Abstract
Glucocorticosteroids are the mainstay treatment for chronic asthma; however, adverse effects can limit their usefulness. We previously determined in experimental asthma that chronic administration of β2-adrenoceptor inverse agonists reduced airway hyperresponsiveness and indexes of inflammation. However, the effect of co-administration of glucocorticosteroids with β2-adrenoceptor inverse agonists is unknown. Therefore, we evaluated the anti-inflammatory effect of co-administration of dexamethasone, a glucocorticosteroid, and nadolol, a β2-inverse agonist, in a murine asthma model. We measured eosinophils and cytokines in bronchoalveolar lavage fluid and mucin content in epithelial cells after exposure to different concentrations of dexamethasone and nadolol. Dexamethasone was administered for 3 days and nadolol for 24 days prior to ovalbumin challenge. Both drugs were continued during five daily intranasal challenges with ovalbumin. Independent administration of dexamethasone (0.4 mg/kg/day) or nadolol (25 ppm) reduced bronchoalveolar lavage eosinophils by 58% and 36%, respectively (P < 0.05). Co-administration of both drugs yielded an additive reduction in eosinophils (81%, P < 0.05). Co-administration of both drugs (dexamethasone 0.4 mg/kg/day and nadolol 25 ppm) also yielded a greater reduction in mucin volume density (83%) than either drug alone (18% for dexamethasone and 62% for nadolol) and greater than high-dose dexamethasone (71%) alone (P < 0.05). Similarly, co-administration of both drugs (dexamethasone 0.4 mg/kg/day and nadolol 25 ppm) yielded an additive effect on the reduction of type 2 cytokines in bronchoalveolar lavage fluid equivalent to the administration of a 10-fold higher dose of dexamethasone. In Summary, the simultaneous administration of a glucocorticosteroid and a β2-adrenoceptor inverse agonist was more effective at reducing indexes of airway inflammation than either drug given alone; suggesting nadolol may possess “glucocorticoid-sparing” properties.
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Acknowledgments
This work was supported by training grant 5T32AI053831 to Long P. Nguyen and research grant 5R01AI079236-02 to Bond, Dickey, and Tuvim, both from the National Institutes of Health. The authors wish to thank Professor Brian J. Knoll for his support and scientific critique of this manuscript.
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Richard A. Bond is a shareholder in Inverseon, Inc.
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Nguyen, L.P., Singh, B., Okulate, A.A. et al. Complementary anti-inflammatory effects of a β-blocker and a corticosteroid in an asthma model. Naunyn-Schmiedeberg's Arch Pharmacol 385, 203–210 (2012). https://doi.org/10.1007/s00210-011-0692-0
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DOI: https://doi.org/10.1007/s00210-011-0692-0