Human lung cell beta 2-adrenergic receptors desensitize in response to in vivo administered beta-agonist

Few studies have addressed whether target tissue adrenergic receptors in humans undergo desensitization in response to agonist administration. To determine whether lung cell beta 2-adrenergic receptors (beta 2-AR) undergo such desensitization, we harvested bronchial epithelial cells and alveolar macrophages via bronchoscopy from eight normal subjects before and after inhalation of six doses of the beta-agonist metaproterenol given over 24 h. After metaproterenol inhalation, beta 2-AR expression as determined by 125I-labeled cyanopindolol binding decreased approximately 70% on bronchial epithelial cells, from 6.3 +/- 0.7 to 2.0 +/- 0.2 fmol/mg (P < 0.001) and to a similar extent on macrophages from 13.3 +/- 0.4 to 3.9 +/- 0.6 fmol/mg (P < 0.001). Agonist inhalation also resulted in impairment of beta 2-AR function in both cell types. With bronchial epithelial cells, maximal isoproterenol-stimulated adenosine 3',5'-cyclic monophosphate (cAMP) accumulation decreased from 9.5 +/- 1.8 to 4.9 +/- 1.2 pmol/10(6) cells (P = 0.003), which amounts to a 48 +/- 6% desensitization. Isoproterenol-stimulated cAMP accumulation in alveolar macrophages decreased from 39.5 +/- 9.0 to 2.9 +/- 0.3 pmol/10(6) cells (P = 0.007), equivalent to 86 +/- 5% desensitization. The cAMP response to forskolin in both cell types was unaffected by metaproterenol inhalation. Thus administration of inhaled beta-agonists results in substantial downregulation and functional desensitization of lung cell beta 2-AR. This supports the concept of a dynamically regulated beta 2-AR in humans, the function of which can be attenuated in relevant target tissues by administration of standard doses of beta-agonist.