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 induce airway hyperreactivity. Tracheal strip preparations were contracted with carbachol. Both rac- and (R;R)-formoterol (2 and 1 mumol/l, respectively) produced an immediate relaxation, followed by a slow recovery of tone. (S;S)-Formoterol (2 mumol/l) had no effect on smooth muscle tone. Similar results were obtained with the enantiomers of terbutaline. In other strip preparations of the trachea or the main bronchi, cholinergic or nonadrenergic/noncholinergic (NANC) excitatory responses were evoked by electrical field-stimulation. The eutomers, (R;R)-formoterol and (R)-terbutaline, inhibited concentration-dependently both cholinergic and NANC-induced contractions. The distomers, (S;S)-formoterol and (S)-terbutaline, showed qualitatively the same effects but were about 1,000 times less potent than the corresponding eutomer. In a third series of experiments, either enantiomer of formoterol was administered to an electrically stimulated vagus nerve-trachea tube preparation. The nerve-induced contractions were inhibited by both enantiomers, but (S;S)-formoterol was about 1,000 times less potent than (R;R)-formoterol. For both enantiomers of formoterol, about tenfold higher concentrations 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.
Källström
B L
BL
Department of Pharmacology, Preclinical R&D, Astra Draco AB, Lund, Sweden.
Sjöberg
J
J
Waldeck
B
B
D000318:Adrenergic beta-Agonists / Q000009:adverse effects*; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000502:physiology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced*; D002217:Carbachol / Q000494:pharmacology; D002794:Choline / Q000494:pharmacology; D004558:Electric Stimulation; D004848:Epithelium / Q000502:physiology; D004983:Ethanolamines / Q000009:adverse effects*; D000068759:Formoterol Fumarate; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013726:Terbutaline / Q000009:adverse effects*; D014132:Trachea / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D002217:Carbachol; D013726:Terbutaline; D002794:Choline; D000068759:Formoterol Fumarate