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

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