| Budget Amount *help |
¥3,950,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2007: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2006: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Research Abstract |
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
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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
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