Am. J. Respir. Cell Mol. Biol., Vol 13, No. 5, Nov 1995, 540-546.
Functional desensitization of beta agonist responses in human lung mast cells
LK Chong, AH Morice, WW Yeo, RP Schleimer and PT Peachell
Department of Medicine and Pharmacology, University of Sheffield, Royal Hallamshire Hospital, United Kingdom.
The beta adrenergic agonist isoprenaline inhibited the IgE-triggered
release of the preformed mediator histamine from human lung mast cells
(HLMC) in a dose-dependent fashion. After prolonged (> or = 4 h)
preexposure of HLMC to isoprenaline, there was a subsequent diminution in
the effectiveness of a second exposure of isoprenaline to inhibit the
release of histamine from activated HLMC. This induced hyporesponsiveness
to isoprenaline was both concentration and time dependent. Although maximal
levels of desensitization were obtained after an initial prolonged (14-h)
preincubation with a high (10(-5) M) concentration of isoprenaline,
exposure of HLMC for a shorter (4-h) time period with a lower (3 x 10(-7)
M) concentration of isoprenaline was also effective at inducing a
functional desensitization to isoprenaline. The inhibitory activity of the
beta 2 agonist fenoterol was attenuated after a prolonged (14-h)
pretreatment step with isoprenaline (10(-5)M), whereas the inhibitory
properties of other adenylate cyclase activators, prostaglandin E2 and
forskolin, were not affected appreciably. Prolonged (12-h) exposure of HLMC
to the beta agonists fenoterol, salbutamol, and terbutaline also induced
hyporesponsive states of beta agonists, qualitatively similar to that
obtained with isoprenaline. The beta receptor antagonist propranolol, if
coincubated with isoprenaline during the prolonged pretreatment step,
protected against the subsequent refractoriness of the HLMC to
isoprenaline. The glucocorticoid dexamethasone failed to prevent the
isoprenaline-induced functional desensitization. In total, these results
indicate that prolonged exposure of HLMC to beta agonists induces a state
of selective hyporesponsiveness to agonists that act at beta
adrenoreceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
