Background: The combination of β2-adrenergic agonists and glucocorticosteroids is frequently used to control bronchial asthma. It is believed that the co-administration of glucocorticosteroids will reduce the tachyphylaxis to β2-adrenergic agonists. Objective: To analyse the effects of glucocorticosteroids on the response to high concentrations of β2-adrenergic agonists. Methods: We have compared the effects of high doses of terbutaline, alone or in combination with dexamethasone, on the relaxation induced by in vitro β2-adrenergic agonists in guinea pig trachea. Results: Terbutaline (100 mg/kg/day), for 7 days, induced a marked homologous desensitization. The addition of dexamethasone (0.2 or 2 mg/kg/day) to the treatment did not prevent the development of desensitization, which was even more marked in the group treated with terbutaline and the higher doses of dexamethasone, compared with the group treated with terbutaline alone. Conclusion: Our results suggest a negative interaction between high doses of β2-adrenergic agonists and glucocorticosteroids in the airway smooth muscle of guinea pigs.

Keywords:
β2-Adrenergic agonists, Glucocorticosteroids, Desensitization, Trachea, guinea pig, Smooth muscle
1.
Fernandes LB, Knight DA, Rigby PJ, Spina D, Paterson JW, Goldie RG: β-Adrenoceptor desensitization in guinea pig isolated trachea. Eur J Pharmacol 1988;157:135–145.
2.
Seco AJ, Salgueiro ME, Manso G: Acute and chronic treatment with glucocorticosteroids, modifying the β2-adrenergic response of the guinea-pig trachea. Lung 1995;173:321–328.
3.
Goldie RG, Spina D, Paterson JW: Beta agonist-induced desensitization in pig bronchus. J Pharmacol Exp Ther 1986;237:275–282.
4.
Avner BP, Jenne JW: Desensitization of isolated human bronchial smooth muscle to β receptor agonists. J Allergy Clin Immunol 1981;68:51–57.
5.
Brink C: Tolerance of guinea-pig airway muscle preparations to relaxant agonists induced by chronic exposure to isoprenaline in vivo. Br J Pharmacol 1981;73:13–19.
6.
Nerme V, Abrahamsson T, Vauquelin G: Chronic isoproterenol administration causes altered beta adrenoceptor Gs-coupling in guinea pig lung. J Pharmacol Exp Ther 1990;252:1341–1346.
7.
Nishikawa M, Mak JCW, Shirasaki H, Harding SE, Barnes PJ: Long-term exposure to norepinephrine results in down-regulation and reduced mRNA expression of pulmonary β-adrenergic receptors in guinea pigs. Am J Respir Cell Mol Biol 1994;10:91–99.
8.
Buur T, Clausen T, Holmberg E, Johansson U, Waldeck B: Desensitization by terbutaline of β-adrenoceptors in guinea-pig soleus muscle: Biochemical alterations associated with functional changes. Br J Pharmacol 1982;76:313–317.
9.
Hauck RW, Böhm M, Gengenbach S, Sunder-Plassmann L, Fruhmann G, Erdmann E: β2-Adrenoceptors in human lung and peripheral mononuclear leukocytes of untreated and terbutaline-treated patients. Chest 1990;98:376–381.
10.
Larsson K, Martinsson A, Hjemdahl P: Influence of β-adrenergic receptor function during terbutaline treatment on allergen sensitivity and bronchodilator response to terbutaline in asthmatics subjects. Chest 1992;101:953–960.
11.
Tashkin DP, Conolly ME, Deutsch RI, Hui KK, Littner M, Scarpace P, Abrass I: Subsensitization of beta-adrenoceptors in airways and lymphocytes of healthy and asthmatic subjects. Am Rev Respir Dis 1982;125:185–193.
12.
Lipworth BJ, Struthers AD, McDevitt DG: Tachyphylaxis to systemic but not to airway responses during prolonged therapy with high dose inhaled salbutamol in asthmatics. Am Rev Respir Dis 1989;140:586–592.
13.
Nelson HS: β-Adrenergic agonists; in Barnes PJ, Grunstein MM, Leff AR, Woolcock AJ (eds): Asthma. Philadelphia, Lippincott-Raven Publishers, 1997, vol 2, pp 1507–1521.
14.
Sears MR: Is the routine use of inhaled β-adrenergic agonists appropriate in asthma treatment? No. Am J Respir Crit Care Med 1995;151:600–601.
15.
Wanner A: Is the routine use of inhaled β-adrenergic agonists appropriate in asthma treatment? Yes. Am J Respir Crit Care Med 1995;151:597–599.
16.
Hadcock JR, Malbon CC: Regulation of β-adrenergic receptors by ‘permissive’ hormones. Glucocorticoids increase steady-state levels of receptor mRNA. Proc Natl Acad Sci USA 1988;85:8415–8419.
