STERIC ASPECTS OF FORMOTEROL AND TERBUTALINE - IS THERE AN ADVERSE EFFECT OF THE DISTOMER ON AIRWAY SMOOTH-MUSCLE FUNCTION

Experiments were made on isolated tissues from guinea-pig to test the hypothesis that the distomers of rac-beta(2)-adrenoceptor agonists ind uce airway hyperreactivity. Tracheal strip preparations were contracte d with carbachol. Both rac- and (R;R)-formoterol (2 and 1 mu mol/l, re spectively) produced an immediate relaxation, followed by a slow recov ery of tone. (S;S)-Formoterol (2 mu mol/l) had no effect on smooth mus cle tone. Similar results were obtained with the enantiomers of terbut aline. In other skip preparations of the trachea or the main bronchi, cholinergic or nonadrenergic/noncholinergic (NANC) excitatory response s were evoked by electrical field-stimulation. The eutomers, (R;R)-for moterol and (R)-terbutaline, inhibited concentration-dependently both cholinergic and NANC-induced contractions. The distomers, (S;S)-formot erol and (S)-terbutaline, showed qualitatively the same effects but we re about 1,000 times less potent than the corresponding eutomer. In a third series of experiments, either enantiomer of formoterol was admin istered to an electrically stimulated vagus nerve-trachea tube prepara tion. The nerve-induced contractions were inhibited by both enantiomer s, but (S;S)-formoterol was about 1,000 times less potent than (R;R)-f ormoterol. For both enantiomers of formoterol, about tenfold higher co ncentration was required to obtain the same degree of inhibition when given intratracheally as compared with administration in the external medium. There was no indication in any of the experimental approaches that (S;S)-formoterol or (S)-terbutaline might enhance the response to cholinergic or NANC-related stimuli. (C) 1997 Wiley-Liss, Inc.