Effects of vibegron, a novel β3-adrenoceptor agonist, and its combination with imidafenacin or silodosin in a rat with partial bladder outlet obstruction.

Maruyama, Itaru; Yamamoto, Seigo; Tsuchioka, Kumi; Yamazaki, Takanobu

doi:10.1016/j.ejphar.2020.173096

Cited by 10 publications

(6 citation statements)

References 42 publications

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“…Cystometry measurements were conducted as described previously. 10,11,15 Female rats were anesthetized with isoflurane. A lower abdominal midline incision was performed to expose the bladder, and an Atom feeding catheter (3Fr; Atom Medical) was inserted into the bladder dome.…”

Section: Cystometry Measurementsmentioning

confidence: 99%

KPR‐5714, a selective transient receptor potential melastatin 8 antagonist, improves voiding dysfunction in rats with bladder overactivity but does not affect voiding behavior in normal rats

Watanabe

Fujimori

Matsuzawa

et al. 2022

Neurourology and Urodynamics

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Aims: Transient receptor potential melastatin 8 (TRPM8) has a role in the abnormal sensory transduction of the bladder and is involved in the pathophysiology of hyperactivity bladder disorders. The aim of this study is to examine the effects of KPR-5714, a novel and selective TRPM8 antagonist, on voiding dysfunction induced by bladder afferent hyperactivity via mechanosensitive C-fibers in rats. Methods: The effects of intragastric administration of KPR-5714 on bladder overactivity induced by intravesical instillation of 10 mM ATP were investigated using cystometry in conscious female rats. We examined the effects of oral administration of KPR-5714 on voiding behavior using a metabolic cage in normal male rats and rats with an intratesticular injection of 3% acetic acid.Results: In cystometry measurements, the intercontraction interval was decreased by intravesical ATP instillation. KPR-5714 (0.1, 0.3, and 1 mg/kg) dose-dependently prolonged the shortened intercontraction interval provoked by ATP. In voiding behavior measurements, intratesticular injection of acetic acid decreased the mean voided volume and increased voiding frequency. KPR-5714 (0.1 and 0.3 mg/kg) dose-dependently increased the mean voided volume and decreased voiding frequency without affecting the total voided volume in these rats. However, KPR-5714 (1 and 10 mg/kg) did not influence the voiding behavior in normal rats. Conclusion:The present results suggest that KPR-5714 improves voiding dysfunction by inhibiting the enhanced activity of mechanosensitive bladder C-fibers in rats with bladder overactivity and shows no significant change in voiding behavior in normal rats.

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Section: Cystometry Measurementsmentioning

confidence: 99%

KPR‐5714, a selective transient receptor potential melastatin 8 antagonist, improves voiding dysfunction in rats with bladder overactivity but does not affect voiding behavior in normal rats

Watanabe

Fujimori

Matsuzawa

et al. 2022

Neurourology and Urodynamics

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“…Vibegron was suspended in 20% polyethylene glycol, using an agate mortar and pestle, to generate a 3 mg/mL solution; then, the drug (10 mL/kg or 30 mg/kg body weight) or vehicle was orally administered by gavage once a day in the morning between 2 to 4 weeks after spinal cord transection, during which DO evident as non‐voiding contractions (NVCs) was shown to be established in SCI mice 5 . Although there is limited information on the dosage of vibegron in animal studies, a recent study showed that vibegron at 10 to 100 mg/kg reduced NVCs dose‐dependently in a rat model of bladder outlet obstruction 6 . Thus, the dosage (30 mg/kg) of vibegron was selected according to this study as well as other reports using another β3‐adrenoceptor agonist, mirabegron, in rodent models, 7,8 and confirmed to show the therapeutic efficacy for DO in SCI mice in preliminary experiments.…”

Section: Methodsmentioning

confidence: 99%

“…5 Although there is limited information on the dosage of vibegron in animal studies, a recent study showed that vibegron at 10 to 100 mg/kg reduced NVCs dose-dependently in a rat model of bladder outlet obstruction. 6 Thus, the dosage (30 mg/kg) of vibegron was selected according to this study as well as other reports using another β3-adrenoceptor agonist, mirabegron, in rodent models, 7,8 and confirmed to show the therapeutic efficacy for DO in SCI mice in preliminary experiments.…”

Section: Vibegron Administrationmentioning

confidence: 99%

Effects of a new β3‐adrenoceptor agonist, vibegron, on neurogenic bladder dysfunction and remodeling in mice with spinal cord injury

