On the Site and Mechanism of Action of β3-Adrenoceptor Agonists in the Bladder

The clinical success of mirabegron as the first a3-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome, has resulted in substantial interest in its site and mechanism of action. Even if the adrenergic innervation of the bladder and urethra has been well studied, the location(s) of a3-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of a3-AR stimulation have still not been established. The recent demonstration of a3-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies, and functional data strongly suggest that a3-ARs can be found these structures. However, recent studies suggest that the a3-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that a3-AR activation during bladder filling inhibits acetylcholine release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exclude that other mechanisms may be contributing, and supports combined approaches to reduce afferent activity for treatment of the OAB syndrome.