RESUMO
OBJECTIVE: To evaluate voiding behavior characteristics in intact and sham mice, and to examine whether intact mice show changes in "normal" micturition with aging. METHODS: A total of 72 8-week-old mice were divided into two groups - intact and sham - and the latter group was subjected to a sham of partial bladder outlet obstruction surgery. Urination frequency was evaluated (through metabolic cages) at 1, 2, 3, 6 and 12 months after the surgery (or at the equivalent time points for the intact mice). To address possible mechanisms for aging and surgical effects on urinary behavior, quantitative real-time polymerase chain reaction assays were carried out. Primary data were evaluated using scatter plots and descriptive statistics. RESULTS: In sham mice, urination frequency showed strong variation at the earlier post-surgical time points (especially at 1 month), with variation decreasing with time. Quantitative real-time polymerase chain reaction showed that the serotonin 2C receptor-encoding mRNA accumulated to >28-fold higher levels at 24 months compared with 3 months in intact mice. A major limitation of the quantitative real-time polymerase chain reaction experiments was that we did not separate whole bladder into muscle and mucosa. CONCLUSIONS: Although a sham operation is typically used in partial bladder outlet obstruction experiments to provide control animals, the sham group might itself show increased variation in micturition frequency at early times after surgery, compared with intact animals.
Assuntos
Obstrução do Colo da Bexiga Urinária , Animais , Camundongos , Mucosa , RNA Mensageiro , MicçãoRESUMO
OBJECTIVE: To investigate the effect of chronic administration of an alpha-1 blocker on micturition patterns in long-term partial bladder outlet obstruction. METHODS: Mice were divided into three groups: a normal group, in which animals were fed a standard diet; a partial bladder outlet obstruction group, in which the proximal urethra was tied and animals were fed a standard diet; and a partial bladder outlet obstruction + naftopidil group, in which the proximal urethra was tied and animals were fed a standard diet containing naftopidil. Micturition behavior was evaluated in all groups for 6 months after partial bladder outlet obstruction surgery. The parameters evaluated included voided volume, time per void, urination frequency and total urine volume. Quantitative assessment of gene expression was also carried out. RESULTS: Total urine volume, as well as total and average voided volume during night, was significantly decreased in partial bladder outlet obstruction + naftopidil mice compared with partial bladder outlet obstruction animals. The levels of transcripts encoding 5-hydroxytryptamine 2A and tissue inhibitor of metalloproteinase 2 were significantly decreased in the partial bladder outlet obstruction + naftopidil group compared with the partial bladder outlet obstruction group. CONCLUSIONS: Long-term administration of an alpha-1 blocker seems to reverse the disturbance of the micturition pattern caused by partial bladder outlet obstruction. Mechanistically, this effect might be mediated by changes in the expression of a serotonin receptor and/or in the activity of the fibrogenesis pathway.
Assuntos
Obstrução do Colo da Bexiga Urinária , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Inibidor Tecidual de Metaloproteinase-2 , Obstrução do Colo da Bexiga Urinária/tratamento farmacológico , MicçãoRESUMO
The circadian clock programs daily rhythms and coordinates multiple behavioural processes, including micturition. Partial bladder outlet obstruction (pBOO) in mice produces hyperactive voiding. However, long-term effects of pBOO on bladder function have not been clarified. In this study, we investigated micturition under conditions of impaired circadian bladder function by inducing long-term pBOO by tying the proximal urethra. Micturition behavior was evaluated at 1, 3, 6 and 12 months after surgery. We used automated voided stain on paper method for a precise micturition recording for mice. And quantitative assessment of gene expression was performed at 24 months after pBOO surgery using qRT-PCR procedure. The micturition frequencies in the pBOO group were significantly decreased at 3, 6, and 12 months compared to those at 1 month after operation in the same group (p < 0.05). Body weight of pBOO mice was significantly increased compared to sham operated mice at 12 months. The expression level of mRNA was exhibited a 3.4-fold nominal increased for a 5-HT2B receptor in the pBOO group compared to the sham group. The current study found that long-term pBOO led to disruption of the circadian bladder function (the day/night cycle) in mice, similar to those observed in human as nocturia. This disruption is possible involvement of the gain of body weight and/or serotonergic alteration after pBOO.
Assuntos
Relógios Circadianos/genética , Receptor 5-HT2B de Serotonina/genética , Obstrução do Colo da Bexiga Urinária/genética , Micção/genética , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Contração Muscular/genética , RNA Mensageiro/genética , Uretra/metabolismo , Uretra/patologia , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Obstrução do Colo da Bexiga Urinária/patologia , Micção/fisiologiaRESUMO
Estrogens play undisputedly important physiological roles, but lifetime exposure to estrogens has also been linked to the development of breast cancer. Moreover, imbalanced estrogen levels have been associated with various symptoms such as osteoporosis and menopausal disorders. For the improvement of such estrogen imbalances, estrogenic reagents with regulatory properties have shown promising potential. Herein, we report the construction of a 12-arylbenzoacridine library via a diversity-oriented strategy that furnished non-toxic estrogenic and anti-estrogenic agents. Derivatives with a hydroxy group at the molecular edge exhibit potent binding affinity to the estrogen receptor α (ERα) and ERß (IC50 < µM), while binding to the estrogen-related receptor γ (ERRγ), i.e., an orphan nuclear receptor on which estrogens often trigger unfavorable events, was not observed. These findings offer valuable insights into 12-arylbenzoacridines as a novel platform for the development of selective estrogen-receptor modulators (SERMs).