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Salmeterol, a long‐acting β 2 ‐adrenoceptor agonist mediating cyclic AMP accumulation in a neuronal cell line
Author(s) -
McCrea Karen E.,
Hill Stephen J.
Publication year - 1993
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1993.tb13856.x
Subject(s) - isoprenaline , agonist , salmeterol , chemistry , endocrinology , medicine , partial agonist , intracellular , antagonist , atenolol , pharmacology , receptor , biology , biochemistry , stimulation , asthma , blood pressure
1 The accumulation of cyclic AMP stimulated by salmeterol, a long‐acting β 2 ‐adrenoceptor agonist and by isoprenaline, a non‐selective β‐adrenoceptor agonist have been compared in the B50 neuroblastoma cell line. 2 Salmeterol produced a concentration‐dependent increase in the accumulation of total [ 3 H]‐cyclic AMP in B50 cells yielding an EC 50 value of 37 n m which was lower than that obtained with isoprenaline (294 n m ). The maximum response to salmeterol was only 46% of that obtained with isoprenaline. 3 The β 2 ‐adrenoceptor antagonist, ICI 118551, inhibited the responses to both salmeterol (apparent K D 2.2 n m ) and isoprenaline (apparent K D 1.6 n m ). However, the β 1 ‐adrenoceptor antagonist, atenolol, produced no significant effect at concentrations up to 100 μ m . 4 Salmeterol (1 μ m ) changed the concentration‐response curve of isoprenaline in the manner of a partial agonist interacting with a full agonist. The K D of salmeterol obtained from the interaction was 55.6 n m . 5 Whereas salmeterol has a slow onset of action in airway smooth muscle compared to other β 2 ‐adrenoceptor agonists, in B50 monolayers both salmeterol and isoprenaline produced a rapid increase in cyclic AMP accumulation ( t 1/2 1.1 min and 0.4 min respectively). 6 Despite the existence of cyclic AMP efflux mechanisms that exist in this cell line it was possible to investigate the duration of agonist action by measuring intracellular levels of the second messenger. Replacement of drug‐containing medium with fresh buffer led to a rapid reduction in intracellular levels of cyclic AMP in isoprenaline‐stimulated cells whereas cyclic AMP accumulation was sustained for much longer periods in salmeterol‐stimulated cells. However, the persistent action of salmeterol could be reversed by the addition of a β 2 ‐selective antagonist. 7 These results confirm that salmeterol has a high affinity, but low efficacy (relative to isoprenaline) for β 2 ‐adrenoceptors coupled to cyclic AMP accumulation and that the drug persists at its site of action for long periods in the B50 neuronal cell line.