Salmeterol inhibition of mediator release from human lung mast cells by β-adrenoceptor-dependent and independent mechanisms

1 The long-acting beta(2)-adrenoceptor agonist, salmeterol (10(-9)-10(-5) M), inhibited the IgE-mediated release of histamine from human lung mast cells (HLMC) in a dose-dependent fashion. Additional beta-adrenoceptor agonists were studied and the rank order of potency for the inhibition of histamine release from HLMC was isoprenaline > salmeterol > salbutamol. Approximate EC50 values for the inhibition of histamine release were 10 nM for isoprenaline and 100 nM for salbutamol. An EC50 value for salmeterol could not be calculated because maximal responses to salmeterol were not observed over the concentration range employed. 2 Both salmeterol and isoprenaline inhibited the generation of sulphopeptidoleukotrienes (sLT) more potently and more efficaciously than the release of histamine from immunologically-activated HLMC. Salmeterol (EC50<0.1 nM) was more potent than isoprenaline (EC50 0.4 nM) at attenuating sLT generation. 3 The beta-adrenoceptor antagonist, propranolol (1 mu M), and the selective beta(2)-adrenoceptor antagonist, ICI 118,551 (0.1 mu M), both caused rightward shifts in the dose-response curve for the inhibition of histamine release by isoprenaline. The antagonism of salmeterol effects by propranolol and ICI 118,551 was more complex. At lower concentrations (<1 mu M) of salmeterol, both antagonists shifted the dose-response curve to salmeterol rightward. At a higher concentration (10 mu M) of salmeterol, neither ICI 118,551 nor propranolol was an effective antagonist of the salmeterol-mediated inhibition of histamine release. 4 Prolonged exposure (4 h) of HLMC to isoprenaline (1 mu M) caused an approximately 50% reduction in the effectiveness of a second exposure to isoprenaline (10 mu M) at inhibiting the release of histamine, whereas this pretreatment did not affect the salmeterol (10 mu M) inhibition of histamine release. 5 Isoprenaline (10(-9)-10(-5) M) caused a dose-dependent increase in total cell cyclicAMP levels in purified HLMC which paralleled the inhibition of histamine release. Salmeterol (10(-9)-10(-5) M) was considerably less potent than isoprenaline at increasing HLMC cyclicAMP levels. 6 In summary, these data indicate that salmeterol is an effective inhibitor of the stimulated release of mediators from HLMC. The present data also suggest that salmeterol may act to inhibit mediator release from HLMC by beta-adrenoceptor-dependent and independent mechanisms.