A comparison of β ₂ -adrenoceptor desensitisation induced by olodaterol and formoterol in human lung mast cells and airway smooth muscle cells

Background: The novel ultra-long-acting β 2 -adrenoceptor agonist olodaterol has been developed for the management of asthma and COPD. Aims and Objectives: To compare the effects of olodaterol with formoterol and salbutamol on FcεRI-dependent human lung mast cell (HLMC) histamine release, and on β 2 -adrenoceptor (β 2 -AR) desensitisation in HLMCs, the HMC-1 human mast cell line and human airway smooth muscle (ASM) cells. Experimental Approach: FcεRI-dependent histamine release was measured using a radioenzymatic assay. β 2 -AR desensitisation was measured by vasodilator-stimulated phosphoprotein (VASP) phosphorylation (HMC-1 and ASM) and histamine release (HLMCs). Key Results: Olodaterol and formoterol inhibited FcεRI-dependent HLMC histamine release (IC 50 : 6.7 x 10 -11 M and 6.9 x 10 -11 M, respectively). Olodaterol was more potent than formoterol at inducing VASP phosphorylation in HMC-1 cells (EC 50 : 8.1 x 10 -11 M and 4.2 x 10 -10 M, respectively) (p<0.001). Olodaterol was more potent than formoterol at inducing VASP phosphorylation in ASM cells (EC 50 : 8.3 x 10 -10 M and 1.6 x 10 -8 M, respectively) (p<0.04). Long-term (24 h) incubation with all β 2 -agonists induced mast cell β 2 -AR desensitisation. At their EC 50 concentrations, formoterol induced ASM β 2 -AR desensitisation (p<0.001) but olodaterol did not (p<0.05 compared to formoterol). Conclusions and Implications: Olodaterol is a potent, effective inhibitor of FcεRI-dependent HLMC mediator release, with a less pronounced desensitisation in ASM cells compared to formoterol at moderate doses.