17.
Mak JCW, Nishikawa M, Barnes PJ: Glucocorticosteroids increase β2-adrenergic receptor transcription in human lung. Am J Physiol 1995;268:L41–L46.
18.
Peters MJ, Adcock IM, Brown CR, Barnes PJ: β-Adrenoceptor agonists interfere with glucocorticoid receptor DNA binding in rat lung. Eur J Pharmacol 1995;289:275–281.
19.
Adcock IM, Stevens DA, Barnes PJ: Interactions of glucocorticoids and β2-agonists. Eur Respir J 1996;9:160–168.
20.
Nishikawa M, Mak JCW, Shirasaki H, Barnes PJ: Differential down-regulation of pulmonary β1- and β2-adrenoceptor messenger RNA with prolonged in vivo infusion of isoprenaline. Eur J Pharmacol 1993;247:131–138.
21.
Barnes PJ: Beta-adrenergic receptors and their regulation. Am J Respir Crit Care Med 1995;152:838–860.
22.
Buchheit K-H, Hofmann A, Fozard JR: Salbutamol-induced airway hyperreactivity in guinea pigs is not due to a loss of its bronchodilator effect. Eur J Pharmacol 1995;287:85–88.
23.
Wang Z-L, Bramley AM, McNamara A, Paré PD, Bai TR: Chronic fenoterol exposure increases in vivo and in vitro airway responses in guinea pigs. Am J Respir Crit Care Med 1994;149:960–965.
24.
Inman MD, O’Byrne PM: The effect of regular inhaled albuterol on exercise-induced bronchoconstriction. Am J Respir Crit Care Med 1996;153:65–69.
25.
O’Connor BJ, Aikman SL, Barnes PJ: Tolerance to the nonbronchodilator effects of inhaled β2-agonists in asthma. N Engl J Med 1992;327:1204–1208.
26.
Sears MR, Taylor DR, Print CG, Lake DC, Li Q, Flannery EM, Yates DM, Lucas MK, Herbison GP: Regular inhaled beta-agonists treatment in bronchial asthma. Lancet 1990;336:1391–1396.
27.
Vathenen AS, Knox AJ, Higgins BG, Britton JR: Rebound increase in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1988;1:554–558.
28.
Wahedna I, Wong CS, Wisniewski AFZ, Pavord ID, Tattersfield AE: Asthma control during and after cessation of regular beta2-agonist treatment. Am Rev Respir Dis 1993;148:707–712.
29.
Wong CS, Wahedna I, Pavord ID, Tattersfield AE: Effect of regular terbutaline and budesonide on bronchial reactivity to allergen challenge. Am J Respir Crit Care Med 1994;150:1268–1273.
30.
Liggett SB: Molecular and genetics basis of β-adrenergic receptor function and regulation; in Barnes PJ, Grunstein MM, Leff AR, Woolcock AJ (eds): Asthma. Philadelphia, Lippincott-Raven Publishers, 1997, vol 1, pp 299–312.
31.
Gustafsson B, Persson CGA: Effect of three weeks treatment with budesonide on in vitro contractile and relaxant airway effects in the rat. Thorax 1989;44:24–27.
32.
Mak JCW, Nishikawa M, Shirasaki H, Miyayasu K, Barnes PJ: Protective effects of a glucocorticoid on down-regulation of pulmonary β2-adrenergic receptors in vivo. J Clin Invest 1995;96:99–106.
33.
Lemoine H, Overlack C, Köhl A, Worth H, Reinhardt D: Formoterol, fenoterol and salbutamol as partial agonists for relaxation of maximally contracted guinea pig tracheae: Comparison of relaxation with receptor binding. Lung 1992;170:163–180.
34.
Barnes PJ, Adcock I: Anti-inflammatory actions of steroids: Molecular mechanisms. Trend Pharmacol Sci 1993;14:436–441.
35.
Adcock IM, Brown CR, Gelder CM, Shirasaki H, Peters MJ, Barnes PJ: Effects of glucocorticoids on transcription factor activation in human peripheral blood mononuclear cells. Am J Physiol 1995;268:C331–C338.
36.
Cockcroft DW, Swystun VA, Bahagat R: Interaction of inhaled β2 agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine. Am J Respir Crit Care Med 1995;152:1485–1489.
37.
Kalra S, Swystun VA, Bhagat R, Cockcroft DW: Inhaled corticosteroids do not prevent the development of tolerance to the bronchoprotective effect of salmeterol. Chest 1996;109:953–956.
38.
Wilding PJ, Clark MM, Oborne J, Bennett JA, Tattersfield AE: Effect of regular terbutaline on the airway response to inhaled budesonide. Thorax 1996;51:989–992.
© 2000 S. Karger AG, Basel
2000
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