Bladder outlet obstruction in elderly men due to prostatic hypertrophy, malignancy, or urethral stricture disease is common and can result in detrusor dysfunction. This dysfunction, manifested as detrusor hyperreflexia or areflexia, is often irreversible once the obstruction is surgically relieved and may cause recurrent urinary infections or a progressive deterioration in renal function. The goal of this study is to go beyond previous morphological investigations and to determine, using electrophysiological and pharmacological methods, whether this bladder dysfunction is due to a myogenic mechanism and/or a change in the micturition neural reflex. In Phase I partial bladder outlet obstruction will be created in male and female Sprague-Dawley rats by ligation of the proximal urethra over a 1 mm glass rod. Sham surgery will be performed in control rats. Rats will be stratified according to sex and duration of obstruction. Obstruction will be monitored using bladder weight, light microscopy, and urodynamics. A subset of rats will undergo deligation of the urethra at varying times after surgery to determine reversibility of bladder dysfunction. The development of detrusor hyperreflexia and areflexia will be documented using cystometrographics. Each component of the micturition reflex will be examined in both obstructed and unobstructed rats using in vivo electrical stimulation and recording neural evoked responses, intra-arterial and intrathecal drug administration, and intracellular recording techniques. Investigation into the possible role of enkephalins, vasoactive intestinal polypeptide and substance P in this dysfunction will be made by noting immunohistochemical and pharmacological changes between obstructed and unobstructed rats. The effect of aging on cystometrographic, electrophysiologic, and pharmacologic changes will be examined. Phase II will involve a continuation of these animal studies and possible urodynamic and immunohistochemical studies on elderly men with bladder outlet obstruction. Once the mechanism of bladder dysfunction and determinants of its reversibility are elucidated, surgical guidelines and possible pharmacologic therapy can be established.
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