Beta-adrenoceptor agonists interfere with glucocorticoid receptor DNA binding in rat lung.
Inhaled beta 2-adrenoceptor agonists are the most effective bronchodilator treatment in asthma, yet paradoxically high doses may be associated with increased asthma morbidity and mortality. Steroids are the most effective therapy in controlling asthmatic inflammation and act by binding to specific sequences of DNA (GRE), thus modulating gene transcription. We report that in rat lung, the beta 2-adrenoceptor agonists, salbutamol and fenoterol, decrease the binding of glucocorticoid receptors to GRE, by 46 +/- 4% although it has no effect on the affinity or number of glucocorticoid receptors. The inhibition of GRE binding by salbutamol is concentration-dependent, can be blocked by propranolol and is seen following forskolin treatment. This effect appears to be due to an interaction between the glucocorticoid receptor and the transcription factor, cAMP response element binding protein (CREB), which is activated by high concentrations of beta 2-adrenoceptor agonists. We suggest that by this mechanism high doses of inhaled beta 2-adrenoceptor agonists may inhibit the anti-inflammatory effects of endogenous glucocorticoids and exogenous corticosteroids used for asthma therapy.
Peters
M J
MJ
Department of Thoracic Medicine, National Heart and Lung Institute, London, UK.
Adcock
I M
IM
Brown
C R
CR
Barnes
P J
PJ
D000420:Albuterol / Q000494:pharmacology; D000818:Animals; D001345:Autoradiography; D001667:Binding, Competitive; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005280:Fenoterol / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000819:agonists* / Q000187:drug effects*; D013997:Time Factors
D011965:Receptors, Glucocorticoid; D005280:Fenoterol; D003907:Dexamethasone; D004247:DNA; D000242:Cyclic AMP; D000420:Albuterol