Studies in vivo and in vitro of terbutaline-induced β-adrenoceptor desensitization in healthy subjects

1. β-Adrenoceptor function was studied in eight healthy subjects before, during and 24 and 72 h after cessation of 2 weeks continuous oral treatment with the β₂-adrenoceptor agonist terbutaline (sustained release, 7.5 mg twice daily). In vivo, blood pressure, heart rate, plasma noradrenaline and plasma cyclic AMP responses to isoprenaline (0.01, 0.02 and 0.05 μg min⁻¹ kg⁻¹ intravenously) were related to the plasma concentrations of isoprenaline. For comparison, β₂-adrenoceptor function was evaluated in lymphocytes in vitro by studies of isoprenaline-induced accumulation of cyclic AMP and radioligand binding studies using ¹²⁵I-iodohydroxybenzylpindolol.

2. In vivo, the β₂-mediated plasma cyclic AMP response to isoprenaline was markedly attenuated during terbutaline treatment and was still reduced by 38% (P < 0.05) 72h. after discontinuation of treatment. The blood pressure and heart rate responses to isoprenaline were unaffected by treatment. Isoprenaline-induced elevations of plasma noradrenaline concentrations were markedly reduced during terbutaline treatment. This indicates an attenuation of isoprenaline-induced increases in sympathetic nerve function and could explain why no attenuation of the isoprenaline-induced vasodilatation was observed. Thus, plasma cyclic AMP seems to be a better marker than diastolic blood pressure when evaluating β₂-adrenoceptor responsiveness in vivo in man, since it is not influenced by counter-regulatory increases in sympathetic nerve activity and/or noradrenaline overflow from sympathetic nerves.

3. In lymphocytes, the isoprenaline-stimulated cyclic AMP accumulation was reduced by 75% and the β-adrenoceptor binding sites were reduced by 40% 12 h after dosing. Also the lymphocyte β₂-adrenoceptors recovered slowly after withdrawal of treatment. Normal responsiveness was not restored within 72 h after the last dose of terbutaline.

4. Thus, we obtained evidence in vivo and in vitro showing a markedly attenuated β₂-adrenoceptor function, which persisted at least 72 h after discontinuation of terbutaline treatment. The slow rate of resensitization of β₂-adrenoceptors after withdrawal may have practical implications in the treatment of, for example, asthma, since a state of ‘physiological β₂-adrenoceptor blockade’ seems to be produced by β₂-agonist treatment.