Snyder D W, Liberati N J, McCarthy M M
Department of Pharmacology, Stuart Pharmaceuticals, Wilmington, Delaware.
J Pharmacol Methods. 1988 May;19(3):219-31. doi: 10.1016/0160-5402(88)90024-1.
A new conscious animal model for evaluating leukotriene antagonists is described. The model consists of monitoring the change in the respiratory pattern induced by aerosol administration of various airway constrictors in six guinea pigs secured in a plexiglass chamber by a neck yoke. The animals are pretreated with indomethacin (10 mg/kg, i.p.) and propranolol (5 mg/kg, i.p.) 30 min prior to the challenge. After a 30-min stabilization period, the animals are challenged by various agonists delivered via a Monaghan ultrasonic nebulizer at a flow rate of 2.0 L/min for 5 min. The end point is defined as the onset of slow, labored abdominal breathing (dyspnea) measured in seconds. Peptide leukotrienes (LTs) (30 nM-60 microM) produced concentration-related decreases in time to dyspnea with a rank order of potency of LTD4 greater than LTC4 greater than LTE4. LTD4 was 1,000-fold more potent than histamine or carbachol. Pretreatment of the animals with either FPL55712 or LY171883 delayed the time to reach dyspnea induced by LTD4. In contrast, pyrilamine, cyproheptadine, and phenoxybenzamine failed to alter LTD4-induced dyspnea. The results indicate that this model is useful in assessing the efficacy of LT receptor antagonists in vivo.
描述了一种用于评估白三烯拮抗剂的新型清醒动物模型。该模型包括通过颈部轭架将六只豚鼠固定在有机玻璃舱中，监测通过雾化吸入各种气道收缩剂所诱导的呼吸模式变化。在激发前30分钟，动物用吲哚美辛（10毫克/千克，腹腔注射）和普萘洛尔（5毫克/千克，腹腔注射）进行预处理。经过30分钟的稳定期后，通过莫纳汉超声雾化器以2.0升/分钟的流速给予各种激动剂对动物进行激发，持续5分钟。终点定义为以秒为单位测量的缓慢、费力的腹式呼吸（呼吸困难）的发作。肽白三烯（LTs）（30纳摩尔至60微摩尔）使达到呼吸困难的时间呈浓度相关的减少，效力顺序为LTD4大于LTC4大于LTE4。LTD4的效力比组胺或卡巴胆碱强1000倍。用FPL55712或LY171883预处理动物可延迟由LTD4诱导的达到呼吸困难的时间。相比之下，吡苄明、赛庚啶和酚苄明未能改变LTD4诱导的呼吸困难。结果表明该模型可用于评估体内LT受体拮抗剂的疗效。
