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.

Figure 1

Analysis of voiding behaviour in unstressed, stressed, stress + mirabegron and stress + solifenacin mice measured as (A) total voided area, (B) urinary frequency, (C) average void size and (D) number of small voids. Data is presented as mean ± SEM (n = 6) and was analysed using two-way ANOVA with two-way repeated measures ANOVA (**p < 0.01, ***p < 0.001, Unstressed vs Stressed), (⁺p < 0.05, ^+ ++p < 0.001 Stressed vs Stress + Mirabegron), (*p < 0.05, ^###p < 0.01 Stressed vs Stress + Solifenacin).

Figure 2

Effects of water avoidance stress or treatment of stressed mice with mirabegron or solifenacin on (A) plasma corticosterone, (B) the volume pressure relationship, and spontaneous phasic contractions in isolated bladders measured as (C) frequency and (D) amplitude. Data is presented as mean ± SEM (n = 6) and was analysed using one-way ANOVA (A), two-way ANOVA (B) with Tukey multiple comparisons test or Kruskal–Wallis with Dunn’s multiple comparisons test (C,D) (**p < 0.01 vs Unstressed; ^#p < 0.05, ^##p < 0.01 vs Stressed).

Figure 3

Effect of water avoidance stress or stress plus treatment with mirabegron or solifenacin on cumulative carbachol concentrations measured as (A) change in pressure and (B) normalised to KCl response; and phasic response to 1 µM carbachol measured as (C) frequency and (D) amplitude of phasic contractions. Data represents mean ± SEM (n = 6) and was analysed using two-way ANOVA with Tukey multiple comparisons test (A,B) or Kruskal–Wallis test Dunn’s multiple comparisons test (C,D) (A: *p < 0.05 Stressed vs Unstressed; C: *p < 0.05, **p < 0.01 Stressed vs Unstressed; ^#p < 0.05 Stress + Solifenacin vs Stressed).

Figure 4

Responses of isolated whole bladders from unstressed, stressed, and mirabegron and solifenacin treated mice to electrical field stimulation measured as (A) change in intravesical pressure and (B) normalised to KCl response; and (C) cumulative concentrations of the beta-adrenoceptor agonist isoprenaline following carbachol pre-contraction (1 µM). Data represent mean ± SEM (n = 6) and was analysed using two-way ANOVA with Tukey multiple comparisons test (*p < 0.05, **p < 0.01 Unstressed vs Stressed).

Figure 5

Effect of water avoidance stress or stress and treatment with mirabegron or solifenacin on total release of (A,B) ATP and (C,D) ACh into the intraluminal fluid (from inside of the bladder lumen) and serosal fluid (from the bathing solution) following distension of isolated whole bladders to 20 mmHg. Data is presented as mean ± SEM (n = 6) and was analysed using one-way ANOVA with Tukey–Kramer multiple comparisons test (**p < 0.01 vs Unstressed; ^##p < 0.01 vs Stressed).