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

Neurourol Urodyn. 2020 Nov;39(8):2120-2127. doi: 10.1002/nau.24486. Epub 2020 Aug 20.

Abstract

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 vibegron-treated 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.

Keywords: detrusor overactivity; mice; spinal cord injury; urodynamics; vibegron.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adrenergic beta-3 Receptor Agonists / pharmacology*
  • Adrenergic beta-3 Receptor Agonists / therapeutic use
  • Animals
  • Disease Models, Animal
  • Female
  • Mice
  • Pyrimidinones / pharmacology*
  • Pyrimidinones / therapeutic use
  • Pyrrolidines / pharmacology*
  • Pyrrolidines / therapeutic use
  • Rats, Sprague-Dawley
  • Spinal Cord Injuries / complications*
  • Spinal Cord Injuries / physiopathology
  • Treatment Outcome
  • Urinary Bladder, Neurogenic / drug therapy*
  • Urinary Bladder, Neurogenic / etiology
  • Urinary Bladder, Neurogenic / physiopathology
  • Urination / drug effects*
  • Urodynamics / drug effects*

Substances

  • Adrenergic beta-3 Receptor Agonists
  • N-(4-((5-(hydroxy(phenyl)methyl)pyrrolidin-2-yl)methyl)phenyl)-4-oxo-4,6,7,8-tetrahydropyrrolo(1,2-a)pyrimidine-6-carboxamide
  • Pyrimidinones
  • Pyrrolidines