Vesicourethral function in mice with genetic disruption of neuronal nitric oxide synthase.
OBJECTIVE
Nitric oxide is thought to play an important role in neuromodulation of the lower urinary tract. We therefore studied the lower urinary tract function of mice in whom the gene encoding for neuronal nitric oxide synthase had been disrupted (nNOS knockout).


METHODS
Female mice, both control and nNOS knockout, underwent voiding, urodynamic and muscle strip testing as well as histologic studies. Neuronal mechanisms assessed histologically included nitric oxide, cholinergic, adrenergic, vasoactive intestinal polypeptide (VIP), and nonspecific neuronal protein (protein gene product 9.5 [PGP 9.5]).


RESULTS
No differences in voiding were observed between normals and nNOS knockout mice. On urodynamic studies, bladder capacity was higher in the experimental than in the normal animals (25.3 +/- 11.8 vs. 17.4 +/- 5.6 ml./gm. x 1000, p < 0.05) as was the maximal bladder pressure at leakage (70.1 +/- 15.9 vs. 59.5 +/- 12.8 cm. H20, p < 0.05). After treatment with L-NAME or L-Arginine, there was no significant difference between the groups. Muscle bath studies showed no differences in bladder contractility or relaxation after chemical and electrical stimulation. Histologic studies confirmed virtually no nNOS or nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase in the nNOS knockout mice, but no difference in the total number of nerves (PGP 9.5) and of cholinergic, adrenergic or VIP-staining nerves was detected between groups.


CONCLUSIONS
Despite disruption of the main pathway for synthesis of neuronal nitric oxide, nNOS knockout mice voided normally, demonstrate normal muscle bath responses, and have normal numbers of all nerves studied (except those staining for NO). Further studies are underway to elucidate the compensatory mechanisms in these animals.
Sutherland
R S
RS
Department of Urology, University of California School of Medicine, San Francisco, USA.
Kogan
B A
BA
Piechota
H J
HJ
Bredt
D S
DS
D000818:Animals; D004558:Electric Stimulation; D005260:Female; D007552:Isotonic Solutions / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics*; D014521:Urethra / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D001743:Urinary Bladder / Q000187:drug effects / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D014554:Urination; D014563:Urodynamics
D007552:Isotonic Solutions; C051865:Krebs-Ringer solution; D019001:Nitric Oxide Synthase