There is evidence that downregulation and desensitization of airway beta 2-adrenoceptors (beta 2-AR) develops after continuous exposure to long-acting beta 2-agonists such as
formoterol and
salmeterol. To investigate the facilitatory effects of acute administration of systemic
corticosteroid on
bronchodilator subsensitivity, as might occur in the setting of acute
asthma, 12 subjects with moderately severe
asthma, with a mean FEV1 of 66% predicted, of whom were all receiving inhaled corticosteriod, were randomized to receive either inhaled placebo (PL) or inhaled
formoterol (
FM) 24 micrograms twice daily for 4 wk in a double-blind crossover study. Subjects were also genotyped in terms of beta 2-Ar polymorphism at loci 16 and 27. A dose-response curve (DRC) and duration-time profile for FM (12 to 108 micrograms) was produced 1 h after administration of placebo
tablets and after injection at 3 wk, and 1 h after administration of oral
prednisolone, 50 mg, and intravenous
hydrocortisone, 200 mg, at 4 wk. Comparisons between treatments were made with area-under-curve (AUC) measurements as the change from baseline. There was a significant rightward shift in the DRC after FM as opposed to placebo for delta FEV1 (as AUC, L.h): 2.51 versus 4.22 (95% CI: 0.54 to 2.89; p = 0.01) and delta FEF25-75 (as AUC, L x 10(3)): 11.30 versus 19.94 (95% CI: 2.12 to 15.12; p = 0.01). This was significantly reversed by
steroid (S) for FEV1 (FM versus FM+5): 2.51 versus 3.57 (95% CI: 0.11 to 2.27; p = 0.03) and for FEF25-75: 11.30 versus 18.47 (95% CI: 2.52 to 11.70; p = 0.005). Lymphocyte beta 2-AR density (log Bmax; fmol/10(6) cells) showed significant upregulation 3 h after
steroid (FM+5 versus FM): 0.34 versus 0.24 (95% CI: 0.02 to 0.18; p = 0.01). For heart-rate response (as AUC, beats), there was subsensitivity with FM versus PL: 2,700 versus 5,200 (95% CI: 40 to 5,000; p < 0.001), and this was reversed by
steroid (FM+5 versus FM): 9,600 versus 2,700 (95% CI: 4,900 to 8,800; p < 0.001). This reversal by systemic
corticosteroid appears to be generally independent of beta 2-AR polymorphism at loci 16 and 27. In conclusion, we have demonstrated that
bronchodilator subsensitivity occurs after regular inhaled FM in asthmatic patients, and is rapidly reversed by systemic
corticosteroid. Thus, in acute
asthma, systemic
corticosteroid should be administered a soon as possible, in order to restore normal airway beta 2-AR sensitivity, particularly in patients who are receiving regular long-acting beta 2-agonists.