Abstract
Long-term treatment with β2-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.
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.
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.
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.
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).
Coincubation of dexamethasone with isoprenaline (120 min; 30 μmol l−1) preserved the effect of isoprenaline on relaxation (129±15%).
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 (Bmax) to 64±1.6% (P<0.05), while the antagonist affinity (KD) for [3H]-CGP-12177 remained unchanged.
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 Bmax (160±22.1% vs 142.3±28.7%) or KD (5.0 nmol l−1 vs 3.5 nmol l−1) compared to the controls.
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.
Keywords: Human bronchi; human lung parenchyma; β-adrenoceptor agonist; corticosteroid; isoprenaline, dexamethasone; aminophylline; desensitization; down-regulation; asthma
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