Study in the pathophysiology of overactive bladder-Effects of bladder ischemia and hyperlipidemia

研究目的：Watanabe遗传性高脂血症（WHHL）家兔存在动脉粥样硬化病变。文献报道，WHHL兔是研究动脉粥样硬化发生、发展及缺血相关病理变化的良好模型。材料和方法：选用6月龄、12月龄和24月龄3组雄性WHHL家兔，并选用与之年龄、性别相匹配的日本白色家兔作为对照组。连续测定每只家兔的排尿次数和每次排尿量3天。然后进行充盈性膀胱测压。处死后取膀胱行HE染色及S-100蛋白和CGRP神经元免疫组化染色。另外，将膀胱平滑肌条悬置在器官浴中，用氨甲酰胆碱、KCl（80 mM）和 关于我们 和电场刺激进行评价。结果：12和24月龄WHHL兔排尿次数和排尿量分别显著高于和低于对照组（P < 0. 05），而24月龄WHHL兔排尿次数和排尿量显著低于对照组（P < 0. 05）。在对照组中，组织氧合在组间无显著差异。在WHHL兔，有显着的年龄相关性降低膀胱组织氧合。12月龄WHHL兔膀胱测压结果显示，与对照组相比，无排尿性收缩、排尿间隔缩短、排尿量减少。在24 M龄WHHL兔中，异常发现加重。在功能研究中，卡巴胆碱和EFS引起的6和12月龄WHHL家兔的收缩与对照组相比显著增加。而24只M WHHL兔的反应明显减弱。WHHL组S-100蛋白阳性神经元密度随年龄增长而明显降低。12和24月龄WHHHL兔海马CGRP阳性神经元密度明显增加。WHHL组神经元ACh和ATP释放明显减少。结论：WHHL兔存在膀胱缺血性功能障碍。在膀胱缺血的早期阶段，平滑肌对神经递质的反应性增加可能导致逼尿肌过度活动。在慢性期，传入神经元的激活也可能导致逼尿肌过度活动。此外，逼尿肌活动不足是由平滑肌面积减少和对神经递质的反应性降低引起的，这可能是由神经递质释放减少引起的。少

Aims of study : Watanabe heritable hyperlipidemic(WHHL)rabbits have atherosclerotic lesions. It is reported that WHHL rabbit is a good model for study of the development and progression of atherosclerosis and the ischemia-related pathological changes. To clarify the process of ischemia-to bladder dysfunction, we evaluated the histological, physiological and pharmacological changes in bladder of WHHL rabbits.Materials and methods : Male WHHL rabbits in three age groups (6 months : 6 M, 12 months : 12 M and 24 months : 24 M) and the age and sex-matched Japanese white rabbits(control group)were used. Each rabbit was continuously measured the number of micturition and each micturition volume for 3 days. Then, filling cystometry was performed. After sacrifice, bladders were obtained for HE stainings and immunohistochemical stainings for S-100 protein and CGRP neurons. In addition, bladder smooth muscle strip was suspended in organ bath, and the contractions induced by carbachol, KC1(80 mM)a … More nd electrical field stimulation were evaluated. Neuronal and non-neuronal ACh and ATP release in both groups were measured using microdialysis procedure.Results : The number of micturition and voided volume in 12 and 24 M old WHHL rabbits were significantly higher and lower than that of the control, respectively. In the control groups, tissue oxygenation was not significant difference among groups. In WHHL rabbits, there was significant age-related decrease in bladder tissue oxygenation. Cystometric findings in 12 M old WHHL rabbits showed the non-voiding contractions, shorter interval micturition and lower micturition volume, as compared with the control. The abnormal findings worsened in the 24 M old WHHL rabbits. In the functional study, the contractions induce by carbachol and EFS in 6 and 12 M old WHHL rabbits significantly, increased, as compared with control. However, the responses significantly deceased in 24 M WHHL rabbits. In WHHL groups, the density of S-100 protein positive neuron significantly decreased with age. While, the density of CGRP positive neurons significantly increased in 12 and 24 M old WHHHL rabbits. Neuronal ACh and ATP releases in WHHL group significantly decreased. Stretch-induced non-neuronal ACh and ATP significantly increased in WHHL group.Conclusions : The data demonstrated the ischemia-induced bladder dysfunction in WHHL rabbits. In the early phase of bladder ischemia, increased smooth muscle responsiveness to neurotransmitters may contribute to detrusor overactivity. In the chronic phase, activation of afferent neurons may also contribute to the detrusor overactivity. Furthermore, detrusor underactivity was caused by decrease in smooth muscle area, and decreased responsiveness to neurotransmitters, which may be induced by decreased releases in neurotransmitters. Less