Molecular mechanisms for the persistent bronchodilatory effect of the β2-adrenoceptor agonist salmeterol


Georges Vauquelin, Department of Molecular and Biochemical Pharmacology, Free University of Brussels (VUB), Building E.5.10, Pleinlaan 2, B-1050 Brussel, Belgium. E-mail:


Background:  β2-adrenoceptor agonists are effective bronchodilators. In vitro studies demonstrated long-lasting airway smooth muscle relaxation by salmeterol after washout, the quick disappearance of this effect in presence of antagonists and its recovery after antagonist removal. Current explanations invoke salmeterol accumulation in the membrane (‘diffusion microkinetic’ model) or the existence of salmeterol-binding ‘exosites’. An alternative model based on ‘rebinding’ of a dissociated ligand to the receptor molecules also produces an apparent decrease in the ligand's dissociation rate in the absence of competing ligands.

Purpose and approach:  Computer-assisted simulations were performed to follow the receptor-occupation by a salmeterol-like ligand and a competing ligand as a function of time. The aptness of the models to describe the above in vitro findings was evaluated.

Key results:  The ‘diffusion microkinetic’ model is sufficient to explain a long-lasting β2-adrenoceptor stimulation and reassertion as long as the membrane harbors a high concentration of the agonist. At lower concentration, ‘rebinding’ and, in second place, ‘exosite’ binding are likely to become operational.

Conclusions and implications:  The ‘rebinding’ and ‘exosite’ binding mechanisms take place at a sub-cellular/molecular scale. Pending their demonstration by experiments on appropriate, simple models such as intact cells or membranes thereof, these mechanisms remain hypothetical in the case of salmeterol. Airway smooth muscle contraction could also be governed by additional mechanisms that are particular to this macroscopic approach.