Urinary tract infections (UTIs) and interstitial cystitis (IC) are two pathologic conditions of the urinary system which predominately affect women and which have medical, psychological, sociological and economic implications. The unifying hypothesis of this proposal is that nitric oxide (NO), a small lipophilic gaseous molecule, which is released from non-adrenergic, noncholinergic neurons and which is synthesized in a variety of mammalian tissues including macrophages and neutrophils, acts as a mediator in UTIs and IC. We have shown that: 1) urine particulate fractions from asymptomatic women has greater NOS activity than that observed in asymptomatic men; 2) an isoform of NO synthase (NOS) has increased activity in urine pellets of men and women with UTIs and that this NOS has properties similar to that of an inducible NOS isoform (iNOS) that has been described in macrophages and neutrophils; 3) female patients with IC have less NOS activity in their urine pellet particulate fraction than do controls or patients with UTIs; and 4) IC bladder tissue pellet NOS activity is comparable to IC urine pellet particulate NOS activity and that this activity appears to be an iNOS-like activity. To test our hypothesis we plan to: 1) determine the cell type in the urine pellet which contains the iNOS-like activity; 2) isolate and characterize the isoform of NOS that is present in the urine pellet and which is increased during UTI by utilizing antibodies or cDNA probes; 3) determine whether NOS is involved in the induction of the pathologic aspects of UTIs or is a part of the reparative response to the UTI; 4) determine the effect of inducers of iNOS on NOS levels in cultured cells isolated from urine as a function of the time course of the UTI; 5) determine if increases in NOS activity in response to agents that activate iNOS differ in inflammatory cells isolated from urine of men and women; 6) characterize -NANC contraction-relaxation phenomena in bladder specimens from normal and IC patients; 7) assess NOS activity, function and isoenzyme type(s) in urine and bladder biopsies of IC patients and controls and 8) assess NOS activity as a function of the response to treatment in patients with IC. The data obtained may provide a rationale for the development of therapies for these pathologic states.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Yale University
Schools of Medicine
New Haven
United States
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Wheeler, Marcia A; Ayyagari, Rajasekhara R; Wheeler, George L et al. (2005) Regulation of cyclic nucleotides in the urinary tract. J Smooth Muscle Res 41:1-21
Salz, Whitney; Eisenberg, Dan; Plescia, Janet et al. (2005) A survivin gene signature predicts aggressive tumor behavior. Cancer Res 65:3531-4
Kang, Walter S; Tamarkin, Frank J; Wheeler, Marcia A et al. (2004) Rapid up-regulation of endothelial nitric-oxide synthase in a mouse model of Escherichia coli lipopolysaccharide-induced bladder inflammation. J Pharmacol Exp Ther 310:452-8
Sheryka, Elinore; Wheeler, Marcia A; Hausladen, Derek A et al. (2003) Urinary interleukin-8 levels are elevated in subjects with transitional cell carcinoma. Urology 62:162-6
Hausladen, Derek A; Wheeler, Marcia A; Altieri, Dario C et al. (2003) Effect of intravesical treatment of transitional cell carcinoma with bacillus Calmette-Guerin and mitomycin C on urinary survivin levels and outcome. J Urol 170:230-4
Smith, S D; Wheeler, M A; Plescia, J et al. (2001) Urine detection of survivin and diagnosis of bladder cancer. JAMA 285:324-8
Wheeler, M A; Yoon, J H; Olsson, L E et al. (2001) Cyclooxygenase-2 protein and prostaglandin E(2) production are up-regulated in a rat bladder inflammation model. Eur J Pharmacol 417:239-48
Korting, G E; Smith, S D; Wheeler, M A et al. (1999) A randomized double-blind trial of oral L-arginine for treatment of interstitial cystitis. J Urol 161:558-65
Swana, H S; Smith, S D; Perrotta, P L et al. (1999) Inducible nitric oxide synthase with transitional cell carcinoma of the bladder. J Urol 161:630-4
Smith, S D; Wheeler, M A; Weiss, R M (1998) Detection of urinary tract infections by reduction of nitroblue tetrazolium. Kidney Int 54:1331-6

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