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Lookup NU author(s): Professor James Gillespie
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Prostaglandin E-2 (PGE(2)) is well known to modulate urinary bladder functions, but it is also thought to be involved in the pathophysiology of lower urinary tract dysfunctions, since high levels of PGE(2) have been found in overactive bladder (OAB) patients. beta-Adrenoceptors are major players in detrusor muscle relaxation, and the selective beta(3)-adrenoceptor (AR) agonist mirabegron was recently approved for the treatment of overactive bladder (OAB). beta-Adrenoceptor modulation of PGE(2) excitatory effects on bladder detrusor muscle was investigated by i.v. mirabegron after intravesical PGE(2) infusion in conscious rats. Non-voiding activity (NVA) was assessed under isovolumetric conditions. In addition, mirabegron and isoprenaline (0.01-10 mu M) were studied on PGE(2)-increased micro-contractile activity during isometric tension recordings of intact isolated bladder muscle strips. Our investigations showed that PGE(2) dramatically increased NVA in vivo and spontaneous micro-contractions in vitro. In vivo administration of mirabegron (0.1, 0.3 and 3 mg/kg) reduced PGE(2)-augmented NVA in dose-dependent manner, while the PGE(2)-increased micro-contractions in isolated bladder strips were poorly inhibited. Isoprenaline inhibited PGE(2)-augmented micro-contractions in a concentration-dependent manner and had a higher potency compared to mirabegron. The apparent pKB of 7.25 for metoprolol at the isoprenaline concentration-response curve for PGE(2)-augmented micro-contractions suggests a beta(1)-AR-mediated.
Author(s): Granato C, Korstanje C, Guilloteau V, Rouget C, Palea S, Gillespie JI
Publication type: Article
Publication status: Published
Journal: Naunyn-Schmiedeberg's Archives of Pharmacology
Print publication date: 01/07/2015
Online publication date: 11/06/2015
Acceptance date: 25/05/2015
ISSN (print): 0028-1298
ISSN (electronic): 1432-1912
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