Even though β₂-agonists major mechanism is airway smooth muscle relaxation, β₂-agonists may affect other cellular types and functions, exerting the so called “non-bronchodilator effects” (Fig. 6-7).

Figure 6: Actions of β₂-agonists in asthma.

Focusing on asthma (Fig. 6), the most relevant non-bronchodilator effects of LABAs include the reduction of mast cells mediators release (e.g. histamine): this is a particularly important protective effect, especially against acute exacerbations of asthma, which can be very often mediated by mast-cell activation. In addition, β₂-agonists inhibit plasma exudation by preventing separation of endothelial cells in postcapillary venules, due to their interaction with β₂-receptors present on postcapillary venular endothelial cells, reducing therefore an important component of the inflammatory process. In this way, LABAs may produce anti-inflammatory and anti-oedematous effects in the airways. Furthermore, β₂-agonists may also affect the activation of airway sensory nerves, inducing an inhibitory effect.⁷

Figure 7: Actions of β₂-agonists in COPD.⁸

The following non-bronchodilator effects of LABAs are relevant in COPD management (Fig.7): decreased neutrophils number and their adhesion to airway endothelial cells, reduction of airway microvascular leakage (as seen before for asthma as well), which is increased in COPD. Additionally, it has been recognised an increase in ciliary beating due to β₂-agonists, through their effect on epithelial β₂-receptors and this may increase mucociliary clearance. Of further interest, LABAs reduce adherence of bacteria to airway epithelial cells and this might reduce bacterial exacerbations in COPD. These non-bronchodilator effects are likely to be reduced with continuous administration: this could be prevented by the additional administration of an ICS, which could counteract β₂-receptors down-regulation associated to a chronic administration of β₂-agonists.^5,8