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.
D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000328:Adult; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001999:Bronchoscopy; D004847:Epithelial Cells; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009921:Metaproterenol / Q000008:administration & dosage / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D012016:Reference Values
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D009921:Metaproterenol