β₃‐Adrenoceptors in the normal and diseased urinary bladder—What are the open questions?

Abstract

β3‐Adrenoceptor agonists are used in the treatment of overactive bladder syndrome. Although the relaxant response to adrenergic stimulation in human detrusor smooth muscle cells is mediated mainly via β3‐adrenoceptors, the plasma concentrations of the therapeutic dose of mirabegron, the only clinically approved β3‐adrenoceptor agonist, are considerably lower than the EC50 for causing direct relaxation of human detrusor, suggesting a mechanism of action other than direct relaxation of detrusor smooth muscle. However, the site and mechanism of action of β3‐adrenoceptor agonists in the bladder have not been firmly established. Postulated mechanisms include prejunctional suppression of ACh release from the parasympathetic nerves during the storage phase and inhibition of micro‐contractions through β3‐adrenoceptors on detrusor smooth muscle cells or suburothelial interstitial cells. Implications of possible desensitization of β3‐adrenoceptors in the bladder upon prolonged agonist exposure and possible causes of rarely observed cardiovascular effects of mirabegron are also discussed. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

Inhibition of Female and Male Human Detrusor Smooth Muscle Contraction by the Rac Inhibitors EHT1864 and NSC23766

“…As an alternative option, b 3 -adrenoceptor agonists have been recently introduced for treatment of storage symptoms (Nambiar et al, 2018). They may improve storage symptoms by decreasing the bladder smooth muscle tone by inhibition of cholinergic nerve activity via retrograde release of adenosine (D'Agostino et al, 2000;Chapple et al, 2014;Silva et al, 2017;Igawa et al, 2019;Silva et al, 2019). However, it becomes increasingly clear, that their efficacy is not higher than that of anticholinergics (Nambiar et al, 2018), so that the overall situation regarding medical treatment of OAB and storage symptoms still remains inadequate.…”

β3 Adrenoceptor‐induced cholinergic inhibition in human and rat urinary bladders involves the exchange protein directly activated by cyclic AMP 1 favoring adenosine release

“…Concordant staining of human tissues with two or more antibodies (e.g. MC4198 and AAR‐007) provides the most compelling evidence for β 3 ‐adrenoceptor labelling in immunohistochemistry studies (Cernecka, Ochodnicky, Lamers, & Michel, ; Silva et al, ; reviewed in Igawa et al, ). As for the EPAC immunostaining, we used a rabbit polyclonal antibody directed against amino acids 526‐541 of EPAC1 (Abcam, Ab21236; Figure c) and a mouse monoclonal antibody raised against amino acids 1‐70 of the human EPAC1 (Santa Cruz, SC‐28366; Figure f).…”

“…Selective β 3 -adrenoceptor agonists, such as mirabegron, are increasingly prescribed as alternatives to anti-muscarinic drugs in the treatment of overactive bladder (OAB) syndrome (Angulo, Khullar, Nitti, & Siddiqui, 2013;Marcelissen, Rashid, Antunes-Lopes, Delongchamps, & Geavlete, 2019). Regardless of their clinical success and that they are associated with fewer side effects compared to anti-muscarinic drugs, controversy exists regarding the dominant localization of β 3 -adrenoceptors on detrusor smooth muscle fibres and the molecular mechanism(s) underlying their overall mechanism (Andersson, 2017;Igawa & Aizawa, 2017;Igawa, Aizawa, & Michel, 2019;Okeke, Gravas, & Michel, 2017).…”

Solifenacin/Mirabegron Induces an Acute Compliance Increase in the Filling Phase of the Capacity-Reduced Urinary Bladder: A Pressure-Volume Analysis in Rats

“…In addition to their well-established effects on the detrusor, the results of the present study revealed that the therapeutic effects of solifenacin and mirabegron on OAB-like symptoms could be attributed to an increased compliance, the visco-elastic property of the bladder itself. Nevertheless, because solifenacin and mirabegron are shown to exhibit their effects not restrictively on the detrusor but also on the urothelium, local perfusion, and afferent/afferent arms/centers of neural circuitry ( Igawa et al, 2019 ) the potential role of these candidates in solifenacin/mirabegron-increased compliance needs further investigations.…”