EFFECTS OF BETA(2)-AGONIST-TREATMENT AND DEXAMETHASONE-TREATMENT ON RELAXATION AND REGULATION OF BETA-ADRENOCEPTORS IN HUMAN BRONCHI AND LUNG-TISSUE

1 Long-term treatment with beta(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 beta-adrenoceptor desensitization, human bronchial muscle r elaxation was studied in isolated bronchial rings after pretreatment w ith beta(2)-adrenoceptor agonists. Additionally, the influence of pret reatment with dexamethasone on desensitization was studied. 2 The effe ct of beta(2)-agonist incubation alone and after coincubation with dex amethasone on density and affinity of beta-adrenoceptors was investiga ted by radioligand binding experiments. 3 In human isolated bronchi, i soprenaline induces a time-and concentration-dependent beta-adrenocept or desensitization as judged from maximal reduction in potency by a fa ctor of 7 and reduction of 73 +/- 4% in efficacy of isoprenaline to re lax human bronchial smooth muscle. 4 After an incubation period of 60 min with 100 mu mol l(-1) terbutaline, a significant decline in its re laxing efficacy (81 +/- 8%) and potency (by a factor 5.5) occurred. 5 Incubation with 30 mu mol 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 w ith isoprenaline (120 min; 30 mu mol l(-1)) preserved the effect of is oprenaline on relaxation (129 +/- 15%). 7 In radioligand binding exper iments, pretreatment of lung tissue for 60 min with isoprenaline (30 m u mol l(-1)) resulted in a decrease in beta-adrenoceptor binding sites (B-max) to 64 +/- 1.6% (P < 0.05), while the antagonist affinity (K-D ) for [H-3]-CGP-12177 remained unchanged. 8 In contrast, radioligand b inding studies on lung tissue pretreated with either dexamethasone (30 mu mol l(-1)) or isoprenaline (30 mu mol l(-1)) plus dexamethasone (3 0 mu mol 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 n mol l(-1)) compared to the controls. 9 In conclusion, pretreatment of human bronchi with beta-adrenoceptor agonists leads to functional dese nsitization and, in lung tissue, to down-regulation of beta-adrenocept ors. This effect can be counteracted by additional administration of d examethasone. Our model of desensitization has proved useful for the i dentification of mechanisms of beta-adrenoceptor desensitization and c ould be relevant for the evaluation of therapeutic strategies to count eract undesirable effects of long-term beta-adrenoceptor stimulation.