Influence of agonist intrinsic activity on the desensitisation of β 2-adrenoceptor-mediated responses in mast cells

1 The aim of the present study was to determine whether the intrinsic activity of an agonist influences the extent of desensitisation of β ₂-adrenoceptor-mediated responses in human lung mast cells. 2 The effects of a wide range of β-adrenoceptor agonists (10 ^-10-10 ^-5 M) on the IgE-mediated release of histamine from mast cells were determined. The intrinsic activity of agonists was established by comparing the maximal inhibitory response (E _max) of an agonist relative to the maximal response obtained with the full agonist, isoprenaline. The intrinsic activity order for the inhibition of histamine release was isoprenaline (1.0) > formoterol (0.94) > fenoterol (0.89) > terbutaline (0.84) > salbutamol (0.69) > clenbuterol (0.65) > salmeterol (0.30) > dobutamine (0.20). 3 There was a significant (P < 0.05) positive correlation (r = 0.81) between the extent to which β-adrenoceptor agonists inhibited histamine release and the degree to which the agonists caused elevations in cAMP in mast cells. 4 Further studies investigated the effects of long-term (24 h) incubation of mast cells with β-adrenoceptor agonists on the subsequent ability of isoprenaline to inhibit histamine release. At concentrations of agonists selected to occupy a large percentage (88%) of β ₂-adrenoceptors, there was a significant (P < 0.05) correlation (r = 0.73) between the relative intrinsic activity of agonists as inhibitors of histamine release and the extent of functional desensitisation induced by the agonists. At lower receptor occupancies, however, there was no correlation between the relative intrinsic activity of agonists and the extent of agonist-induced desensitisation. 5 These data indicate that, under experimental conditions where high receptor occupancies prevail, agonist intrinsic activity influences the extent of desensitisation of β ₂-adrenoceptor-mediated responses in mast cells.