Evaluation of the effects of the R- and S-enantiomers of salbutamol on equine isolated bronchi.

Abstract: Equine obstructive pulmonary disease, also known as heaves or recurrent airway obstruction (RAO) is a common equine pulmonary disease with some similarities to human asthma and COPD, which represents a major cause of morbidity and loss of lung performance. Salbutamol has been widely used for the treatment of human airway diseases and has usually been prepared as the racemic form of the drug. However, recently the R-enantiomer of salbutamol has been introduced into clinical practice in the treatment of asthma in humans and this has been suggested to be an improvement on the racemic form of the drug; therefore thus the S-enantiomer has been demonstrated to have adverse effects in the lung and thus using the R-enantiomer may improve the therapeutic ratio. However, little is known about the properties of the R- and S-enantiomers of salbutamol in equine airways and the present study has evaluated the relaxant effects of racemic β(2)-agonists in comparison with the R- and S-enantiomers in isolated equine isolated bronchi, as well as the bronchoprotective effects of these drugs on cholinergic and histaminergic pathway. Methods: We have studied the effects of the R- and S-enantiomers of salbutamol on bronchi isolated from RAO-affected or unaffected horses. The first study assayed the relaxant effects of R- and S-salbutamol on isolated bronchial rings contracted with carbachol or histamine at a sub-maximal concentration (EC70). A second study evaluated the effects of R- and S-salbutamol on semi-logarithmic cumulative concentration-response curves induced by carbachol or histamine. Specific software was used to calculate statistical significance and the appropriate sigmoidal curve-fitting model. Results: Neither enantiomers of salbutamol caused a relaxant effect on the sub-maximal plateau contractile effects of carbachol; in fact, both R- and S-salbutamol induced a slight, but significant contraction (P ≤ 0.05) compared to the controls. In contrast, R-salbutamol induced a significant relaxation of bronchi pre-contracted with histamine (RAO-unaffected: 92.06% ± 2.00; RAO-affected 100.20 ± 3.99; P ≤ 0.01). S-salbutamol induced a weak relaxation (RAO-unaffected: 15.81% ± 5.65; RAO-affected 12.36 ± 5.15) when compared to that induced by papaverine. The incubation with either R- or S-salbutamol shifted rightward (P ≤ 0.001) the carbachol contraction curve in RAO-unaffected bronchi, but not in RAO-affected bronchi, compared to control tissues. R-salbutamol induced a reduction in E(max) values (C: 9.07 gr ± 0.68; R-salb.: 6.36 gr ± 0.21; P ≤ 0.01) in normal bronchi. On the contrary it reduced the histamine potency in RAO-affected bronchi (EC50 7.10 μM ± 0.35, P < 0.001). The incubation with S-salbutamol shifted leftward the histamine concentration curve in both normal bronchi (C: 7.00 μM ± 0.29; S-salb.: 2.25 μM ± 0.19; P ≤ 0.001) and bronchi from RAO-affected horses (C: 2.80 μM ± 0.26; S-salb.: 1.50 μM ± 0.80; P ≤ 0.05). Conclusions: Our studies have demonstrated that S-salbutamol elicited a modest increase in contraction of equine airway smooth muscle induced by carbachol and induced a significant hyperresponsiveness to histamine. These results confirm the ability of the S-enantiomer of salbutamol to potentiate the contractile effect of certain spasmogens on airway smooth muscle. Such an adverse effect would be determined in the airways of horses with RAO and suggest that if salbutamol is to be used in the treatment of symptoms of RAO in horses, the R-enantiomer, rather than the racemic mixture should be considered.