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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Physician Scientist Award (K11)
Project #
5K11DK001732-05
Application #
3086357
Study Section
Special Emphasis Panel (ADDK)
Project Start
1988-07-01
Project End
1991-12-31
Budget Start
1990-01-01
Budget End
1990-12-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Spitsbergen, J M; Stewart, J S; Tuttle, J B (1995) Altered regulation of nerve growth factor secretion by cultured VSMCs from hypertensive rats. Am J Physiol 269:H621-8
Tuttle, J B; Steers, W D; Albo, M et al. (1994) Neural input regulates tissue NGF and growth of the adult rat urinary bladder. J Auton Nerv Syst 49:147-58
Tuttle, J B; Mackey, T; Steers, W D (1994) NGF, bFGF and CNTF increase survival of major pelvic ganglion neurons cultured from the adult rat. Neurosci Lett 173:94-8
Tuttle, J B; Creedon, D J (1993) Pharmacology of nerve growth factor output by target cells. Ann N Y Acad Sci 692:273-6
Steers, W D; Kolbeck, S; Creedon, D et al. (1991) Nerve growth factor in the urinary bladder of the adult regulates neuronal form and function. J Clin Invest 88:1709-15
Steers, W D; Mackway, A M; Ciambotti, J et al. (1990) Effects of streptozotocin-induced diabetes on bladder function in the rat. J Urol 143:1032-6
Steers, W D (1990) Neural control of penile erection. Semin Urol 8:66-79
Steers, W D; Ciambotti, J; Erdman, S et al. (1990) Morphological plasticity in efferent pathways to the urinary bladder of the rat following urethral obstruction. J Neurosci 10:1943-51
Mallory, B; Steers, W D; De Groat, W C (1989) Electrophysiological study of micturition reflexes in rats. Am J Physiol 257:R410-21
Steers, W D; de Groat, W C (1989) Effects of m-chlorophenylpiperazine on penile and bladder function in rats. Am J Physiol 257:R1441-9

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