Protective Effects of Antimuscarinics on the Bladder Remodeling After Bladder Outlet Obstruction

Abstract

Background/Aims: Overactive bladder associated with bladder outlet obstruction (BOO) is a highly prevalent condition, which is usually treated with antimuscarinics. However, the potential effects of antimuscarinics on the structure and function of bladder have not been investigated thus far. Methods: Sprague-Dawley(R) rats accepted bladder neck obstruction surgery or sham surgery, and then received treatment of three different antimuscarinics (Solifenacin, Darifenacin, and Tolterodine) or vehicle. After 3, 6 and 12 weeks, the bladder function and structure were measured. The effect of antimuscarinics on cellular alteration in vitro was observed under mechanical stimulation. Bladder morphology were examined by immunohistochemistry, and the bladder function were investigated by cystometry and strip contractility test. The expression of muscarinic receptors and inflammatory cytokines were measured by PCR and Western blotting. Results: Here we demonstrate, both in vitro and in vivo, that antimuscarinics are protective regulators for the bladder structure and function. Antimuscarinics decrease the weight of bladders with BOO. Antimuscarinics improve the voiding parameter and enhance the contraction of bladder smooth muscle. The results also show that antimuscarinics inhibit the proliferation of bladder smooth muscle cells both in vivo and in vitro, it can reduce the collagen deposition and inflammatory cytokines in bladders with BOO. During this process, the expression of M2 and M3 receptors was altered by antimuscarinics. Conclusion: Antimuscarinics could reverse the structural and functional changes of BOO bladder wall at cellular and tissue level, and the alteration of M2 and M3 receptors may be involved in this biological process.

Systematic Analysis of Transcriptomic Profile of the Effects of Low Dose Atropine Treatment on Scleral Fibroblasts using Next-Generation Sequencing and Bioinformatics

“…Accumulating evidence revealed that anticholinergics have anti-remodeling effects 14-16, and our results also showed that gene expression across atropine-treated scleral fibroblasts were associated with anti-remodeling effects via metabolic and structural pathways. We identified 389 differentially expressed genes in scleral fibroblasts treated with low dose atropine as compared with the control group.…”

“…Anticholinergics have shown potential anti-remodeling effects of airway and lung tissues in both in vivo and in vitro studies 14,15. Antimuscarinics also demonstrated protective effects in bladder remodeling in bladder outlet obstruction situations through direct antagonistic effect and reduced muscarinic receptor expressions 16. Atropine is a non-selective antimuscarinic agent evident to be effective in preventing the progression of myopia in children 17,18, and a lower concentration of topically administered atropine could prevent myopia onset in premyopic children with lower incidence of adverse effects such as photophobia and blurry vision 19.…”

M3 receptor modulates extracellular matrix synthesis via ERK1/2 signaling pathway in human bladder smooth muscle cells

“…Release of nonneuronal acetylcholine, a muscarinic receptor agonist, can be elevated by mechanical stimuli, which are common changes in BOO 21,22 . A previous study has demonstrated that M 2 and M 3 receptors were in high protein expression levels in BOO rats 8 . In our study, we found that the activation of muscarinic receptors, mainly on the M3 receptor, can increase the protein expression of TIMP‐1 and TIMP‐2, which may inhibit the activity of MMPs and reduce the degradation of collagen 23 .…”

“…Previous studies in chronic obstructive pulmonary diseases (COPD) and asthma, suggested that M receptors played an important role in the process of lung tissue remodeling 7 . Our past research demonstrated that protein levels of M 2 and M 3 receptors were elevated in BOO rats and M receptor antagonists could noticeably ameliorate ECM deposition, indicating that M receptors might participate in the regulation of ECM turnover in bladders 8 …”

Urethral meatus stricture BOO stimulates bladder smooth muscle cell proliferation and pyroptosis via IL‑1β and the SGK1‑NFAT2 signaling pathway

“…BOO leads to urothelial inflammasome activity, bladder hypertrophy and fibrosis, and bladder smooth muscle cell (BSMc) proliferation (2,3). Stress stimulation, hypoxia and other conditions induce bladder remodeling during Boo, which can also result in progressive tissue remodeling of the bladder (4,5). Pathological alterations in Boo-induced bladder remodeling occur in three stages: hypertrophy, compensation and decompensation (6).…”