Effects of β2-agonist- and dexamethasone-treatment on relaxation and regulation of β-adrenoceptors in human bronchi and lung tissue

Abstract

1. Long-term treatment with B2-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 β2-adrenoceptor agonists. Additionally, the influence of pretreatment with dexamethasone on desensitization was studied. 2. The effect of β2-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 1-1 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 [3H]-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 1-1) 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.