The duration of action of non-beta 2-adrenoceptor mediated responses to salmeterol

1. To investigate further the mechanism of the long duration of action of the selective beta 2-adrenoceptor agonist, salmeterol, we have determined the duration of action of some responses to salmeterol which are not mediated through beta 2-adrenoceptors. 2. In the presence of propranolol (1 microM), salmeterol (1-30 microM) caused concentration-related relaxation of superfused, pre-contracted strips of guinea-pig gastric fundus. On washing the tissues, these relaxant responses were rapidly lost, the time to 50% recovery being approximately 30 min. 3. In human neutrophils, salmeterol (1-100 microM) caused concentration-related inhibition of FMLP-induced O2- release. Propranolol (1 microM) had little or no effect on the inhibitory activity of salmeterol. Washing the cells twice over a 40 min period caused a marked reduction of the inhibitory activity of salmeterol. 4. In guinea-pig superfused trachea, in the absence of propranolol, infusions of (RS)-salmeterol (10-30 nM) and the less potent (S)-enantiomer of salmeterol (300-3000 nM) inhibited electrically-induced contractile responses. When the infusion was stopped, there was no recovery from the inhibitory responses within 200 min. In the presence of propranolol (1 microM), infusions of (RS)-salmeterol (10 microM) and (S)-salmeterol (10-100 microM) also inhibited the contractile responses, but, in contrast, on stopping the infusions differences were observed in recovery times. Thus no appreciable recovery was observed from the responses to (RS)-salmeterol, whereas a rapid loss of inhibition was observed on stopping the infusion of (S)-salmeterol, the time to 50% recovery being 30-35 min. 5. These relatively short-lasting effects of salmeterol which are not mediated through beta 2-adrenoceptors, contrast with the persistence of the responses which are mediated through beta 2-adrenoceptors seen in a variety of tissues, but are similar to the rate of dissociation of salmeterol observed from artificial membranes. These observations suggest that the sustained agonist activity of salmeterol is peculiar to responses mediated by beta 2-adrenoceptors.