Effects of vibegron, a novel β 3-adrenoceptor agonist, and its combination with imidafenacin or silodosin in a rat with partial bladder outlet obstruction

Eur J Pharmacol. 2020 Jul 5;878:173096. doi: 10.1016/j.ejphar.2020.173096. Epub 2020 Apr 4.

Abstract

Urgency is regarded as a core symptom of overactive bladder (OAB) and may correspond to detrusor overactivity (DO). One of the causes of OAB in men is bladder outlet obstruction (BOO) associated with benign prostatic hyperplasia (BPH). Vibegron is a novel selective β3-adrenoceptor agonist recently approved for the treatment of OAB. However, in OAB patients with BPH (BPH/OAB), the effects of vibegron on storage functions, especially DO and voiding functions have not been fully investigated. In this study, we evaluated the effects of a single administration of vibegron on storage function (particularly focusing on non-voiding contractions [NVC] considered a surrogate marker for DO) and voiding functions, using a rat model of partial BOO as a model for BPH/OAB. Furthermore, the utility of vibegron in combination with imidafenacin (an antimuscarinic) or silodosin (an α1A-adrenoceptor blocker) was evaluated. Six weeks after establishment of BOO, the frequency and amplitude of NVC, evaluated by cystometrography, increased. Vibegron inhibited the frequency of NVC without affecting voiding function (micturition pressure, residual volume, and voiding efficiency). Imidafenacin and silodosin also inhibited the frequency of NVC; however, the inhibitory effects of vibegron were stronger than those of imidafenacin or silodosin. The combination of vibegron with imidafenacin or silodosin additively inhibited the frequency of NVC without worsening the voiding function. These results suggest the possibility that vibegron is effective as a single agent for the amelioration of storage symptoms in BPH/OAB patients and is useful in combination with either antimuscarinics or α1-adrenoceptor blockers.

Keywords: Benign prostatic hyperplasia; Imidafenacin; Overactive bladder; Silodosin; Vibegron; β(3)-adrenoceptor agonist.

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists / pharmacology*
  • Adrenergic beta-3 Receptor Antagonists / pharmacology*
  • Animals
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Female
  • Humans
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • Male
  • Muscarinic Antagonists / pharmacology*
  • Prostatic Hyperplasia / drug therapy*
  • Pyrimidinones
  • Pyrrolidines
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic / metabolism
  • Urinary Bladder / drug effects
  • Urinary Bladder Neck Obstruction / complications
  • Urinary Bladder Neck Obstruction / drug therapy*
  • Urinary Bladder, Overactive / drug therapy*
  • Urination / physiology

Substances

  • Adrenergic alpha-1 Receptor Antagonists
  • Adrenergic beta-3 Receptor Antagonists
  • Imidazoles
  • Indoles
  • Muscarinic Antagonists
  • 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
  • Receptors, Adrenergic
  • silodosin
  • imidafenacin