Terbutaline-induced desensitization of human lymphocyte beta 2-adrenoceptors. Accelerated restoration of beta-adrenoceptor responsiveness by prednisone and ketotifen.

Abstract

We investigated, in 36 healthy volunteers, the effects of prednisone and ketotifen on recovery of lymphocyte j2-adrenoceptor density (determined by (-)-'"iodocyanopindolol binding) and responsiveness (assessed by lymphocyte cyclic AMP IcAMPI responses to 10 AtM (-)-isoprenaline) after desensitization by the p2-agonist terbutaline. Terbutaline (3 X 5 mg/d) decreased lymphocyte #2-adrenoceptor density by -40-50%; concomitantly, lymphocyte cAMP responses to 10 ,gM (-)-isoprenaline were significantly reduced. After withdrawal of terbutaline 2-adrenoceptor, density and responsiveness gradually increased, reaching predrug levels after 4 d.Prednisone (1 X 100 mg orally) accelerated ,f2-adrenoceptor recovery; only 8-10 h after administration of the steroid ,62-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 (32-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached pretreatment levels. Furthermore, ketotifen simultaneously applied with terbutaline completely prevented terbutaline-induced decrease in lymphocyte i2-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 #2-adrenoceptor density in healthy volunteers not pretreated with terbutaline, but shifted the ratio high-to-low affinity state of the lymphocyte j#2-adrenoceptor toward high affinity state.We conclude that glucocorticoids as well as ketotifen can accelerate recovery of density and responsiveness of lymphocyte B2-adrenoceptors desensitized by long-term treatment with 2-agonists. Such an effect may have clinical implications for preventing tachyphylaxis of asthmatic patients against therapy with 02-agonists.

Thr164Ile polymorphism of the human β2-adrenoceptor exhibits blunted desensitization of cardiac functional responses in vivo

“…We and others have shown in several studies that, in humans, chronic oral treatment with the ␤ 2 AR agonist terbutaline causes desensitization of ␤ 2 AR-mediated effects (3,5,7,(14)(15)(16). Very recently, we found that, in contrast to in vitro observations (11), the extent of terbutaline-induced desensitization of cardiac ␤ 2 AR responses after a 2-wk oral treatment with 3 ϫ 5 mg/day terbutaline was not different in volunteers carrying the Gly16Gly or Glu27Glu allele; however, volunteers homozygous Glu27Glu exhibited a delayed onset in desensitization (7).…”

“…To answer this question, in the present study, we assessed in 6 healthy volunteers heterozygous for Thr164Ile ␤ 2 AR polymorphism and in 10 volunteers homozygous WT ␤ 2 AR terbutaline infusion induced increase in heart rate (HR) and shortening of the HR-corrected duration of the electromechanical systole [QS 2 c; an established measure of contractility (2)] before and after 2-wk treatment with 3 ϫ 5 mg/day terbutaline, a protocol that has been shown to evoke desensitization of ␤ 2 AR responses in vivo (3,5,7,16).…”

Tolerance with beta 2‐adrenoceptor agonists: time for reappraisal.

“…The steroid had no effect on receptors that had not been down-regulated. A single dose of 100 mg oral prednisolone produced similar up-regulation, within 8 to 10 h of receiving Review 115 the drug [56]. The mechanism of this effect is not yet fully understood, but it may involve an increase in the rate of de novo synthesis of receptors or, a reversal or inhibition of internalisation of receptors from the cell surface.…”

“…Ketotifen has been shown both to accelerate upregulation of previously down-regulated lymphocyte 2-receptors, and to attenuate down-regulation. This has been found to correlate with an attenuation of the tolerance to systemic, and airway f2-mediated effects in normal subjects [56,64]. Ketotifen has also been shown to up-regulate lymphocyte P2-receptors in asthmatics, a change associated with an improvement in pre-bronchodilator peak flows but no change in reversibility [59].…”

Beyond the dogma: novel 2-adrenoceptor signalling in the airways

“…many pro-inflammatory and immune cells, including mast cells [35], macrophages [36], neutrophils [37], lymphocytes [38], eosinophils [39], epithelial and endothelial cells [40,41], and both type I and type II alveolar cells [10,42,43]. Thus, many cell types within the lung that are implicated in the pathogenesis of asthma are potential targets of inhaled b 2 -adrenoceptor agonists.…”