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

Gotoh D1, Shimizu N1, Wada N1, Kadekawa K1, Saito T1, Mizoguchi S1, Kurobe M1, Torimoto K2, Fujimoto K2, Yoshimura N1

Research Type

Basic Science / Translational

Abstract Category

Pharmacology

Abstract 232
Autonomic Pharmacology
Scientific Podium Short Oral Session 12
Wednesday 4th September 2019
17:07 - 17:15
Hall H2
Animal Study Detrusor Overactivity Pharmacology Physiology Spinal Cord Injury
1.University of Pittsburgh, 2.Nara Medical University
Presenter
D

Daisuke Gotoh

Links

Abstract

Hypothesis / aims of study
Neurogenic lower urinary tract dysfunction due to spinal cord injury (SCI) includes detrusor overactivity (DO), low bladder compliance, and detrusor-sphincter dyssynergia (DSD). The primary treatments for patients with these conditions are the use of anticholinergic medication and/or clean intermittent self-catheterization. Nonetheless, anticholinergic medication often causes adverse events such as dry mouth and constipation. Vibegron is a new β3-adrenoceptor agonist that was approved for the treatment of overreactive bladder in Japan in 2018. It has been reported that β3-adrenoceptor agonists such as mirabegron cause fewer clinical adverse events than anticholinergic medication (1). Therefore, vibregon could be potentially used to treat patients with neurogenic bladder dysfunction due to SCI. However, the effects of vibegron on bladder dysfunction and bladder wall remodeling after SCI are not previously demonstrated. Therefore, we examined the bladder activity and the fibrotic and ischemic changes in the bladders of SCI mice with or without vibegron treatment.
Study design, materials and methods
We used female C57BL/6N mice (9 weeks old) in this study and divided them into three groups: Group A of spinal cord intact mice; Group B of SCI mice treated with a vehicle; and Group C of SCI mice treated with vibegron. The mice in the SCI groups underwent Th8-9 spinal cord transection followed by oral administration of a vehicle or vibegron (30 mg/kg/day) by oral gavage once a day in the morning for 2 to 4 weeks after spinal cord transection. The bladder of spinalized mice was emptied by abdominal compression once daily after the spinal cord transection. We evaluated the urodynamic parameters using awake cystometry and the mRNA levels of fibrosis-related molecules and ischemia markers 4 weeks after SCI induction.  In cystometry, we measured maximal micturition pressure (MP), intercontraction intervals (ICI), postvoid residual (PVR), bladder capacity, bladder compliance, and voiding efficiency by continuous cystometry and the number of non-voiding contractions (NVCs) per voiding and the time to the first NVC by single cystometry. NVC was defined as an increase in intravesical pressure of more than 8 cmH2O above the baseline. Gene expression of fibrosis markers such as type 1 collagen, type 3 collagen, transforming growth factor beta 1 (TGF-β1), and fibroblast growth factor (FGF), and ischemia markers such as hypoxia-inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) were quantified using  real-time PCR. All values are expressed as means ± standard deviations. We used the Mann Whitney U test to evaluate statistical differences between the groups. A P-value < 0.05 was considered statistically significant.
Results
The number of NVC per voiding cycle was significantly lower in the group C than in the group B (15.3 ± 8.9 vs. 29.7 ± 11.3 contractions) (Figure 1). The time required to induce the 1st NVC was significantly longer in the group C compared to the group B (1488.0 ± 409.5 vs. 782.7 ± 399.7 seconds).The ICI was also significantly longer in the group C than in the group B (4.3 ± 2.3 vs. 2.4 ± 0.5 minutes). However, there were no significant differences in MP, PVR, bladder capacity, bladder compliance, and voiding efficiency between groups B and C. In molecular studies, we observed marked increases in mRNA expression of type 1 collagen (3.5-fold), type 3 collagen (2.1-fold), FGF (3.1-fold), and HIF-1α (4.0-fold) at 4 weeks in the group B compared to the group A (Figure 2). The increased expression of type 1 and type 3 collagen at 4 weeks was significantly reduced in the group C (2.0-fold and 1.2-fold, respectively) when compared to the group B. The expression of TGF-β1 mRNA was decreased (0.4-fold) at 4 weeks in the group B compared to the group A, and further reduced significantly (0.1-fold of group A) in the group C. There were no significant differences in the expression of VEGF among the three groups.
Interpretation of results
Previous studies in rodent SCI models demonstrated that the afferent limb of micturition reflexes inducing NVCs and voiding bladder contractions are probably controlled by C-fiber and Aδ-fiber afferent pathways, respectively, after SCI (2). In this study, because vibegron treatment decreased SCI-induced DO evident as reduced NVC, our results indicate that vibegron is useful for the treatment of neurogenic detrusor overactivity dependent on the activation of C-fiber bladder afferent pathways. Additionally, vibegron treatment improved bladder remodeling associated with tissue fibrosis as shown by the reduced mRNA expression of type 1 collagen, type 3 collagen, and TGF-β1 after vibegron administration although the decrease in TGF-β1 expression after 4-weeks SCI in the group B was unexpected.
Concluding message
Vibegron, a new β3-adrenoceptor agonist approved for OAB, reduced the number of NVCs, delayed the appearance of the 1st NVC, and improved the mRNA expression of type 1 collagen, type 3 collagen, and TGF-β1 in SCI mice. Thus, vibegron treatment could be effective for reducing SCI-related neurogenic detrusor overactivity and remodeling in the bladder.
Figure 1
Figure 2
References
  1. Neurourol Urodyn. 36: 1097-1103, 2017
  2. Am J Physiol Renal Physiol. 313: F796-F804, 2017.
Disclosures
<span class="text-strong">Funding</span> DOD W81XWH-17-1-0403, NIH P01DK093424, KAKENHI for Early-Career Scientists (18K16751) <span class="text-strong">Clinical Trial</span> No <span class="text-strong">Subjects</span> Animal <span class="text-strong">Species</span> mouse <span class="text-strong">Ethics Committee</span> University of Pittsburgh Institutional Animal Care and Use Committee