Effects of acute and chronic administration of β-adrenoceptor ligands on airway function in a murine model of asthma

The clinical effects of treatment with beta-adrenoceptor (beta-AR) agonists and antagonists in heart failure vary with duration of therapy, as do the effects of beta-AR agonists in asthma. Therefore, we hypothesized that chronic effects of beta-blockers in asthma may differ from those observed acutely. We tested this hypothesis in an antigen (ovalbumin)-driven murine model of asthma. Airway resistance responses (R-aw) to the muscarinic agonist methacholine were measured by using the forced oscillation technique. In comparison with nontreated asthmatic mice, we observed that: (i) The beta-AR antagonists nadolol or carvedilol, given as a single i.v. injection (acute treatment) 15 min before methacholine, increased methacholine-elicited peak R-aw values by 33.7% and 67.7% (P < 0.05), respectively; when either drug was administered for 28 days (chronic treatment), the peak R-aw values were decreased by 43% (P < 0.05) and 22.9% (P < 0.05), respectively. (h) Chronic treatment with nadolol or carvedilol significantly increased beta-AR densities in lung membranes by 719% and 828%, respectively. (iii) Alprenolol, a beta-blocker with partial agonist properties at beta-ARs, behaved as a beta-AR agonist, and acutely reduced peak R-aw value by 75.7% (P < 0.05); chronically, it did not alter R-aw. (iv) Salbutamol, a beta-AR partial agonist, acutely decreased peak R-aw by 41.1%; chronically, it did not alter R-aw. (v) None of the beta-blockers produced significant changes in eosinophil number recovered in bronchoalveolar lavage. These results suggest that beta-AR agonists and beta-blockers with inverse agonist properties may exert reciprocating effects on cellular signaling dependent on duration of administration.