Modulation of Purinergic Contractility in the Murine Detrusor

Fong, Zhihui (2021) Modulation of Purinergic Contractility in the Murine Detrusor. Doctoral thesis, Dundalk Institute of Technology.

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β3-adrenoceptor (β3-AR) agonists, such as Mirabegron, relax the urinary bladder and have been approved for the treatment of overactive bladder (OAB) since 2012. However, the exact cellular mechanisms that mediate the effects of these drugs are still unclear. Contraction of the bladder is regulated by release of acetylcholine, and to a lesser extent adenosine triphosphate (ATP), from parasympathetic nerves. It is known that β3-AR agonists can inhibit acetylcholine responses in the bladder, but their effects on ATP responses have not been systematically investigated. This is an important issue, as ATP responses are upregulated in patients with OAB. The purpose of this study was to examine the cellular mechanisms underlying β3-AR-induced inhibition of bladder contractions, with a particular focus on the role of a novel cyclic adenosine monophosphate (cAMP) effector, exchange protein directly activated by cAMP (EPAC). Isometric tension recordings were obtained from strips of murine detrusor and electrophysiology studies were performed on both freshly dispersed murine detrusor myocytes and HEK cells transfected with P2X1 receptor plasmids, respectively. The key findings of this study were: 1) β3-AR agonists were more effective at inhibiting purinergic contractions compared to cholinergic contractions of the murine bladder; 2) cholinergic and purinergic contractions of the bladder were inhibited by activation of protein kinase A (PKA) and EPAC; 3) EPAC-induced inhibition of purinergic responses in the bladder were attenuated by Kv7 channel blockers; 4) EPAC directly inhibited P2X1 receptors, and amino acids located at positions 21-23 on the N-terminus of the P2X1 receptor are critical for this effect and; 5) Rac1, a member of the Rho family of small GTPases, may be involved in EPAC-mediated inhibition of purinergic responses. These data suggest that β3-AR agonists reduce the amplitude of ATP- induced contractions of the bladder via activation of EPAC, which inhibits P2X1 receptors on detrusor myocytes.

Item Type: Thesis (Doctoral)
Subjects: Science > Biology
Research Centres: UNSPECIFIED
Depositing User: Gerard Sergeant
Date Deposited: 17 Nov 2021 12:29
Last Modified: 05 Jul 2022 10:53
License: Creative Commons: Attribution-Noncommercial-Share Alike 4.0

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