Effects of a new β3‐adrenoceptor agonist, vibegron, on neurogenic bladder dysfunction and remodeling in mice with spinal cord injury
Daisuke Gotoh, Nobutaka Shimizu, Naoki Wada, Katsumi Kadekawa, Tetsuichi Saito, Shinsuke Mizoguchi, Yosuke Morizawa, Shunta Hori, Makito Miyake, Kazumasa Torimoto, William C. de Groat, Kiyohide Fujimoto, Naoki Yoshimura
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.