Gotoh

Shimizu

Wada

et al. 2020

Neurourology and Urodynamics

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Aims: To examine vibegron effects on lower urinary tract dysfunction (LUTD) in mice with spinal cord injury (SCI). Methods: Female mice underwent Th8-9 spinal cord transection and were orally administered vehicle or vibegron after SCI. We evaluated urodynamic parameters at 4 weeks after SCI with or without vibegron. Fibrosis-and ischemia-related messenger RNA (mRNA) and protein levels of collagen and elastin were measured in bladders of vehicle-and vibegron-treated SCI mice, and spinal intact mice. Results: Non-voiding contractions (NVCs) were significantly fewer (15.3 ± 8.9 vs 29.7 ± 11.4 contractions; P < .05) and the time to the first NVC was significantly longer (1488.0 ± 409.5 vs 782.7 ± 399.7 seconds; P < .01) in vibegrontreated SCI mice vs vehicle-treated SCI mice. mRNAs levels of collagen types 1 and 3, transforming growth factor-β1 (TGF-β1), and hypoxia-inducible factor-1α (HIF-1α) were significantly upregulated in vehicle-treated SCI mice compared with spinal intact and vibegron-treated SCI mice (Col 1: 3.5 vs 1.0 and 2.0-fold; P < .01 and P < .05, Col 3: 2.1 vs 1.0 and 1.2-fold; P < .01 and P < .05, TGF-β1: 1.2 vs 1.0 and 0.9-fold; P < .05 and P < .05, HIF-1α: 1.4 vs 1.0 and 1.0-fold; P < .05 and P < .01). Total collagen and elastin protein levels in vehicle-and vibegron-treated SCI mice did not differ. Conclusions: Vibegron reduced NVCs, delayed the first NVC, and improved collagen types 1 and 3, TGF-β1, and HIF-1α mRNA expression in SCI mice. Vibegron might be effective for SCI-induced LUTD.

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“…Vibegron was resuspended in 20% polyethylene glycol 400 with 80% distilled water in a volume of 10 ml/kg. 6 Because of the species difference in b3-adrenoceptor expression between rodents and humans, which shows approximately 80-fold lower affinity in rodents, 10 a 30-mg/kg vibegron dose was selected for the present study.…”

Section: Animal Preparationmentioning

confidence: 99%

“…4,5 Recently, it was reported that vibegron with imidafenacin or silodosin additively inhibited the frequency of NVCs without worsening voiding function in a rat model of partial bladder outlet obstruction as a model for BPH/OAB. 6 However, the therapeutic efficacy of vibegron in patients with neurogenic LUTD is not well elucidated. In this regard, we recently reported that vibegron treatment can reduce DO in association with a reduction in fibrotic changes of the bladder in SCI mice; 7 however, the underlying mechanisms for the improvement in DO by vibegron are still not well clarified.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of vibegron, a novel β3‐adrenoreceptor agonist, for lower urinary tract dysfunction in mice with spinal cord injury

et al. 2021

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Abbreviations & Acronyms Actb = b actin ATF3 = activating transcription factor 3 BPH = benign prostatic hyperplasia CMG = cystometrogram DO = detrusor overactivity DRG = dorsal root ganglia iNOS = inducible nitric oxide synthase LUTD = lower urinary tract dysfunction MP = micturition pressure mRNA = messenger RNA NVC = nonvoiding contraction OAB = overactive bladder PCR = polymerase chain reaction PVR = postvoid residual urine SCI = spinal cord injury SI = spinal intact TRPA1 = transient receptor potential cation channel subfamily A member 1 TRPV1 = transient receptor potential cation channel subfamily V member 1

show abstract

Effects of vibegron, a novel β3-adrenoceptor agonist, and its combination with imidafenacin or silodosin in a rat with partial bladder outlet obstruction.

Cited by 10 publications

References 42 publications

KPR‐5714, a selective transient receptor potential melastatin 8 antagonist, improves voiding dysfunction in rats with bladder overactivity but does not affect voiding behavior in normal rats

KPR‐5714, a selective transient receptor potential melastatin 8 antagonist, improves voiding dysfunction in rats with bladder overactivity but does not affect voiding behavior in normal rats

Effects of a new β3‐adrenoceptor agonist, vibegron, on neurogenic bladder dysfunction and remodeling in mice with spinal cord injury

Efficacy of vibegron, a novel β3‐adrenoreceptor agonist, for lower urinary tract dysfunction in mice with spinal cord injury

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