Boskabady M H, Adel-Kardan S
Department of Physiology, Ghaem Medical Centre, Mashhad University of Medical Sciences, Mashhad, Iran.
Pharmacology. 1999 Jun;58(6):300-8. doi: 10.1159/000028295.
Drug delivery to the receptor sites and receptor affinity could be determinant factors for increased bronchial responsiveness seen in asthma. Competitive antagonism blockade which is measured as dose ratio - 1 (DR-1) depends only on these two factors. Therefore, in this study we examined the muscarinic receptor blockade by atropine on isolated tracheal chains of sensitized compared to control guinea pigs. An experimental model of asthma was induced in guinea pigs by sensitization of animals with injection and inhalation of ovalbumin (OA). The responses of tracheal chains of sensitized and control animals (for each group n = 10) to cumulative concentrations of methacholine in the absence and presence of 5 nmol/l atropine were measured, and the effective concentrations of methacholine causing 50% of maximum response (EC50 M) were obtained. The atropine blockade (DR-1) was calculated by: (post-atropine EC50 M/EC50 M) - 1. The responses of tracheal chains to 0.1% OA, relative to contraction obtained by 10 mmol/l methacholine, were also measured. The tracheal responses of sensitized guinea pigs were significantly higher than those of control animals to both OA (mean +/- SEM, 55.94 +/- 5.22 vs. 2.59 +/- 0.85%, p < 0.001) and methacholine (EC50 M for asthmatic and control animals were 0.88 +/- 0.27 and 2.00 +/- 0.26 micromol, respectively, p < 0.01). The muscarinic receptor blockade by atropine (DR-1) was also significantly higher in tracheas of asthmatic compared to that of control animals (131.12 +/- 19.82 vs. 24.50 +/- 3.19, p < 0.001). There were significant correlations between tracheal response to OA and EC50 M (r = -0.644, p = 0.002) and also between DR-1 and tracheal responses to both OA (r = 0.738, p < 0.001) and EC50 M (r = -0.679, p < 0.001). This enhanced muscarinic receptor blockade in tracheal chains of sensitized animals confirms our previous findings which was predicted to be due to the increased drug delivery to the receptors. Drug delivery could also be a determinant factor for bronchial responsiveness to stimuli in asthma.
药物输送到受体部位以及受体亲和力可能是哮喘中支气管反应性增加的决定性因素。以剂量比-1（DR-1）衡量的竞争性拮抗阻断仅取决于这两个因素。因此，在本研究中，我们检测了与对照豚鼠相比，阿托品对致敏豚鼠离体气管链的毒蕈碱受体阻断作用。通过给动物注射和吸入卵清蛋白（OA）使其致敏，从而在豚鼠中诱导出哮喘实验模型。测量了致敏动物和对照动物（每组n = 10）的气管链在不存在和存在5 nmol/l阿托品的情况下对累积浓度的乙酰甲胆碱的反应，并获得了引起最大反应50%的乙酰甲胆碱的有效浓度（EC50 M）。阿托品阻断作用（DR-1）通过以下公式计算：（阿托品处理后的EC50 M/EC50 M）-1。还测量了气管链对0.1% OA的反应，相对于10 mmol/l乙酰甲胆碱引起的收缩反应。致敏豚鼠的气管对OA（平均值±标准误，55.94±5.22对2.59±0.85%，p < 0.001）和乙酰甲胆碱（哮喘动物和对照动物的EC50 M分别为0.88±0.27和2.00±0.26 μmol，p < 0.01）的反应均显著高于对照动物。与对照动物相比，哮喘动物气管中阿托品的毒蕈碱受体阻断作用（DR-1）也显著更高（131.12±19.82对24.50±3.19，p < 0.001）。气管对OA的反应与EC50 M之间（r = -0.644，p = 0.002）以及DR-1与气管对OA（r = 0.738，p < 0.001）和EC50 M（r = -0.679，p < 0.001）的反应之间均存在显著相关性。致敏动物气管链中毒蕈碱受体阻断作用的增强证实了我们之前的发现，预计这是由于药物向受体的输送增加所致。药物输送也可能是哮喘中支气管对刺激反应性的一个决定性因素。
