The reassertion profiles of long acting β2-adrenoceptor agonists in the guinea pig isolated trachea and human recombinant β2-adrenoceptor.
Long acting β(2)-adrenoceptor agonists as exemplified by salmeterol and formoterol, exhibit reassertion behaviour in isolated airway preparations. This phenomenon is the inhibition of relaxation by a β(2)-antagonist (e.g. sotalol), followed by the re-establishment of the relaxation when all drugs have been washed out and in the absence of any further agonist addition to the bathing solution. In this study we have compared the reassertion behaviour of salmeterol and formoterol with the new long acting β(2)-adrenoceptor agonists indacaterol, carmoterol and three Pfizer agonists (PF610,355, PF613,322, UK503590) in the guinea pig isolated trachea and in a novel assay developed in CHO cells expressing the recombinant human β(2)-adrenoceptor. The results obtained can be divided into two groups: salmeterol-like (persistent duration of action following agonist removal--coupled with reassertion behaviour), as exemplified by indacaterol, PF610,355, PF613,322 and UK503,590 and, formoterol-like (short duration of agonist action and little reassertion behaviour unless supramaximal concentrations are used), as exemplified by carmoterol. Results are discussed in the context of the two theories proposed to explain the long duration of action of salmeterol (binding to a specific 'exosite' of the β(2)-adrenoceptor) and formoterol (membrane deposition: micro-kinetic theory). Our data suggest that the micro-kinetic theory is an adequate explanation to explain the long duration of action of the β(2)-adrenoceptor agonists studied in these two assays, although with the current data set we cannot definitively exclude the 'exosite' theory.
Allergy and Respiratory Biology, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK. sheena.patel@pfizer.com
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Patel
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Summerhill
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Stanley
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Perros-Huguet
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Trevethick
D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D011485:Protein Binding; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000378:metabolism; D000068299:Salmeterol Xinafoate; D013997:Time Factors; D014132:Trachea / Q000187:drug effects*
D058666:Adrenergic beta-2 Receptor Agonists; D001993:Bronchodilator Agents; D004983:Ethanolamines; D018343:Receptors, Adrenergic, beta-2; D000068299:Salmeterol Xinafoate; D000420:Albuterol; D000068759:Formoterol Fumarate