Formoterol and salmeterol induce a similar degree of β2-adrenoceptor tolerance in human small airways but via different mechanisms.

BACKGROUND AND PURPOSE

Steroids prevent and reverse salbutamol-induced β(2)-adrenoceptor tolerance in human small airways. This study examines the effects of the long-acting β(2) agonists (LABAs) formoterol and salmeterol, and the ability of budesonide to prevent desensitization.

EXPERIMENTAL APPROACH

Long-acting β(2) agonists in the presence and absence of budesonide were incubated with human precision-cut lung slices containing small airways. Tolerance was deduced from measurements of reduced bronchodilator responses to isoprenaline and correlated with β(2)-adrenoceptor trafficking using a virally transduced, fluorescent-tagged receptor. The ability of the LABAs to protect airways against muscarinic-induced contraction was also assessed.

KEY RESULTS

Following a 12 h incubation, both formoterol and salmeterol attenuated isoprenaline-induced bronchodilatation to a similar degree and these effects were not reversible by washing. Pre-incubation with budesonide prevented the desensitization induced by formoterol, but not that induced by salmeterol. Formoterol also protected the airways from carbachol-induced bronchoconstriction to a greater extent than salmeterol. In the epithelial cells of small airways, incubation with formoterol promoted receptor internalization but this did not appear to occur following incubation with salmeterol. Budesonide inhibited the formoterol-induced reduction in plasma membrane β(2)-adrenoceptor fluorescence.

CONCLUSIONS AND IMPLICATIONS

Although both formoterol and salmeterol attenuate isoprenaline-induced bronchodilatation, they appear to induce β(2)-adrenoceptor tolerance via different mechanisms; formoterol, but not salmeterol, enhances receptor internalization. Budesonide protection against β(2)-adrenoceptor tolerance was correlated with the retention of receptor fluorescence on the plasma membrane, thereby suggesting a mechanism by which steroids alter β(2)-adrenoceptor function.