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

Allergic bronchospasm in sensitized guinea-pigs was totally suppressed by acute subcutaneous infusion of rac-salbutamol (0.69 mu g/kg per mi n) for <1 h. More prolonged infusion of rac-salbutamol induced a progr essive susceptibility to inhaled antigen so that, by 48 h, animals col lapsed and died following inhalation of antigen. In anaesthetized anim als, acute infusion of rac-salbutamol (1.67 mu g/kg per min) suppresse d airway obstruction, an effect that can be attributed to beta(2)-adre noceptor activation by the eutomer OR-salbutamol). Acute intravenous i nfusion 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 anti gen because the bronchodilator action of the eutomer predominates over hyperreactivity attributable to the distomer. Conversion from protect ion to susceptibility was not determined by reduced beta 2-adrenocepto r activation since animals could be protected from a lethal response t o antigen by inhalation of rac-isoprenaline or by subcutaneous injecti on of rac-salbutamol. The seeming progressive loss of efficacy of R-sa lbutamol may result from disproportionate accumulation of S-salbutamol if, as in man, there is stereospecific metabolism of R-salbutamol. Th e 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 hyperresponsi veness was not evidenced following section of the vagus nerves. No mec hanism has yet been established which might account for this property of S-salbutamol or for other S-enantiomers of sympathomimetics.