班布特罗对豚鼠实验性哮喘的作用及其机理研究

目的 研究班布特罗对豚鼠实验性哮喘的作用、药效学及药动学特点及作用机制。方法 组胺和卵清蛋白诱发在体豚鼠实验性哮喘模型,使用豚鼠离体气管片和肺条进行研究。结果 班布特罗剂量依赖性抑制组胺和卵清蛋白诱发的豚鼠哮喘,班布特罗对豚鼠气管片无松弛作用,而灌服其后的松弛气管片和肺条血浆呈剂量依赖性,且对肺条的松弛作用强于气管片。其峰效应出现于给药后4h前后,作用持续24h以上。结论 班布特罗作为特布他林的前药对豚鼠实验性哮喘的作用缓和而持久。     

班布特罗对豚鼠支气管收缩反应的扩张作用

目的:观察班布特罗对豚鼠支气管收缩反应的影响。方法:用哮喘发作潜伏期、肺机械功能及离体气管平滑肌松弛试验观察班布特罗的支气管扩张作用。结果:班布特罗ig后1h、4h和24h均能延长组胺诱导的豚鼠哮喘潜伏期,ED_(50)(95％可信限)分别为0.74(0.60-0.92),0.75(0.61-0.91),1.00(0.77-1.30)mg·kg~(-1),其作用持续时间明显长于特布他林。班布特罗2或10mg·kg~(-1)在抗原攻击前2h ig部分或几乎完全抑制致敏豚鼠抗原攻击引起的气道阻力增加和肺顺应性降低。但在离体试验中,班布特罗对氨甲酰胆碱引起的气管平滑肌收缩反应和静息肺组织条无明显松弛作用。结论:班布特罗通过缓慢代谢发挥其长效支气管扩张作用。     

班布特罗对豚鼠支气管收缩反应的扩张作用

观察班布特罗对豚鼠支气管收缩反应的影响。方法：用哮喘发作潜伏期,肺机械功能及离体气管平滑肌松弛试验观察班布特罗的支气管扩张作用。结果：班布特罗ｉｇ后１ｈ,４ｈ和２４ｈ均能延长组胺诱导的豚鼠哮喘潜伏期,ＥＤ５０分别为０．７４,０．７５,１．００ｍｇ．ｋｇ＾－１,其作用持续时间明显长于特布他林。     

盐酸氮(艹卓)斯汀对豚鼠实验性哮喘的作用及其机理研究

目的 :观察盐酸氮 艹卓 斯汀 (azelastinehydrochlo ride ,AZ)对豚鼠实验性哮喘的作用 ,并探讨其作用机制。方法 :采用组胺和乙酰胆碱诱发在体豚鼠实验性哮喘模型 ,观察AZ的整体作用 ;采用豚鼠离体气管螺旋条 ,观察AZ对组胺所致的豚鼠离体气管螺旋条痉挛的拮抗作用。结果 :AZ能够剂量依赖性地拮抗组胺和乙酰胆碱的引喘作用 ,明显延长引喘潜伏期 ,显著减少抽搐动物发生率 ,其ED50 为 0 .2 16mg·kg-1,95 %可信限为 0 .2 14～ 0 .2 19mg·kg-1。AZ可剂量依赖性地拮抗组胺对离体气管平滑肌的收缩作用 ,使组胺量效曲线平行右移 ,其pA2 值为 8.99。结论 :预先给予AZ能显著拮抗组胺和乙酰胆碱所诱发的在体豚鼠实验性哮喘 ,抑制组胺所致的气管螺旋条收缩     

硝普钠平作喘用的观察

确普钠能直接松驰豚鼠离体气管平滑肌;能非竞争性拮抗组胺引起的豚鼠离体肺条收缩;对组胺诱发的豚鼠肺条收缩有解痉作用;气雾吸入或吞下给药对豚鼠药物性哮喘有保护作用;气雾吸入对猪蛔虫蛋白抗原诱发的犬过敏性哮喘具有保护作用。确普钠能提高豚鼠离体气管平滑肌cAMP的含量,这可能是它平喘作用的机制。     

