系数分别为０５２和００４．结论：介导外源性ＮＥ收缩大鼠ＭＶＢ的功能性受体为α１ＡＡＲ     

多剂量口服5-单硝酸异山梨酯缓释片及普通片的药代动力学和生物利用度研究

对１０名健康男性受试者连续６ｄ多剂量交叉ｐｏＩＳ５ＭＮ缓释片和普通片的药代动力学性质和相对生物利用度进行了研究。结果表明：ＩＳ５ＭＮ缓释片和普通片的Ｔｍａｘ分别为５０ｈ和１４ｈ（Ｐ＜００５），前者的缓释效果十分明显；ＡＵＣ经对数转换后的多种统计分析表明，ＩＳ５ＭＮ缓释片（４０ｍｇ）与ＩＳ５ＭＮ普通片（２０ｍｇ×２）生物等效；ＩＳ５ＭＮ缓释片的相对生物利用度为１０８９５％；ＩＳ５ＭＮ缓释片和普通片的Ｃｍｉｎ分别为７４２０ｎｇ·ｍｌ－１和１３４４２ｎｇ·ｍｌ－１（Ｐ＜００５），而两种制剂的其他药代动力学参数如Ｃｍａｘ，ＡＵＣ２４０，ＡＵＣ∞０，Ｋｅ，Ｔ１／２以及波动系数（ＦＩ）等均无显著性差异（Ｐ＜００５）。多次给药后两种制剂都无明显的蓄积。     

速激肽受体拮抗剂对豚鼠离体气道平滑肌的作用

速激肽ＮＫ－２受体拮抗剂ＳＲ－４８９６８能抑制抗原诱导的气管和支气管平滑肌收缩；ＮＫ－１受体拮抗剂ＣＰ－９６３４５仅抑制支气管的收缩。两药均抑制辣椒素和Ｐ物质引起的支气管平滑肌收缩；对组胺和氨甲酰胆碱引起气管，支气管收缩作用无明显影响。结果证明速激肽参与抗原诱地的气道平滑肌收缩，速激肽受体拮抗剂具有抗过敏性哮喘的作用。     

Rho kinase inhibitors: a novel therapeutical intervention in asthma?

In asthma, inflammatory mediators that are released in the airways by recruited inflammatory cells and by resident structural cells result in airway hyperresponsiveness caused by increased bronchoconstriction. In addition, chronic inflammation appears to drive remodelling of the airways that contributes to the development of fixed airway obstruction and airway hyperresponsiveness in chronic asthma. Airway remodelling includes several key features such as excessive deposition of extracellular matrix proteins in the airway wall (fibrosis) and increased abundance of contractile airway smooth muscle encircling the airways. Current asthma therapy fails to inhibit these features satisfactorily. This review focuses on Rho kinase as a potential drug target in asthma, as compelling evidence from animal models and ex vivo studies suggests a central role for this enzyme and its associated signalling in acute and chronic airway hyperresponsiveness.     

Bronchodilator and anti-inflammatory activities of SCA40: Studies in human isolated bronchus, human eosinophils, and in the guinea-pig in vivo

