THE DURATION OF ACTION OF NON-BETA(2)-ADRENOCEPTOR MEDIATED RESPONSESTO SALMETEROL

1 To investigate further the mechanism of the long duration of action of the selective beta(2)-adrenoceptor agonist, salmeterol, we have det ermined the duration of action of some responses to salmeterol which a re not mediated through beta(2)-adrenoceptors. 2 In the presence of pr opranolol (1 mu M), salmeterol (1-30 mu M) caused concentration-relate d relaxation of superfused, pre-contracted strips of guinea-pig gastri c fundus. On washing the tissues, these relaxant responses were rapidl y lost, the time to 50% recovery being approximately 30 min. 3 In huma n neutrophils, salmeterol (1-100 mu M) caused concentration-related in hibition of FMLP-induced O-2(-) release. Propranolol (1 mu M) had litt le or no effect on the inhibitory activity of salmeterol. Washing the cells twice over a 40 min period caused a marked reduction of the inhi bitory activity of salmeterol. 4 In guinea-pig superfused trachea, in the absence of propranolol, infusions of (RS)-salmeterol (10-30 nM) an d the less potent (S)-enantiomer of salmeterol (300-3000 nM) inhibited electrically-induced contractile responses. When the infusion was sto pped, there was no recovery from the inhibitory responses within 200 m in. In the presence of propranolol (1 mu M), infusions of (RS)-salmete rol (10 mu M) and (S)-salmeterol (10-100 mu M) also inhibited the cont ractile responses, but, in contrast, on stopping the infusions differe nces 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-la sting effects of salmeterol which are not mediated through beta(2)-adr enoceptors, contrast with the persistence of the responses which are m ediated through beta(2)-adrenoceptors seen in a variety of tissues, bu t are similar to the rate of dissociation of salmeterol observed from artificial membranes. These observations suggest that the sustained ag onist activity of salmeterol is peculiar to responses mediated by beta (2)-adrenoceptors.