Keir Sandra, Page Clive, Spina Domenico
Sackler Institute of Pulmonary Pharmacology, Division of Pharmacology and Therapeutics, GKT School of Biomedical Sciences, King's College London, London.
J Allergy Clin Immunol. 2002 Sep;110(3):388-94. doi: 10.1067/mai.2002.126661.
It has recently been suggested that regular treatment with racemic beta(2)-adrenoceptor agonists might result in bronchial hyperresponsiveness (BHR) to a range of spasmogens, and this might be due to adverse effects of the distomer.
We sought to determine whether BHR induced by means of continuous exposure to racemic and S-albuterol was mediated by sensory nerves.
Naive or ovalbumin-sensitized guinea pigs were treated for 10 days with RS-, R-, or S-albuterol (1 mg.kg(-1).d(-1)) through subcutaneously implanted minipumps. Lung function was then determined in response to a number of spasmogens and assessed on the basis of an increase in total airway resistance. A separate group of animals were chronically treated with capsaicin (80 mg/kg) before the albuterol treatment.
Treatment with RS- or S-albuterol increased airway responsiveness to bradykinin, leukotriene C(4), and capsaicin in naive guinea pigs (P <.05) and to histamine and ovalbumin in immunized guinea pigs (P <.05). Chronic treatment with capsaicin prevented the development of RS- and S-albuterol-induced BHR in these models. The bronchodilator efficacy of acute intravenously administered RS-albuterol was unaffected in RS-, R-, or S-albuterol-treated guinea pigs compared with in vehicle-treated animals.
We have provided evidence demonstrating that continuous exposure to RS- and S-albuterol increases bronchial responsiveness to a range of stimuli, an effect not attributed to beta-adrenoceptor occupancy or desensitization. Furthermore, capsaicin-sensitive sensory nerves mediate the development of BHR, at least in part.
最近有研究表明，长期使用消旋β₂肾上腺素受体激动剂可能会导致支气管对一系列致痉剂产生高反应性（BHR），这可能是由于对映体杂质的不良反应所致。
我们试图确定持续暴露于消旋沙丁胺醇和S-沙丁胺醇所诱导的BHR是否由感觉神经介导。
将未致敏或卵清蛋白致敏的豚鼠通过皮下植入微型泵，用消旋、R-或S-沙丁胺醇（1 mg·kg⁻¹·d⁻¹）治疗10天。然后测定肺功能对多种致痉剂的反应，并根据总气道阻力的增加进行评估。另一组动物在沙丁胺醇治疗前用辣椒素（80 mg/kg）进行长期治疗。
在未致敏的豚鼠中，用消旋或S-沙丁胺醇治疗可增加气道对缓激肽、白三烯C₄和辣椒素的反应性（P <.05），在免疫的豚鼠中可增加对组胺和卵清蛋白的反应性（P <.05）。在这些模型中，用辣椒素进行长期治疗可预防消旋和S-沙丁胺醇诱导的BHR的发生。与用赋形剂治疗的动物相比，急性静脉注射消旋沙丁胺醇的支气管扩张疗效在接受消旋、R-或S-沙丁胺醇治疗的豚鼠中未受影响。
我们提供的证据表明，持续暴露于消旋和S-沙丁胺醇会增加支气管对一系列刺激的反应性，这种效应并非归因于β肾上腺素受体的占据或脱敏。此外，辣椒素敏感的感觉神经至少部分介导了BHR的发生。