There is currently interest in the use of inhibitors of cyclic nucleotide phosphodiesterases (PDE) as potential anti-asthma agents. In this study we examined the effects of SCA40 (6-bromo-8-methylaminoimidazol[1,2-a] pyrazine-2-carbonitrile), a preferential inhibitor of PDE 3 also endowed with PDE 4 and 5 inhibitory activities, on isolated bronchus and eosinophil functions and in an animal model of asthma. SCA40 (1 nM–0.1 mM) produced concentration-dependent inhibition of spontaneous and stimulated tone of human isolated bronchus and reached a maximal relaxation similar to that of theophylline (3 mM). The potency (–log EC₅₀ values) of SCA40 against spontaneous tone (6.52 ± 0.10) was greater than against tone raised by equieffective concentrations (∼ 70%) of histamine (5.76 ± 0.06), leukotriene C₄ (5.44 ± 0.11), and acetylcholine (4.98 ± 0.09). In the presence of cytochalasin B, the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP; 0.5 μM) induced leukotriene C₄ production in human eosinophils isolated in discontinuous metrizamide gradients. The production of leukotriene C₄ was inhibited by SCA40 in a concentration-related fashion (–log IC₅₀ = 6.04 ± 0.20; n = 6). Rolipram, a selective PDE 4 inhibitor, was also effective (–log IC₅₀ = 7.29 ± 0.32) but the selective PDE 3 inhibitor SKF94120 was scarcely effective (< 10% inhibition for 10 μM). In ovalbumin sensitized guinea-pigs, SCA40 (1 mg kg^–1, i.p.) given 30 min before antigen challenge significantly inhibited the acute bronchoconstriction produced by aerosol antigen (5 mg ml^–1, 30 s) (antigen response was 185 ± 13 and 91 ± 21 cmH₂O l^–1 s^–1 in control and SCA40-treated animals, respectively, P < 0.05). Pretreatment with SCA40 (1 mg kg^–1, i.p., 30 min pre- and 3 h post-antigen exposure) prevented airway hyperreactivity to histamine which developed 24 h after exposure of conscious guinea-pigs to aerosol antigen. Eosinophil lung accumulation that accompanied airway hyperreactivity was also inhibited by SCA40 (from 6.15 ± 0.86 in control to 1.27 ± 0.27 in treated animals; expressed as eosinophils × 10⁶; P < 0.05). SCA40 (1 mg kg^–1, i.p.) also inhibited the microvascular leakage produced after inhaled antigen (5 mg ml^–1, 30 s) at all airway levels. The haemodynamic effects of SCA40 (1 mg kg^–1, i.p.) consisted of a rapid decrease (peak at 5 min) in mean arterial blood pressure (–39.4 ± 2.4%) and tracheal mucosal blood flow (–13.5 ± 2.0%) that slowly recovered with time. These data support previous work showing that PDE inhibition results in anti-spasmogenic and anti-inflammatory effects. SCA40 was effective in vitro and in vivo and these effects are probably related to its activity as a mixed PDE inhibitor. Received: 13 March 1997 / Accepted: 28 July 1997     

分泌型卷曲相关蛋白5、CXC趋化因子受体4、8-异构前列腺素水平与支气管哮喘病儿气道炎症、气道重塑的关系

目的 探究支气管哮喘病儿血清分泌型卷曲相关蛋白5(SFRP5)、CXC趋化因子受体4(CXCR4)、8-异构前列腺素(8-iso PG)水平与气道炎症、气道重塑的关系及联合评估病情程度的价值。方法 选取2018年1月至2020年8月攀枝花市中心医院收治的支气管哮喘病儿113例作为研究对象,按照病情程度分为轻度组、中度组、重度组,比较三组一般资料、血清SFRP5、CXCR4、8-iso PG水平、气道炎症指标[肿瘤坏死因子-α(TNF-α)、可溶性人基质裂解素2(sST2)、白细胞介素-17(IL-17)]、气道重塑指标[痰液转化生长因子β1(TGF-β1)、基质金属蛋白酶9(MMP-9)、骨桥蛋白(OPN)],分析血清SFRP5、CXCR4、8-iso PG与气道炎症、气道重塑指标及病情程度的关系,评价血清SFRP5、CXCR4、8-iso PG对病情程度的评估价值。结果ACT评分、FEV1占预估值、PEF占预估值、FEV1/FVC：重度组<中度组<轻度组(P<0.05);重度组血清CXCR4、8-iso PG水平分别为(10.69±3.56)μg/L、(37.58±...     

