The novel β3-adrenoceptor agonist mirabegron reduces carbachol-induced contractile activity in detrusor tissue from patients with bladder outflow obstruction with or without detrusor overactivity

Svalø, Julie; Nordling, Jørgen; Bouchelouche, Kirsten; Andersson, Karl‐Erik; Korstanje, Cees; Bouchelouche, Pierre

doi:10.1016/j.ejphar.2012.11.060

Cited by 41 publications

(41 citation statements)

References 28 publications

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“…Here we found that the β3-receptor agonist CL316243 caused 14 less relaxation in BOO than in control detrusor. In all, our results are therefore consistent with prior studies (Svalø et al, 2013, Barendrecht et al, 2009 indicating that relaxation to β3-adrenoceptor stimulation is attenuated following outlet obstruction.…”

Section: Discussionsupporting

confidence: 82%

Non-uniform changes in membrane receptors in the rat urinary bladder following outlet obstruction

Zeng

Ekman

Jiang

et al. 2015

European Journal of Pharmacology

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The aim of the present study was to investigate the expression and distribution of membrane receptors after bladder outlet obstruction (BOO). Partial bladder outlet obstruction (BOO) was induced in female rats and bladders were harvested after either 10 days or 6 weeks of BOO. The expression of different receptors was surveyed by microarrays and corroborated by immunohistochemistry and western blotting. A microarray experiment identified 10 membrane receptors that were differentially expressed compared to sham-operated rats including both upregulated and downregulated receptors. Four of these were selected for functional experiments on the basis of magnitude of change and relevance to bladder physiology. At 6 weeks of BOO, maximal contraction was reduced for neuromedin B and vasopressin (AVP), consistent with reductions of receptor mRNA levels. Glycine receptor-induced contraction on the other hand was increased and receptor mRNA expression was accordingly upregulated. Maximal relaxation by the β3-adrenergic receptor agonist CL316243 was reduced as was the receptor mRNA level.Immunohistochemistry supported reduced expression of neuromedin B receptors, V1a receptors and β3-adrenergic receptors, but glycine receptor expression appeared unchanged. Western blotting confirmed repression of V1a receptors and induction of glycine receptors in BOO.mRNA for vasopressin was detectable in the bladder, suggesting local AVP production. We conclude that changes in receptor expression following bladder outlet obstruction are nonuniform. Some receptors are upregulated, conferring increased responsiveness to agonist, whereas others are downregulated, leading to decreased agonist-induced responses. This study might help to select pharmacological agents that are effective in modulating lower urinary tract symptoms in BOO.3

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Section: Discussionsupporting

confidence: 82%

Non-uniform changes in membrane receptors in the rat urinary bladder following outlet obstruction

Zeng

Ekman

Jiang

et al. 2015

European Journal of Pharmacology

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“…One of these studies demonstrated that the relaxing effects in rat bladder were not affected by co-application of the β 1 -adrenoceptor antagonist CGP 20,712A and the β 2 -adrenoceptor antagonist ICI 118,551 but inhibited when the β 3 -adrenoceptor antagonist SR 58,894A was added on top of ICI 118,551, yielding an apparent pA 2 value of 6.43 for the latter, in line with the Svalo et al (2013). Note that studies a, f, h, n, o, and p were performed against carbachol-induced contraction; studies b, g, l, and m, against KCl-induced contraction; and c, d, e, i, and k, against passive tension.…”

Section: Isolated Tissue Studiesmentioning

confidence: 63%

“…In another study in rat bladder, a comparable potency of mirabegron was detected, but, in that study, the efficacy relative to isoprenaline was slightly smaller . Another study has compared the potency and efficacy of mirabegron and isoprenaline in isolated detrusor strips obtained from patients without bladder dysfunction, bladder outlet obstruction, and bladder outlet obstruction with documented detrusor overactivity (Svalo et al 2013). While mirabegron was consistently less potent than isoprenaline in all three groups, its efficacy was comparable to that of isoprenaline; while the potency of isoprenaline was significantly lower in patients with than without bladder outlet obstruction, smaller numerical differences between groups with mirabegron did not reach statistical significance.…”

Section: Isolated Tissue Studiesmentioning

confidence: 99%

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Igawa

Michel

2012

Naunyn-Schmiedeberg's Arch Pharmacol

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β 3 -Adrenoceptor agonists are an emerging drug class for the treatment of the overactive bladder syndrome, and clinical proof-of-concept data have been obtained for three representatives of this class, mirabegron, ritobegron, and solabegron. We review here the pharmacological profile of these three drugs and discuss the potential clinical relevance of differences between them. In the absence of direct comparative studies, it appears that all three are strong agonists selective for β 3 -vs. β 1 -and β 2 -adrenoceptors in studies with cloned receptor subtypes. The potency of these agonists may be species-dependent, with all three having high potency in the human detrusor. All three agonists were effective in one or more animal models of bladder dysfunction, which typically involved reductions of micturition frequency. Agonist doses effective for bladder function lowered blood pressure in some cases, but the relevance of this for clinical use is difficult to determine due to species differences in the importance of cardiovascular β 3 -adrenoceptors. While limited effects on other organ systems are expected for β 3 -adrenoceptor agonists, this requires further investigation.

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“…In animal models, β-AR agonists have been reported to increase bladder capacity with no change in micturition pressure or residual volume (Fujimura et al 1999;Takeda et al 2002). In vitro investigations on isolated detrusor smooth muscle from human bladders suggested that β 3 -AR activation produces relaxation of basal bladder tension and bladder that has been pre-contracted with carbachol or KCl (Svalø et al 2013).…”

Section: Introductionmentioning

confidence: 98%

Prostaglandin E2 excitatory effects on rat urinary bladder: a comparison between the β-adrenoceptor modulation of non-voiding activity in vivo and micro-contractile activity in vitro

Granato

Korstanje

Guilloteau³

et al. 2015

Naunyn-Schmiedeberg's Arch Pharmacol

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Prostaglandin E2 (PGE2) 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 PGE2 have been found in overactive bladder (OAB) patients. β-Adrenoceptors are major players in detrusor muscle relaxation, and the selective β3-adrenoceptor (AR) agonist mirabegron was recently approved for the treatment of overactive bladder (OAB). β-Adrenoceptor modulation of PGE2 excitatory effects on bladder detrusor muscle was investigated by i.v. mirabegron after intravesical PGE2 infusion in conscious rats. Non-voiding activity (NVA) was assessed under isovolumetric conditions. In addition, mirabegron and isoprenaline (0.01-10 μM) were studied on PGE2-increased micro-contractile activity during isometric tension recordings of intact isolated bladder muscle strips. Our investigations showed that PGE2 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 PGE2-augmented NVA in dose-dependent manner, while the PGE2-increased micro-contractions in isolated bladder strips were poorly inhibited. Isoprenaline inhibited PGE2-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 PGE2-augmented micro-contractions suggests a β1-AR-mediated.

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The novel β3-adrenoceptor agonist mirabegron reduces carbachol-induced contractile activity in detrusor tissue from patients with bladder outflow obstruction with or without detrusor overactivity

Cited by 41 publications

References 28 publications

Non-uniform changes in membrane receptors in the rat urinary bladder following outlet obstruction

Non-uniform changes in membrane receptors in the rat urinary bladder following outlet obstruction

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Prostaglandin E2 excitatory effects on rat urinary bladder: a comparison between the β-adrenoceptor modulation of non-voiding activity in vivo and micro-contractile activity in vitro

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