Terbutaline-induced desensitization of human lymphocyte β2-adrenoceptors. Accelerated restoration of β-adrenoceptor responsiveness by prednisone and ketotifen

Abstract

We investigated, in 36 healthy volunteers, the effects of prednisone and ketotifen on recovery of lymphocyte β2-adrenoceptor density (determined by (-)-125iodocyanopindolol binding) and responsiveness (assessed by lymphocyte cyclic AMP [cAMP] responses to 10 μM (-)-isoprenaline) after desensitization by the β2-agonist terbutaline. Terbutaline (3 x 5 mg/d) decreased lymphocyte β2-adrenoceptor density by ~40-50%; concomitantly, lymphocyte cAMP responses to 10 μM (-)-isoprenaline were significantly reduced. After withdrawal of terbutaline β2-adrenoceptor, density and responsiveness gradually increased, reaching predrug levels after 4 d. Prednisone (1 x 100 mg orally) accelerated β2-adrenoceptor recovery; only 8-10 h after administration of the steroid β2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached values not significantly different from pretreatment levels. Similar effects were obtained with ketotifen (2 mg; thereafter 2 x 1 mg/d for 4 d): 24 h after application of the drug β2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached pretreatment levels. Furthermore, ketotifen simultaneously applied with terbutaline completely prevented terbutaline-induced decrease in lymphocyte β2-adrenoceptor density and responsiveness. Prednisone (1 x 100 mg orally) or ketotifen (2 mg; thereafter 2 x 1 mg/d for 2 d) had no significant influence on lymphocyte β2-adrenoceptor density in healthy volunteers not pretreated with terbutaline, but shifted the ratio high-to-low affinity state of the lymphocyte β2-adrenoceptor toward high affinity state. We conclude that glucocorticoids as well as ketotifen can accelerate recovery of density and responsiveness of lymphocyte β2-adrenoceptors desensitized by long-term treatment with β2-agonists. Such an effect may have clinical implications for preventing tachyphylaxis of asthmatic patients against therapy with β2-agonists.