β₃-Adrenoceptor Agonist Effects on the Urinary Bladder Beyond Detrusor Relaxation

Aims: beta(3)-Adrenoceptor agonists such as mirabegron or vibegron reach pharmacokinetic steady-state within a few days. However, maximum improvements in symptoms of the overactive bladder syndrome are reached at time points later than 4 weeks, that is, detrusor smooth muscle relaxation cannot fully explain clinical effects. Therefore, we review mechanistic studies that have administered such drugs for longer periods of time. Methods: Narrative review. Results: The limited data indicates that beta(3)-adrenoceptor agonists reduce bladder fibrosis and hypertrophy and may induce cell proliferation, and normalize increased apoptosis and ferroptosis. On the other hand, limited data also indicate that detrusor relaxation responses can partly desensitize with prolonged agonist exposure, possibly off-setting effects on fibrosis and hypertrophy. Conclusions: Further long-term studies with beta(3)-adrenoceptor agonists are needed to clarify the role of such processes in clinical improvement of patients with overactive bladder syndrome occurring at time points later than 4 weeks after initiation of treatment.