Effects of β 2 ‐agonist‐ and dexamethasone‐treatment on relaxation and regulation of β ‐adrenoceptors in human bronchi and lung tissue

1 Long‐term treatment with β 2 ‐adrenoceptor agonists can lead to a decreased therapeutic efficacy of bronchodilatation in patients with obstructive pulmonary disease. In order to examine whether or not this is due to β‐adrenoceptor desensitization, human bronchial muscle relaxation was studied in isolated bronchial rings after pretreatment with β 2 ‐adrenoceptor agonists. Additionally, the influence of pretreatment with dexamethasone on desensitization was studied. 2 The effect of β 2 ‐agonist incubation alone and after coincubation with dexamethasone on density and affinity of β‐adrenoceptors was investigated by radioligand binding experiments. 3 In human isolated bronchi, isoprenaline induces a time‐ and concentration‐dependent β‐adrenoceptor desensitization as judged from maximal reduction in potency by a factor of 7 and reduction of 73±4% in efficacy of isoprenaline to relax human bronchial smooth muscle. 4 After an incubation period of 60 min with 100 μmol l −1 terbutaline, a significant decline in its relaxing efficacy (81±8%) and potency (by a factor 5.5) occurred. 5 Incubation with 30 μmol l −1 isoprenaline for 60 min did not impair the maximal effect of a subsequent aminophylline response but led to an increase in potency (factor 4.4). 6 Coincubation of dexamethasone with isoprenaline (120 min; 30 μmol l −1 ) preserved the effect of isoprenaline on relaxation (129±15%). 7 In radioligand binding experiments, pretreatment of lung tissue for 60 min with isoprenaline (30 μmol l −1 ) resulted in a decrease in β‐adrenoceptor binding sites (B max ) to 64±1.6% ( P <0.05), while the antagonist affinity ( K D ) for [ 3 H]‐CGP‐12177 remained unchanged. 8 In contrast, radioligand binding studies on lung tissue pretreated with either dexamethasone (30 μmol l −1 ) or isoprenaline (30 μmol l −1 ) plus dexamethasone (30 μmol l −1 ) for 120 min did not lead to a significant change of B max (160±22.1% vs 142.3±28.7%) or K D (5.0 nmol l −1 vs 3.5 nmol l −1 ) compared to the controls. 9 In conclusion, pretreatment of human bronchi with β‐adrenoceptor agonists leads to functional desensitization and, in lung tissue, to down‐regulation of β‐adrenoceptors. This effect can be counteracted by additional administration of dexamethasone. Our model of desensitization has proved useful for the identification of mechanisms of β‐adrenoceptor desensitization and could be relevant for the evaluation of therapeutic strategies to counteract undesirable effects of long‐term β‐adrenoceptor stimulation.British Journal of Pharmacology (1997) 121 , 1523–1530; doi: 10.1038/sj.bjp.0701289