Each year obstruction of the urinary bladder from prostatism leads to 400,000 surgeries and accounts for the second largest expenditure of Medicare dollars. Although obstruction is unusual in women it can result from surgery for urinary incontinence. Despite the prevalence of this condition and the costs treatment failures due to persistent urgency, frequency and nocturia occur in at least 1/3 of patients. Partial urethral ligation in the rat represents a model for this bladder hyperactivity. Although urodynamic parameters return to unobstructed levels after deligation, urinary frequency persists in 1/3 to 1/2 of rats. Myogenic and neurogenic hypotheses have been put forth to explain the development of increased urinary frequency urgency and nocturia with obstruction. We propose that irritative voiding following relief of obstruction results from persistent derangements in smooth muscle and/or nerve. it has been shown that obstructive changes in bladder smooth muscle are transmitted to its innervation by Nerve Growth Factor (NGF). NGF produced by hypertrophied smooth muscle has been linked to the development of hyperactive voiding. This proposal tests the hypothesis that resolution of urinary frequency in deligated (unobstructed) rats relies on reversal of alterations in detrusor smooth muscle and/or its innervation. This hypothesis will be tested in deligated rats with hyperactive and normal voiding by: 1) evaluating the in vivo responses of smooth muscle to carbachol, and bladder neurons to capsaicin or apomorphine. 2) determining whether changes in smooth muscle content or contractility neuronal size, GAP-43 expression in the sacral spinal cord, a spinal reflex, NGF content in the bladder or ganglia. or NGF receptor (p75/trkA) expression correlate with voiding frequency, and 3) noting if tyrosine kinase inhibitors that block the effects of NGF binding to the trkA receptor prevent myogenic or neural plasticity and urinary frequency. Smooth muscle myosin and actin content will be measured using 2-D gel electrophoresis. In vitro muscle bath responses to cholinergic/purinergic agonists,' KCl and field stimulation will assess smooth muscle contractility. In vivo awake cystometric and voiding responses to carbachol, intravesical capsaicin or apomorphine will assess smooth muscle, afferent and central mechanisms. Sensory and motoneuron areas, GAP-43 expression in the sacral spinal cord and electrophysiological properties of micturition reflexes will provide insight into whether structural and functional changes in bladder reflex pathways persist in deligated rats with hyperactive voiding. Effects of trk inhibitors on cultured bladder smooth muscle and pelvic neurons will address potential in vivo sites of drug action. Examining the ability, of obstructed rats to reverse obstruction-induced smooth muscle and neural changes after deligation will provide insight into the mechanisms for hyperactive voiding. The use of agents to inhibit NGF production or block its action will further test the hypothesis and offer a potential framework for future clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051364-04
Application #
2905867
Study Section
Special Emphasis Panel (SRC (07))
Program Officer
Nyberg, Leroy M
Project Start
1996-05-01
Project End
2000-04-30
Budget Start
1999-05-01
Budget End
2000-04-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Virginia
Department
Urology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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