Effects of prolonged exposure to a β3-adrenoceptor agonist in urinary bladder

• Applicants: Professor Dr. Martin Hennenberg; Professor Dr. Martin C. Michel
• Subject Area: Pharmacology ; Nephrology ; Reproductive Medicine, Urology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547110020

The β3-adrenoceptor (β3AR) agonists mirabegron and vibegron are a guideline recommended treatment for patients with overactive bladder syndrome (OAB). While their efficacy is similar to that of muscarinic receptor antagonists, the β3AR agonists exhibit fewer side effects (especially less dry mouth) and exhibit longer persistence on treatment. β3AR agonists also reduce symptoms in many OAB patients failing on treatment with anticholinergics. However, both drug classes provide symptom relief without curing OAB, implying that continued treatment is required. Initial beliefs that β3AR agonists improve symptoms simply by relaxation of bladder smooth muscle are now considered insufficient to explain their clinical effects. In fact, their prolonged effects on bladder smooth muscle are unclear and have been addressed marginally, if at all in preclinical models. OAB patients exhibit a thickened bladder wall, which may contribute to storage symptoms and bladder dysfunction. β3AR agonists exhibit anti-hypertrophic effects outside the bladder, while β3AR knock-out mice showed enlarged bladders in preliminary observations of a collaborating group. Consequently, β3AR agonists may at least partly alleviate OAB symptoms by reducing bladder hypertrophy. However, data systematically addressing effects of β3AR agonists in cultured bladder smooth muscle cells or impacts on β3AR modulation of bladder enlargement in animal models are to the best of our knowledge not available and, therefore, are a central part of this project. While β3AR are less sensitive to agonist-induced desensitization than other βAR subtypes, desensitization has been shown in various cell types and tissues. Except for one pilot study from our lab, no systematic experimental studies are available. The existing clinical data are not informative because the earliest time point of investigation was 2-4 weeks after initiation of treatment, i.e., a time point when desensitization can be expected to have developed. Thus, it is possible that desensitization limits the clinical efficacy of β3AR agonists in OAB patients, but this has not yet been examined systematically for the detrusor. Consequently, β3AR desensitization and its mechanisms are the second main aim of our project, with both aims being addressed based on the same studies. Thus, our collaborative project will address unresolved aspects related to prolonged exposure of the bladder or isolated bladder smooth muscle cells to β3AR agonists, i.e., growth regulation and desensitization by combining in vivo studies in rats and mice with in vitro studies in human bladder smooth muscle cells. Applicable project parts will be performed at the universities of Mainz (Germany) and Munich (Germany), while collaborating contributions from Duke University in Durham (NC, USA).

• DFG Programme: Research Grants