The reassertion profiles of long acting β2-adrenoceptor agonists in the guinea pig isolated trachea and human recombinant β2-adrenoceptor

Long acting β2-adrenoceptor agonists as exemplified by salmeterol and formoterol, exhibit reassertion behaviour in isolated airway preparations. This phenomenon is the inhibition of relaxation by a β2-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 β2-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 β2-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 β2-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 β2-adrenoceptor agonists studied in these two assays, although with the current data set we cannot definitively exclude the ‘exosite’ theory.