<?xml version="1.0" encoding="UTF-8"?><xml><records><record><source-app name="Biblio" version="7.x">Drupal-Biblio</source-app><ref-type>17</ref-type><contributors><authors><author><style face="normal" font="default" size="100%">A Szczuka</style></author><author><style face="normal" font="default" size="100%">M Wennerberg</style></author><author><style face="normal" font="default" size="100%">Ann Packeu</style></author><author><style face="normal" font="default" size="100%">G Vauquelin</style></author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Molecular mechanisms for the persistent bronchodilatory effect of the beta 2-adrenoceptor agonist salmeterol.</style></title><secondary-title><style face="normal" font="default" size="100%">Br J Pharmacol</style></secondary-title></titles><keywords><keyword><style  face="normal" font="default" size="100%">Adrenergic beta-2 Receptor Agonists</style></keyword><keyword><style  face="normal" font="default" size="100%">Adrenergic beta-Agonists</style></keyword><keyword><style  face="normal" font="default" size="100%">Albuterol</style></keyword><keyword><style  face="normal" font="default" size="100%">Bronchodilator Agents</style></keyword><keyword><style  face="normal" font="default" size="100%">Cell Line</style></keyword><keyword><style  face="normal" font="default" size="100%">Humans</style></keyword><keyword><style  face="normal" font="default" size="100%">Models, Biological</style></keyword><keyword><style  face="normal" font="default" size="100%">Protein Binding</style></keyword><keyword><style  face="normal" font="default" size="100%">Receptor, Cannabinoid, CB1</style></keyword><keyword><style  face="normal" font="default" size="100%">Receptors, Adrenergic, beta-2</style></keyword><keyword><style  face="normal" font="default" size="100%">Salmeterol Xinafoate</style></keyword></keywords><dates><year><style  face="normal" font="default" size="100%">2009</style></year><pub-dates><date><style  face="normal" font="default" size="100%">2009 Sep</style></date></pub-dates></dates><volume><style face="normal" font="default" size="100%">158</style></volume><language><style face="normal" font="default" size="100%">eng</style></language><abstract><style face="normal" font="default" size="100%">&lt;p&gt;&lt;b&gt;BACKGROUND: &lt;/b&gt;Beta(2)-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.&lt;/p&gt;

&lt;p&gt;&lt;b&gt;KEY RESULTS: &lt;/b&gt;The 'diffusion microkinetic' model is sufficient to explain a long-lasting beta(2)-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.&lt;/p&gt;

&lt;p&gt;&lt;b&gt;CONCLUSIONS AND IMPLICATIONS: &lt;/b&gt;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.&lt;/p&gt;
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