马布特罗对豚鼠支气管平滑肌松弛作用和平喘作用的影响

目的 :观察马布特罗对豚鼠的平喘作用和离体豚鼠支气管平滑肌的松弛作用。方法 :用 2 %氯化乙酰胆碱和 0 .1 %组胺等容积混合液喷雾诱发哮喘 ,观察马布特罗 (0 .0 6～ 1mg·kg-1)平喘作用的半数有效量(ED50 )及对引喘潜伏期的影响。用离体豚鼠肺支气管灌流法观察马布特罗 (1 0 -9,1 0 -7,1 0 -3 kg·L-1)对组胺 1 0 -4kg·L-1引起肺支气管灌流量减少的影响。结果 :马布特罗对致痉剂诱发豚鼠哮喘有明显抑制作用 ,减少哮喘诱发抽搐动物数 ,其ED50 为 0 .2mg·kg-1及 95 %可信限为 0 .0 8～0 .49mg·kg-1;马布特罗可剂量依赖性对抗组胺减少肺支气管灌流量作用 ,并显著缩短组胺灌流达固定流量时间。结论 :马布特罗对药物致豚鼠哮喘具有明显平喘作用 ,此作用与其松弛支气管平滑肌作用有关。     

吡布特罗胶囊对豚鼠支气管平滑肌的影响

目的:研究吡布特罗胶囊(PirbuteroI Capsules)对正常及致敏豚鼠支气管收缩的影响及平喘作用。方法:通过离体和整体实验,观察 Pributerol Capsules 对以组胺和乙酰胆碱引起正常豚鼠支气管的收缩和以卵白蛋白诱发的致敏豚鼠支气管收缩的影响。结果:离体实验,PirbuterolCapsules 52mg·L~(-1)对组胺致正常豚鼠气管片的收缩具有对抗作用,对卵白蛋白所致的致敏豚鼠支气管平滑肌收缩有极显著的抑制作用(P<0.01)。对乙酰胆碱所致气管片收缩作用明显;整体实验,Pirbuterol Capsules 18mg·kg~(-1)可显著延长卵白蛋白所致的致敏豚鼠呼吸困难,抽搐和跌倒的潜伏期(P<0.01)。结论:Pirbuterol Capsules 能拮抗组胺刺激引起的正常豚鼠和卵白蛋白引起的致敏豚鼠离体气管片的收缩,抑制致敏豚鼠哮喘的发生。     

左旋沙丁胺醇抑制豚鼠气道平滑肌收缩的实验研究

目的评价左旋沙丁胺醇(R-Salbutamol,R-Sal)对组胺(histamine,His)诱发的豚鼠离体气管条和肺条收缩功能的影响。方法制备豚鼠离体气管条和肺条标本,以定量药理学方法测定10-8、10-7、10-6mol·L-1剂量的R-Sal孵育前后对His诱发的离体标本的收缩反应的舒张作用,并与10-6mol·L-1剂量的Sal进行比较。结果R-Sal可显著抑制His所引起的豚鼠离体气管和肺条的收缩反应,呈剂量依赖性,其作用强于Sal(P<0.01)。结论R-Sal对His诱发的豚鼠离体气管条和肺条的收缩反应具明显的舒张作用。     

金荞麦对家鸽气管纤毛运动和豚鼠离体气管平滑肌舒张的影响

目的研究金荞麦对家鸽纤毛运动和豚鼠离体气管平滑肌舒张的影响。方法气管纤毛运动试验观察不同剂量金荞麦(6,3,1.5 g生药/kg)对家鸽纤毛运动的影响;制备新鲜的豚鼠离体气管片,在K-H缓冲液中观察不同剂量的金荞麦(累积浓度为15,30,60,120 g生药/L)对气管片收缩的影响;制备新鲜的豚鼠离体气管螺旋条,在K-H缓冲液加入组胺,使豚鼠气管螺旋条收缩达高峰后观察不同剂量的金荞麦(15,30,60,120g生药/L)对组胺致气管片收缩的影响。结果金荞麦三个剂量组均能加快家鸽气管内纤毛运动速度(P<0.01或P<0.05);金荞麦60～120 g生药/L溶液能明显松弛正常豚鼠离体气管平滑肌(P<0.01或P<0.05);金荞麦15～120 g生药/L溶液对组胺致豚鼠离体气管平滑肌收缩有明显解痉作用(P<0.01)。结论金荞麦可明显加快家鸽气管纤毛运动;金荞麦可明显松弛豚鼠离体气管平滑肌,并具有一定的浓度依赖性;并对组织胺致豚鼠离体气管平滑肌收缩有明显解痉作用,并呈现一定的浓度依赖性。     

复方地龙汤对变态反应性哮喘的影响

目的：探讨复方地龙汤抗动物变态反应性哮喘的作用。方法：采用组胺喷雾致豚鼠哮喘法：致敏豚鼠离体气管平滑肌过敏性收缩实验法；离体气管片法：肺支气管灌流法进行试验。结果：复方地龙汤水煎液对喷入组胺致喘的豚鼠。能使其哮喘潜伏期延长（P〈0．01）；能使致敏豚鼠离体气管平滑肌过敏性收缩有非常显著的抑制作用（P〈0．01）；在抗组胺实验中，对给予组胺后的豚鼠离体气管片有非常显著的舒张作用（P〈0．01）；使肺支气管灌流速度加快，灌流量增加（P〈0．01）。结论：复方地龙汤求煎液对由各种过敏递质引起的哮喘．有显著的抑制作用。这可能是因为其对在体、离体气管平滑肌均有松弛作用．并拮抗组胺等过敏递质对气道的炎性反应和具有激动体内β-受体和免疫系统。从而发挥其作用的。     

