ß-blockers are currently contraindicated in the treatment of asthma due to their deleterious acute effects. The clinical effects of treatment with ß-adrenoceptor (ß-AR) agonists and antagonists in heart failure vary with duration of therapy, as do the effects of ß-AR agonists in asthma. Therefore, we hypothesized that chronic effects of 'ß-blockers' in asthma may differ from those observed acutely.

Ovalbumin-sensitized and -challenged Balb/cJ mice (male, 20-25g) (Sensitized) were treated for either 28 days (chronic) or 15 min (acute) with salbutamol (SAL, n=10-9 animals; chronic: 0.5 mgkg^-1 day^-1 s.c. / acute: 0.15 mgkg^-1 i.v.), alprenolol (ALP, n=9-18 animals; chronic: 7200 ppm p.o. / acute: 72 mgkg^-1 i.v.), nadolol (NAD, n=9-13 animals; chronic: 250 ppm p.o. / acute: 72 mgkg^-1) or carvedilol (CAR, n=8-15 animals; chronic: 2400 ppm p.o./ acute: 24 mgkg^-1 i.v.) before measuring airway responsiveness to the muscarinic agonist methacholine. Sensitized and control (Ctrl, non-sensitized/non-challenged) mice (n=6-25 animals) were treated with vehicle. Airway resistance (R_aw) was measured using the forced oscillation technique (Evans et al., 2003) (Figure 1). ß-AR density was measured in membranes prepared from lung tissue using the ß-AR radioligand ¹²⁵I-ICYP (5 - 7500 pM) (Table 1). The specific binding was saturable and in all cases displayed a Hill coefficient not different from unity.

Fig. 1 and Table 1 illustrate that CAR and NAD exhibited different acute and chronic effects on both methacholine induced increases in R_aw and B_max values, and showed opposing effects to SAL and ALP. Surprisingly, both chronic CAR and NAD decreased R_aw.

Figure 1: 15 min infusion of ß-AR ligand either significantly reduced (SAL and ALP) or increased (CAR and NAD) R_aw (*P<0.05, ANOVA) compared to Sensitized. 28 d treatment with CAR and NAD significantly decreased R_aw while SAL and ALP had no effect. Please note changes in y-axis for acute CAR and NAD. Values are mean±s.e.m.

Table 1: 15 min treatment with SAL or ALP significantly increased B_max (fM mg^-1 protein) to Ctrl values, while 28 d with CAR or NAD increased B_max values significantly for ß-AR receptors in lung membranes. Values are mean±s.e.m. of n=3-5 animals in each group (*P<0.05 comp. to Sensitized, Student's t-test). Samples were run in triplicate.

Evans, K.L., et al. (2003). J Appl Physiol, 94, 245-52.

The presented work was supported by grants from NIH, AHA, Sandler Program for Asthma Research and GlaxoSmithKline.