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

The clinical success of mirabegron as the first β₃-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 β₃-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of β₃-AR stimulation have still not been established. The recent demonstration of β₃-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 β₃-ARs can be found these structures. However, recent studies suggest that the β₃-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that β₃-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.