title: Complementary anti-inflammatory effects of a β-blocker and a corticosteroid in an asthma model.
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.
authors.affiliation: Department of Pulmonary Medicine, MD Anderson Cancer Center, University of Texas, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors.forename: Long P
authors.initials: LP
authors.lastname: Nguyen
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Singh
authors.forename: Adedoyin A
authors.initials: AA
authors.lastname: Okulate
authors.forename: Victoria Y
authors.initials: VY
authors.lastname: Alfaro
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Tuvim
authors.forename: Burton F
authors.initials: BF
authors.lastname: Dickey
authors.forename: Richard A
authors.initials: RA
authors.lastname: Bond
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003907:Dexamethasone / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000627:therapeutic use*; D007958:Leukocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins / Q000276:immunology; D009248:Nadolol / Q000627:therapeutic use*; D020545:Respiratory Mucosa / Q000187:drug effects / Q000276:immunology
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D005938:Glucocorticoids; D009077:Mucins; D009248:Nadolol; D003907:Dexamethasone