Mirabegron and solifenacin are effective for the management of the increased urinary frequency induced by psychological stress in female mice

Abstract

Evidence to support the effectiveness of β3-adrenoceptor agonist mirabegron and anti-muscarinic solifenacin in the management of bladder dysfunction caused by psychological stress is lacking. This study investigates whether mirabegron or solifenacin reduces the bladder overactivity caused by water avoidance stress (WAS) in mice. Female mice were exposed to WAS for 1 h/day for 10 days and received either placebo, solifenacin or mirabegron in drinking water. Controls were age-matched without stress exposure. Voiding behaviour and functional isolated whole bladder responses during distension and in response to pharmacological agents and electrical field stimulation was investigated. Urinary frequency was significantly increased following stress. Mice treated with mirabegron or solifenacin displayed significantly fewer voiding events compared to the stressed mice, and voiding frequency in drug-treated animals was comparable to unstressed controls. The maximal contractile responses of bladders to carbachol were significantly enhanced by stress and reduced by mirabegron but not solifenacin. The frequency of phasic bladder contractions following stimulation with carbachol was significantly enhanced following stress and remained elevated in the mirabegron treated group. However, treatment with solifenacin significantly reduced the frequency of phasic contractions to unstressed control levels. Solifenacin and mirabegron are beneficial in reducing the overall voiding dysfunction caused by WAS in mice.

Efficacy of KPR‐5714, a selective transient receptor potential melastatin 8 antagonist, on chronic psychological stress‐induced bladder overactivity in male rats

“…Several studies have reported that harvested bladders from female rats of different strains, such as Wistar‐Kyoto, Wistar and SD, with water avoidance stress exposure showed inflammatory conditions, including edema, ulceration, inflammatory cell infiltration, vascular congestion, increased angiogenesis, and an increased number of mast cells 14,16,17 . In addition, serum levels of corticosterone, NGF, and noradrenaline were significantly elevated in female C57BL/6 J mice and Wistar rats subjected to water avoidance stress 13,18 . In the present study, the bladder from male SD rats exposed to water avoidance stress did not exhibit inflammatory responses, morphological differences, and significant differences in the total number of mast cells.…”

“…14,16,17 In addition, serum levels of corticosterone, NGF, and noradrenaline were significantly elevated in female C57BL/6 J mice and Wistar rats subjected to water avoidance stress. 13,18 In the present study, the bladder from male SD rats exposed to water avoidance stress did not exhibit inflammatory responses, morphological differences, and significant differences in the total number of mast cells. In addition, there was no significant difference in serum levels of corticosterone, NGF, and noradrenaline between normal rats and rats subjected to water avoidance stress.…”

“…West et al 13 reported that repeated exposure to water avoidance stress in female C57BL/6J mice produced an overactive bladder phenotype, confirmed by increased voiding frequency and associated with enhanced bladder contractile responses. In this established mice model, mirabegron, a β3‐adrenoceptor agonist, and solifenacin, an anticholinergic drug, administered by drinking water during the 10‐day experimental period decreased urinary frequency and the number of small voids without affecting the total voided area in voiding pattern analysis 13 . In addition to KPR‐5714, we also evaluated the efficacy of mirabegron and tolterodine tartrate, an anticholinergic drug, in rats with water avoidance stress exposure.…”

“…The application of stress‐related animal models has provided valuable tools to study the interaction between lower urinary tract dysfunction and chronic psychological stress 12 . Among others, the water avoidance stress model is used widely to study the underlying mechanisms of chronic stress‐induced lower urinary tract dysfunction and evaluate the efficacy of pharmacological agents 12,13 . Water avoidance stress exposure in rodents produces an overactive bladder phenotype characterized by enhanced bladder contractile responses and increased voiding frequency 14–19 .…”

“…12 Among others, the water avoidance stress model is used widely to study the underlying mechanisms of chronic stress-induced lower urinary tract dysfunction and evaluate the efficacy of pharmacological agents. 12,13 Water avoidance stress exposure in rodents produces an overactive bladder phenotype characterized by enhanced bladder contractile responses and increased voiding frequency. [14][15][16][17][18][19] Water avoidance stress exposure also enhances the activity of afferent nerve fibers, and capsaicin consistently reduces nerve activity in response to bladder distension.…”