血清LTB4及支气管激发试验在咳嗽变异型哮喘中的临床研究

目的探讨血清LTB4在CVA发病中的作用,CVA气道反应性特点及阳性判定标准,寻找早期发现CVA患者敏感的肺功能指标。方法(1)用ELISA法检测支气管哮喘患者和CVA患者血清LTB4水平,并与正常人相比较;(2)以磷酸组胺为气道激发剂进行支气管激发试验,对CVA患者血清LTB4水平与PC20-FEV1相关性进行分析;(3)观察CVA患者组胺激发前后FEV1、PEF、MMEF的变化并比较三者下降的幅度及同步性。结果(1)支气管哮喘组血清LTB4水平(322.6±46.8pg/ml)高于CVA组(176.1±35.3pg/ml)(P<0.05),且两组患者的血清LTB4水平均显著高于正常对照组(83.8±16.7pg/ml)(P<0.01);(2)CVA患者血清LTB4水平与组胺激发浓度呈负相关(r=-0.769,P<0.01);(3)CVA组患者MMIEF激发后(1.69±0.86L/S)与激发前(3.77±1.85L/S)比较下降显著(P<0.05);仅46.4%的患者PEF与FEV1同步下降,但MMEF与FEV1下降均同步,且FEV1下降值≥20%的患者其MMEF下降值均≥35%,比FEV1下降值≥20%多提早出现。结论(1)CVA与典型哮喘一样均存在着LTB4参与的慢性气道炎症,但CVA的气道炎症程度较典型哮喘轻;(2)支气管激发试验可作为除外或确诊CVA的有力依据。由于血清LTB4水平与气道反应性的程度相关,提示在无条件进行支气管激发试验时,可检测血清LTB4水平以辅助诊断CVA;(3)MMEF对于以小气道痉挛为主的CVA患者不失为一个早期且敏感的诊断指标,在反映气道高反应性(AHR)发生部位及程度的敏感性上,MMEF>FEV1>PEF。但是否加用PC35-MMEF<8mg/mL为气道反应性增高指标有待进一步证实。     

Airway fibrosis in a mouse model of airway inflammation

BALB/c mice were sensitized to ovalbumin by systemic injection and then exposed for up to 8 weeks to ovalbumin aerosols in whole body chambers. A pattern of airway inflammation, mucous cell hypertrophy and hyperplasia, and airway remodeling with submucosal fibrosis was observed as lesions evolved over time. Larger conducting airways were removed from the lungs by microdissection. Airway fibrosis was quantified by direct assay for collagen content, which was significantly increased after 4 and 8 weeks of exposure to ovalbumin aerosol. Based upon PCR analysis of mRNA levels in the airways, most of the newly synthesized collagen was Type I. Relaxin, administered by continuous infusion over the second half of a 4-week exposure to ovalbumin, was able to inhibit the accumulation of collagen in the airways of exposed mice. Thus, stimulation of collagen degradation by an activator of collagen breakdown by matrix metalloproteinases appears to be an effective therapeutic strategy in prevention of airway fibrosis in this animal model. Whole body plethysmography of unrestrained mice indicated functional changes in airway reactivity in the lungs of exposed animals occurring in conjunction with the reported structural changes. This result indicates that the ovalbumin-exposed mouse may be a suitable model for examining structure-function relationships in the lungs of animals with a predictable time course of airway inflammation, remodeling, and fibrosis and for testing potential new drugs for treatment of asthma or chronic bronchitis at a mechanistic level.     