地龙汤对豚鼠气道变态反应的影响

目的:探讨地龙汤对动物气道过敏反应的影响。方法:采用组胺喷雾致豚鼠过敏性哮喘法;致敏豚鼠离体气管平滑肌过敏性收缩实验法;抗组胺药实验法进行试验。结果:地龙汤水煎液能使致敏豚鼠离体气管平滑肌过敏性收缩有显著的抑制作用(P<0.01);在抗组胺实验中,对给予组胺后的豚鼠离体气管片有显著的舒张作用(P<0.01)和使肺支气管灌流速度加快,灌流量增加(P<0.01);对喷入组胺致喘的豚鼠,能使其哮喘潜伏期延长(P<0.01)。结论:地龙汤水煎液对气道变态反应性炎症有抗变态反应的作用,对组胺所致过敏性哮喘有阻抗作用。     

艾叶油的呼吸系统药理研究Ⅰ,支气管扩张、镇咳和祛痰作用

目的：探讨艾叶油的扩张气道平滑肌,镇咳,祛痰作用及机制。方法：采用哮喘发作潜伏期,肺机械功能及离体气管平滑肌松弛试验,观察艾叶油的支气管扩张作用;用豚鼠枸橼酸引咳法和小鼠气道酚红排泄法观察艾叶油的镇咳祛痰作用。     

Acute hypersensitivity to aerosolized histamine induced by aerosolized ovalbumin in guinea pigs.

Acute airway hyperresponsiveness can be induced after exposure to aerosolized ovalbumin in sensitized guinea pigs. The purpose of the present studies was to determine if "pro-inflammatory agents" would potentiate and prolong antigen-induced pulmonary hyperresponsiveness to histamine in guinea pigs. Guinea pigs were sensitized to aerosolized ovalbumin by exposing them to a 3 min aerosol, generated ultrasonically from a 10% ovalbumin solution on day 0 and day 7. On day 13 the guinea pigs were exposed to a 3 min aerosol of deionized water or a pro-inflammatory agent (1 microgram/ml PAF, 1 mg/ml LPS, or 4% B. pertussis vaccine). Twenty-four hours later, on day 14, the conscious guinea pigs were challenged with a 3 min aerosolized ovalbumin exposure (under isoproterenol cover) and the individual guinea pig responsiveness to aerosolized histamine was determined 2 and 24 h later in an anesthetized modified Konzett-Rossler preparation. Under these experimental conditions, ovalbumin challenge to sensitized guinea pigs produced only an acute hyperresponsiveness (about a 3-10-fold shift) to aerosolized histamine, which lasted less than 24 h. The pro-inflammatory agents neither potentiated nor prolonged the duration of the hyperresponsiveness.     

雌二醇对离体和在体气管平滑肌收缩活动的抑制作用

目的:研究雌二醇对离体和在体气管平滑肌收缩的作用.方法:(1)将家兔离体气管平滑肌条置于装有Krebs液的肌槽中温育,并通入95％O_2和5％CO_2的混合气体.二导记录仪记录肌条的等长张力.(2)测量肌注雌二醇(1mg/kg)前后乙酰胆碱和组胺引发豚鼠哮喘的潜伏期.结果:(1)雌二醇(100μmol/L)对乙酰胆碱和氯化钾诱发的收缩有明显的舒张作用(舒张百分比分别为39％±5％和45％±19％).其作用可被蚓哚美辛和亚甲蓝部分阻断(26％±8％和28％±13％),但不能被L-NNA、心得安和去除上皮所影响(舒张百分比分别为38％±10％,40％±15％,37％±8％).雌二醇能使乙酰胆碱及氯化钙的量效曲线明显右移(pD_2~′值分别为3.98和4.75).另外,雌二醇可明显抑制乙酰胆碱引起的第Ⅰ时相性收缩,对氯化钙引起的第Ⅱ时相性的收缩无明显影响.(2)肌注雌二醇(1mg/kg)可使豚鼠的引喘潜伏期明显延长.结论:(1)雌二醇对兔离体气管平滑肌的作用是非上皮依赖性的,与抑制电压依赖性钙通道和细胞内钙从内质网的释放有关,还部分与cGMP介导的松弛途径及刺激气道平滑肌释放前列腺素类物质有关,但与β-肾上腺素能受体介导的舒张无关.(2)雌二醇可明显舒张豚鼠在体气管平滑肌.     

