Abstract
The effect of R2-adrenoceptor agonists on airway smooth muscle relaxation may be subject to desensitization. It could be modified by glucocorticosteroid treatment. An increase in the R2 agonist response by gluco corticosteroids in vitro has been described. We studied the effects of acute and chronic treatment with dexamethasone on the relaxation response of tracheal smooth muscle to R2 agonists, fenoterol and salbutamol. Fenoterol showed a greater force of relaxation than salbutamol, and both drugs induced desensitization. Acute treatment with dexamethasone reduced desensitization to both β2 agonists. Chronic treatment (120 μg/kg of dexamethasone for 7 days) reduced the desensitization to fenoterol alone. Dexamethasone (200 μg/kg for 7 days) increased relaxation to salbutamol and reduced desensitization to both drugs. The interaction between β2 agonists and glucocorticosteroids could be important in the clinical use of both drugs in the treatment of asthma.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Avner BP, Jenne JW (1981) Desensitization of isolated human bronchial smooth muscle to β-receptors agonists. J Allergy Clin Immunol 68:51–57
Barnes PJ, Chung KF (1992) Questions about inhaled β2-adrenoceptor agonists in asthma. Trends Pharmacol Sci 13:20–23
Bouvier M, Collins S, O'Dowd BF, Campbell PT, de Blasi A, Kobilka BK, MacGregor C, Irons GP, Caron MG, Lefkowitz RJ (1989) Two distinct pathways for cAMP-mediated down-regulation of the β2-adrenergic receptor. Phosphorylation of the receptor and regulation of its mRNA level. J Biol Chem 264:16786–16792
Collins S (1993) Recent perspectives on the molecular structure and regulation of the β2-adrenoceptor. Life Sci 52:2083–2091
Collins S, Bouvier M, Bolanowski MA, Caron MG (1989) cAMP stimulates transcription of the β2-adrenergic receptor gene in response to short-term agonists exposure. Proc Natl Acad Sci USA 86:4853–4857
Collins S, Caron MG, Lefkowitz RJ (1988) β-Adrenergic receptors in hamster smooth muscle cells are transcriptionally regulated by glucocorticoids. J Biol Chem 263:9067–9070
Collins S, Caron MG, Lefkowitz RJ (1992) From ligand binding to gene expression: new insights into the regulation of G-protein-coupled receptors. Trends Biochem Sci 17:37–39
Fraser CM, Venter JC (1980) The synthesis of β-adrenergic receptors in cultured human lung cells: induction by glucocorticosteroids. Biochem Biophys Res Commun 94:390–397
Fraser CM, Venter JC (1990) Beta-adrenergic receptors. Relationship of primary structure, receptor function, and regulation. Am Rev Respir Dis 141:S22-S30
Fuller RW, Kelsey CR, Cole PJ, Dollery CT, MacDermot J (1986) Dexamethasone inhibits the production of thromboxane B2 and leukotriene B4 by human alveolar and peritoneal macrophages in culture. Clin Sci 67:653–656
Geddes BA, Jones TR, Dvorsky RJ, Lefcoe NM (1974) Interaction of glucocorticoids and bronchodilators on isolated guinea pig tracheal and human bronchial smooth muscle. Am Rev Respir Dis 110:420–427
Hadcock JR, Malbon CC (1988) Regulation of β-adrenergic receptors by “permissive” hormones: glucocorticoids increase steady-state levels of receptor mRNA. Proc Natl Acad Sci USA 85:8415–8419
Hadcock JR, Wang H, Malbon CC (1989) Agonist-induced destabilization of β-adrenergic receptor mRNA. Attenuation of glucocorticoid-induced up-regulation of β-adrenergic receptors. J Biol Chem 264:19928–19933
Larsson K, Martinsson A, Hjemdahl P (1992) Influence of β-adrenergic receptor function during terbutaline treatment on allergen sensitivity and bronchodilator response to terbutaline in asthmatic subjects. Chest 101:953–960
Lefkowitz RJ, Hausdorff WP, Caron MG (1990) Role of phosphorylation in desensitization of the β-adrenoceptor. Trends Pharmacol Sci 11:190–194
Manso G, Baker AJ, Taylor IK, Fuller RW (1992) In vivo and in vitro effects of glucocorticosteroids on arachidonic acid metabolism and monocyte function in nonasthmatic humans. Eur J Respir Dis 5:712–716
Matran R, Naline E, Advenier C, Duroux P (1989) In vitro desensitization of beta-adrenoceptors in guinea pig trachea: interactions between beta-adrenoceptor agonists and influence of adenosine and other drugs. Fundam Clin Pharmacol 3:103–113
Nishikawa M, Mak JCW, Shirasaki H, Harding SE, Barnes PJ (1994) Long-term exposure to norepinephrine results in down-regulation and reduces mRNA expression of pulmonary β-adrenergic receptors in guinea pigs. Am J Respir Cell Mol Biol 10:91–99
O'Donnell SR, Wanstall JC (1978) Evidence that the efficacy (intrinsic activity) of fenoterol is higher than of salbutamol on β-adrenoceptors in guinea pig trachea. Eur J Pharmacol 47:333–340
Palczewski K, Benovic JL (1991) G-protein-coupled receptor kinases. Trends Biochem Sci 16:387–391
Svedmyr N (1990) Actions of corticosteroids on beta-adrenergic receptors. Clinical aspects. Am Rev Respir Dis 141:S31-S38
Vathenen AS, Knox AJ, Higgins BG, Britton JR, Tattersfield AE (1988) Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1:554–558
Weber RW, Smith JA, Nelson HS (1982) Aerosolized terbutaline in asthmatics: development of subsensitivity with long-term administration. J Allergy Clin Immunol 70:417–422
Author information
Authors and Affiliations
Additional information
Offprint requests to: G. Manso
Rights and permissions
About this article
Cite this article
Seco, A.J., Salgueiro, M.E. & Manso, G. Acute and chronic treatment with glucocorticosteroids, modifying the β2-adrenergic response of the guinea pig trachea. Lung 173, 321–328 (1995). https://doi.org/10.1007/BF00176895
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00176895