雷帕霉素对哮喘大鼠气道重塑和白细胞介素-8白细胞介素-10的影响

目的观察雷帕霉素对哮喘大鼠模型气道重塑和肺组织白细胞介素(IL)-8、IL-10的影响,探讨其在干预支气管哮喘气道炎症和气道重塑中的作用机制,为临床研究提供实验依据。方法建立哮喘大鼠气道重塑模型,30只SD大鼠按随机数字法随机分为正常对照组(A)、哮喘组(B)、雷帕霉素干预组(C),每组10只。对肺组织切片行苏木素-伊红染色观察气道重塑情况。采用免疫组织化学和图像分析技术的方法测定各组大鼠肺组IL-8、IL-10的表达。结果哮喘组动物出现管壁增厚、平滑肌增生、黏液分泌增加等气道重塑的特征性改变,免疫组织化学染色显示气道各层细胞及炎性细胞均有IL-8表达增多,且IL-10水平也显著减少。雷帕霉素干预组与哮喘组比较,炎症反应轻微,平滑肌增生、黏液分泌不明显,免疫组织化学染色示各细胞IL-8表达也有所降低,IL-10水平表达增高,与正常对照组比较差异有统计学意义(P<0.05)。结论雷帕霉素可减轻哮喘大鼠的气道炎症和气道重塑,并可降低IL-8表达水平,增高IL-10表达水平,调节失衡的致炎因子/抑炎因子比例,发挥对支气管哮喘的炎症抑制和免疫调节作用。     

Methacholine-induced pulmonary gas trapping in a mouse model of allergic asthma: effect of inhaled budesonide and ciglitazone

Previously, we found pulmonary gas trapping to be a rapid, simple and objective measure of methacholine-induced airway obstruction in na?ve mice. In this study we extended that finding by using methacholine-induced pulmonary gas trapping to differentiate airway responses of ovalbumin-sensitized, ovalbumin-exposed (Positive Control) and ovalbumin-sensitized, sodium chloride-exposed (Negative Control) mice. Additionally, pulmonary gas trapping and enhanced pause were compared following methacholine exposure in sensitized and nonsensitized mice. Finally, we examined by nose-only inhalation the ability of the glucocorticosteroid budesonide and the peroxisome proliferator-activated receptor-gamma agonist ciglitazone to modify methacholine-induced airway responses in ovalbumin-sensitized mice. Positive Controls exhibited a 7.8-fold increase in sensitivity and a 2.4-fold enhancement in the maximal airway obstruction to methacholine versus Negative Controls. Following methacholine, individual Positive and Negative Control mouse enhanced pause values overlapped in 9 of 9 studies, whereas individual Positive and Negative Control mouse excised lung gas volume values overlapped in only 1 of 9 studies, and log[excised lung gas volume] correlated (P=0.023) with in vivo log[enhanced pause] in nonsensitized mice. Finally, budesonide (100.0 or 1000.0 microg/kg) reduced methacholine-mediated airway responses and eosinophils and neutrophils, whereas ciglitazone (1000.0 microg/kg) had no effect on methacholine-induced pulmonary gas trapping, but reduced eosinophils. In conclusion, pulmonary gas trapping is a more reproducible measure of methacholine-mediated airway responses in ovalbumin-sensitized mice than enhanced pause. Also, excised lung gas volume changes can be used to monitor drug interventions like budesonide. Finally, this study highlights the importance of running a positive comparator when examining novel treatments like ciglitazone.     

Inhibition of high-mobility group box 1 in lung reduced airway inflammation and remodeling in a mouse model of chronic asthma

The role of high-mobility group box 1 (HMGB1) in chronic allergic asthma is currently unclear. Both airway neutrophilia and eosinophilia and increase in HMGB1 expression in the lungs in our murine model of chronic asthma. Inhibition of HMGB1 expression in lung in ovalbumin (OVA)-immunized mice decreased induced airway inflammation, mucus formation, and collagen deposition in lung tissues. Analysis of the numbers of CD4⁺ T helper (Th) cells in the mediastinal lymph nodes and lungs revealed that Th17 showed greater increases than Th2 cells and Th1 cells in OVA-immunized mice; further, the numbers of Th1, Th2, and Th17 cells decreased in anti-HMGB1 antibody (Ab)-treated mice. In OVA-immunized mice, TLR-2 and TLR-4 expression, but not RAGE expression, was activated in the lungs and attenuated after anti-HMGB1 Ab treatment. The results showed that increase in HMGB1 release and expression in the lungs could be an important pathological mechanism underlying chronic allergic asthma and HMGB1 might a potential therapeutic target for chronic allergic asthma.