白屈菜总生物碱对豚鼠的平喘作用

目的:观察白屈菜总生物碱的平喘作用。方法:采用磷酸组织胺-氯化乙酰胆碱、卵蛋白引喘诱发豚鼠喘息模型,观察药物对出现喘息性抽搐的潜伏期及抽搐跌倒动物数的影响;采用豚鼠离体肺支气管灌流和离体完整豚鼠气管毛细管试验,测定药物对气管张力的影响。结果:TACM可明显延长引喘潜伏期(P<0.05),减少抽搐跌倒动物数;明显增加肺支气管的灌流量(P<0.05);松弛离体完整气管平滑肌,并可抑制组织胺收缩气管平滑肌效应。结论:TACM有显著的平喘作用。     

Pharmacologic analysis of LY188695 (KB-2413), 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)-benzimidazole difumarate, a potent histamine1 receptor antagonist

LY188695 was evaluated both in vitro and in vivo in the guinea pig to determine its pharmacologic profile. The compound antagonized histamine-induced contractions of ileum, aorta, and trachea with pKB values of 9.9, 9.9, and 9.2 respectively. In the lung parenchymal strip, LY188695 caused a rightward shift of the histamine concentration-response curve with a reduction in the maximal response at all antagonist concentrations tested. The reason for this effect is unknown, but it was not due to a nonspecific depressant action of the compound on the parenchyma. Selectivity was shown by its inactivity against leukotriene D4, bradykinin, prostaglandin F2 alpha, acetylcholine, norepinephrine, and serotonin on various guinea pig and rat smooth muscles. Similarly, H2 receptor-mediated relaxation of the rat uterus was unaltered by LY188695. Increases in total pulmonary impedance caused by i.v. histamine to anesthetized guinea pigs were reduced by as little as 3 micrograms/kg given orally 1 hour prior to histamine challenge. In this system, LY188695 was 15 times more potent than chlorpheniramine and 100 times more potent than terfenadine. Similar responses elicited by acetylcholine were not antagonized by LY188695. A duration of action greater than 4 hours was observed in this model. Ovalbumin given i.v. to sensitized guinea pigs increased total pulmonary impedance which was markedly decreased after oral administration of 30 or 100 micrograms/kg LY188695. These results indicate that LY188695 is a very potent antagonist of H1-mediated responses and suggest that this agent might be useful in disease states characterized by an overproduction of histamine.     

Evaluation of LY163443, 1-[2-hydroxy-3-propyl-4-{[4-(1H-tetrazol-5-ylmethyl)phenoxy]methyl}phenyl]ethanone,as a pharmacologic antagonist of leukotrienes D4 and E4

Summary LY163443,1-[2-hydroxy-3-propyl-4-{[4-(1H-tetrazol-5-ylmethyl)-phenoxy]methyl}phenyl]ethanone, antagonized LTD₄-induced contractions of guinea pig ileum, trachea, and lung parenchyma. Tracheal contractions to LTE₄ were also inhibited by LY163443. The compound had minimal effect against ileal responses to LTC₄ and parenchymal contractions to LTB₄. Furthermore, LY163443.had little to no effect against contractions of isolated smooth muscles to histamine, bradykinin, PGF₂, carbachol, serotonin or U46619. LY163443, given by oral administration to guinea pigs, blocked LTD₄-induced increases in total pulmonary impedance (TPI). Similar responses elicited by histamine or U46619 were unaffected. Increases in TPI in response to i.v. administration of LTC₄ were antagonized by LY163443 given by the same route. Ovalbumin challenge also increased TPI in guinea pigs previously sensitized against this antigen. In such animals, pretreated with pyrilamine, propranolol, and indomethacin, oral administration of LY163443 blocked the increase in TPI caused by ovalbumin. Additionally, LTD₄ given intradermally to guinea pigs caused a vascular leakage which was suppressed by prior oral administration of LY163443. Finally, LY163443 relaxed isolated guinea pig trachea previously contracted with LTD₄, histamine, or carbachol. Relaxation of tissues contracted by these latter two agonists suggested some inherent airway smooth muscle relaxant properties of the molecule. This was further demonstrated by showing some bronchodilator activity in an in vivo setting. Thus, this pharmacologic profile indicates that LY163443, or a member of the same chemical family, warrants consideration as a possible therapeutic agent in the treatment of asthma and in diseases characterized by an overproduction of LTD₄ and LTE₄.Presented in part at the meeting of The Federation of American Societies for Experimental Biology, April 1985, Anaheim, California.