Lung cell b2-adrenergic receptors desensitize in response to in
vivo administered b-agonist in humans.
Turki, Jamal, Stuart A. Green, Kenneth B. Newman, Melenie A. Meyers,
and Stephen B. Liggett.
Departments of Medicine (Pulmonary), Molecular Genetics, and
Pharmacology and the Asthma Center, University of Cincinnati College
of Medicine, Cincinnati, Ohio 45267
APStracts 2:0158L, 1995.
Few studies have addressed whether target tissue adrenergic receptors
undergo desensitization in response to agonist administration in
humans. To determine if lung cell b2AR undergo such desensitization,
we harvested bronchial epithelial cells and alveolar macrophages via
bronchoscopy from 8 normal subjects before and after inhalation of
six doses of the b-agonist metaproterenol given over 24 hours. After
metaproterenol inhalation, b2AR expression as determined by
[125I]cyanopindolol binding decreased 70% on bronchial epithelial
cells from 6.3 +/- 0.7 fmol/mg to 2.0 +/- 0.2 fmol/mg (p <
0.001), and to a similar extent on macrophages from 13.3 +/- 0.4
fmol/mg to 3.9 +/- 0.6 fmol/mg (p < 0.001). Agonist inhalation
also resulted in impairment of b2AR function in both cell types. With
bronchial epithelial cells, maximal isoproterenol stimulated cAMP
accumulation decreased from 9.5 +/- 1.8 pmol/106 cells to 4.9 +/- 1.2
pmol/106 cells (p = 0.003), which amounts to a 48 +/- 6%
desensitization. Isoproterenol stimulated cAMP accumulation in
alveolar macrophages decreased from 39.5 +/- 9.0 pmol/106 cells to
2.9 +/- 0.3 pmol/106 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 b-agonists results in substantial downregulation and
functional desensitization of lung cell b2AR. This supports the
concept of a dynamically regulated b2AR in humans whose function can
be attenuated in relevant target tissues by administration of
standard doses of b-agonist.
Received 5 June 1995; accepted in final form 24 August 1995.
APS Manuscript Number L173-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 September 1995.