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

Abstract

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 (Raw) 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 Raw values by 33.7% and 67.7% (P < 0.05), respectively; when either drug was administered for 28 days (chronic treatment), the peak Raw values were decreased by 43% (P < 0.05) and 22.9% (P < 0.05), respectively. (ii) 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 Raw value by 75.7% (P < 0.05); chronically, it did not alter Raw. (iv) Salbutamol, a beta-AR partial agonist, acutely decreased peak Raw by 41.1%; chronically, it did not alter Raw. (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.

Fig. 1.

Effects of treatments with β-AR ligands on airway responsiveness to methacholine in a murine model of asthma. Asthmatic mice received either a single i.v. bolus injection 15 min before methacholine (Mch) challenge (acute; Upper) or were treated for 28 days (chronic; Lower) with salbutamol via osmotic minipump (C and D), alprenolol in food (E and F), carvedilol in food (G and H), or nadolol in food (I and J). Controls received either saline i.v. or normal mouse chow and were run in parallel (A and B). Average methacholine dose-airway resistance relationships were obtained in control mice (Ctrl, open circles, n = 6-21), nontreated asthmatic mice (NTX, filled circles, n = 7-25), and asthmatic mice treated with the β-AR ligands (open squares, n = 8-19). Values are mean ± SEM. Note the change in the scale of the y axis for G and I. ^*, P < 0.05 compared with NTX; #, P < 0.05 compared with Ctrl (ANOVA).

Fig. 2.

Effects of administration of β-AR ligands on the peak airway responsiveness to cholinergic stimulation. Peak R_aw was determined for each mouse by examining the individual methacholine dose-response curves and choosing the highest R_aw value produced by any of the methacholine doses (most often the next to last dose, 408 μg·kg^-1·min^-1). Shown are the mean peak R_aw ± SEM after treatments with the β-AR agonist salbutamol (A), after acute treatments (B), and after chronic treatment with β-blockers (C), in comparison with nontreated asthmatic mice (NTX; black bars, n = 7-25) and control mice (Ctrl; white bars, n = 6-21). Values are mean ± SEM for the peak R_aw to methacholine of n = 8-19 mice. Note the change in the scale of the y axis for B. ^*, P < 0.05 compared to NTX; #, P < 0.05 compared to Ctrl (ANOVA).