The long-acting β-adrenoceptor agonist, indacaterol, inhibits IgE-dependent responses of human lung mast cells

Background and purpose: The long-acting beta(2)-adrenoceptor agonist, indacaterol, has been developed as a bronchodilator for the therapeutic management of respiratory diseases. The aim of the present study was to determine whether indacaterol has any anti-inflammatory activity. To this end, the effects of indacaterol on human lung mast cell responses were investigated. Experimental approach: The effects of indacaterol, and the alternative long-acting beta-agonists formoterol and salmeterol, were investigated on the IgE-dependent release and generation of histamine, cysteinyl-leukotrienes and prostaglandin D-2 from human lung mast cells. Moreover, the extent to which long-term (24-72 h) incubation of mast cells with long-acting beta-agonists impaired the subsequent ability of beta-agonists to inhibit mast cell responses was assessed. Key results: Indacaterol was as potent and as efficacious as the full agonist, isoprenaline (EC50, similar to 4 nmol.L-1), at inhibiting the IgE-dependent release of histamine from mast cells. Formoterol was a full agonist whereas salmeterol was a partial agonist as inhibitors of histamine release. All three long-acting beta-agonists were effective inhibitors of the IgE-dependent generation of cysteinyl-leukotrienes and prostaglandin D-2. Long-term incubation of mast cells with long-acting beta-agonists led to a reduction in the subsequent ability of beta-agonists to stabilize mast cell responses. This tendency to induce functional desensitization was least evident for indacaterol. Conclusions and implications: Indacaterol is an effective inhibitor of the release of mediators from human lung mast cells. This suggests that, as well as bronchodilation, mast cell stabilization may constitute an additional therapeutic benefit of indacaterol. British Journal of Pharmacology (2009) 158, 267-276; doi: 10.1111/j.1476-5381.2009.00178.x; published online 9 April 2009