Pharmacological characterisation of the β-adrenoceptor expressed by human lung mast cells

Abstract

The nonselective β-adrenoceptor agonist, isoprenaline (p D 2; 8.8±0.2), and selective β 2-adrenoceptor agonists, clenbuterol (9.2±0.4) and salbutamol (7.1±0.1), inhibited the immunoglobulin E-mediated release of histamine from human lung mast cells in a concentration-dependent manner. The β 2-adrenoceptor-selective antagonist, ICI118551 (erythro-(±)-1-(7-methylindan-4-yloyl)-3-isopropylaminobutan-2-ol HCl), antagonised the isoprenaline inhibition of histamine release from human lung mast cells with high affinity (apparent p K B; 9.5±0.2), whereas high concentrations of the β 1-adrenoceptor-selective antagonist, CGP20712A (2-hydroxy-5-(2-(hydroxy-3-(4((1-methyl-4-trifluoromethyl)-1- H-imidazol-2-yl)-phenoxy)-propyl)-aminoethoxyl)-benzamide), were required to reverse the isoprenaline inhibition (apparent p K B; 6.5±0.3). Radioligand binding studies using [ 125I]-iodocyanopindolol ([ 125I]CYP) were performed on membranes derived from purified mast cells (>90% purity). Binding of [ 125I]CYP to mast cell membranes was displaced from a single binding site with a high affinity for ICI118551 (p K i; 8.9±0.1) and low affinity for CGP20712A (p K i; 6.0±0.03), indicative of a homogeneous population of β 2-adrenoceptors. In contrast, in human lung membranes, these antagonists displaced [ 125I]CYP from two sites indicative of a heterogeneous population of β 1-adrenoceptors (20%) and β 2-adrenoceptors (80%). These data indicate that the β-adrenoceptor expressed by human lung mast cells and mediating inhibition of mediator release from these cells is the β 2-adrenoceptor.