HYPERRESPONSIVENESS OF THE AIRWAYS FOLLOWING EXPOSURE OF GUINEA-PIGS TO RACEMIC MIXTURES AND DISTOMERS OF BETA(2)-SELECTIVE SYMPATHOMIMETICS

被引:78
作者
MAZZONI, L
NAEF, R
CHAPMAN, ID
MORLEY, J
机构
[1] Preclinical Research and Development, Sandoz Pharma Ltd.
[2] Quantiles Scotland Ltd., Heriot-Watt University Research Park, Riccarton, Edinburgh EH 14 4AP, Research Avenue South
[3] Department of Applied Pharmacology, National Heart and Lung Institute, London SW3 6LY, Dovehouse Street
来源
PULMONARY PHARMACOLOGY | 1994年 / 7卷 / 06期
关键词
SALBUTAMOL; GUINEA-PIG; AIRWAY HYPERREACTIVITY; ALLERGIC BRONCHOSPASM;
D O I
10.1006/pulp.1994.1043
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Allergic bronchospasm in sensitized guinea-pigs was totally suppressed by acute subcutaneous infusion of rac-salbutamol (0.69 mu g/kg per min) for <1 h. More prolonged infusion of rac-salbutamol induced a progressive susceptibility to inhaled antigen so that, by 48 h, animals collapsed and died following inhalation of antigen. In anaesthetized animals, acute infusion of rac-salbutamol (1.67 mu g/kg per min) suppressed airway obstruction, an effect that can be attributed to beta(2)-adrenoceptor activation by the eutomer OR-salbutamol). Acute intravenous infusion of the distomer (S-salbutamol) (1.67 mu g/kg per min) induced hyperresponsiveness to histamine without having any effect upon airway calibre. It is suggested therefore that subcutaneous infusion of rac-salbutamol initially abrogates the bronchoconstrictor response to antigen because the bronchodilator action of the eutomer predominates over hyperreactivity attributable to the distomer. Conversion from protection to susceptibility was not determined by reduced beta 2-adrenoceptor activation since animals could be protected from a lethal response to antigen by inhalation of rac-isoprenaline or by subcutaneous injection of rac-salbutamol. The seeming progressive loss of efficacy of R-salbutamol may result from disproportionate accumulation of S-salbutamol if, as in man, there is stereospecific metabolism of R-salbutamol. The capacity of S-salbutamol to evoke hyperresponsiveness is shared by S-isoprenaline and S-terbutaline and, as has been shown previously for rac-isoprenaline, the capacity of S-salbutamol to elicit hyperresponsiveness was not evidenced following section of the vagus nerves. No mechanism has yet been established which might account for this property of S-salbutamol or for other S-enantiomers of sympathomimetics.
引用
收藏
页码:367 / 376
页数:10
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