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Lookup NU author(s): Professor James Gillespie
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Spontaneous microcontractions and electrical field stimulation (EFS)-evoked contractions in isolated rat bladder strips from normal and from 6 weeks partial bladder outflow obstruction (pBOO) animals were studied to identify the potential site of action for the beta(3)-adrenoceptor (AR) agonist mirabegron in detrusor overactivity in rats. For this, effects of the beta-AR agonist isoprenaline and mirabegron were tested in presence or absence of selective antagonists for beta-AR subtypes, namely CGP-20712A for beta(1)-AR, ICI-118,551 for beta(2)-AR, and L-748,337 for beta(3)-AR. In detrusor strips from both normal and obstructed animals, EFS-induced contractions were weakly affected by isoprenaline and even less so by mirabegron. In contrast, microcontraction activity was more potently reduced by isoprenaline (pIC50 7.3; Emax +/- 85 %), whereas mirabegron showed a small effect. In pBOO strips, concentration response curves for isoprenaline and mirabegron at inhibition of EFS and spontaneous microcontractions were similar to those in normal strips. Isoprenaline-induced inhibition of microcontractions and EFS was antagonized by the beta(1)-AR antagonist, but not by the beta(2)- and beta(3)-AR antagonists. In the context of beta(3)-AR-mediated bladder functions for mirabegron in other experiments, the current data question a role for effects at spontaneous microcontractions, or neurogenic detrusor stimulation in the mode of action for mirabegron in vivo, since functional bladder effects for mirabegron are reported to occur at much lower concentrations.
Author(s): Gillespie JI, Rouget C, Palea S, Granato C, Korstanje C
Publication type: Article
Publication status: Published
Journal: Naunyn-Schmiedeberg's Archives of Pharmacology
Print publication date: 01/07/2015
Online publication date: 07/06/2015
Acceptance date: 20/05/2015
ISSN (print): 0028-1298
ISSN (electronic): 1432-1912
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