Nitric oxide, formation and effects in the urogenital tract

Abstract: NITRIC OXIDE, FORMATION AND EFFECTS IN THE UROGENITAL TRACT Ingrid Ehren Department of Surgery, Section of Urology and Department of Physiology and Pharmacology Karolinska Institute, S-17 176 Stockholm. Sweden The aim of the thesis was to study the formation and effects of nitric oxide (NO) in the humanurinary tract and in the male reproductive organs. In the human upper and lower urinary tract NO synthase activity was studied via theformation of radiolabeled L-citrulline from L-arginine. In the human upper urinary tract NOsynthase activity was found in the renal pelvis and exogenous NO inhibited spontaneousrhythmic and tonic contractions in both the isolated renal pelvis and the ureter suggesting thatNO is a modulator of renal myogenic pacemaker-induced peristalsis. In the human lowerurinary tract NO synthase activity was high in the prostatic urethra, intermediate in the bladderneck and low in the detrusor which is in good agreement with the nerve-induced smoothmuscle responses and the guanylate cyclase activity. The results suggests that NO is the majormediator for neurogenic dilatation of the bladder neck and urethra during the micturitionreflex. Estrogen and progesterone were shown to induce Ca2+-dependent NO synthase activity inthe female guinea-pig urinary bladder suggesting that estrogen substitution, which reducesirritative bladder symptoms in elderly women, may act by increasing the Ca2+-dependent NOsynthase activity in the lower urinary tract. Irritative bladder symptoms may be caused by various inflammatory conditions in the lowerurinary tract. Since NO synthesis is increased during inflammation in several tissues wemeasured the luminal NO concentration in air from the human urinary bladder withchemiluminescence technique to study weather increased NO production is at hand in patientswith inflammatory conditions in the lower urinary tract. Elevated levels of luminal NOconcentrations were found in urinary bladders with inflammation due to interstitial cystitis andirradiation cystitis. The analysis of NO in air from the urinary bladder may be a simplediagnostic method to indentify patients with cystitis. In the human male reproductive tract NO synthase activity was high, with the highestactivity in the seminal vesicle, prostate and vas deferens. NADPH-diaphorase staining showeda prominent staining of the secretory cells in the vas deferens, seminal vesicle, prostate andurethra but also in the testis and epididymis of man and guinea-pig. NO synthase activity in thesecretory epithelium of the guinea-pig seminal vesicle was 6 times higher than in the musclecoat, suggesting that the major part of the NO synthase activity is localized in the secretorycells. NO synthase inhibitors blocked the secretion of fructose induced by carbachol and nervestimulation, respectively. Furthermore, a NO donor increased the fructose secretion. Theresults suggests that NO formation is a functional step in the secretory response to muscarinicstimulation of the glandular cells of the seminal vesicle. In conclusion, these findings suggest that NO is the mediator for neurogenic dilatation ofthe bladder neck and urethra during the micturition reflex. NO is also suggested as a cellularmediator of secretion in the male reproductive tract indicating an important role of NO in malefertility. Analysis of NO in air from the urinary bladder may be a simple method to identifypatients with cystitis.Key words urinary tract, male reproductive tract, nitric oxide, nitric oxide synthase, NADPH-diaphorase, smooth muscle, secretion, inflammation, sex hormones.STOCKHOLM 1996 ISBN 91-628-2073-7