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.

• Authors: Yasuhiko Igawa, Naoki Aizawa, Martin C Michel
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 176 Issue 14 Pg. 2525-2538 (07 2019) ISSN: 1476-5381 [Electronic] England
• PMID: 30868554 (Publication Type: Journal Article, Review)
• Copyright: © 2019 The British Pharmacological Society.

Chemical References

• Adrenergic beta-3 Receptor Agonists
• Receptors, Adrenergic, beta-3

Topics

• Adrenergic beta-3 Receptor Agonists (blood, pharmacology)
• Animals
• Humans
• Receptors, Adrenergic, beta-3 (metabolism)
• Urinary Bladder (drug effects, metabolism, pathology)