Vesicourethral Function in Mice With Genetic Disruption of Neuronal Nitric Oxide Synthase

Abstract

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.

Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression

“…Of note, no differences between groups were observed in the urethral layers, suggesting that the E 2 -induced urethral resistances were not related to structural changes of the outlet. In ovariectomized and sham-operated control animals, acute inhibition of nNOS increased the bladder pressure at urine leakage, confirming in the female urinary tract the relaxing effect of NO on urethral tone (28). However, such inhibition had no influences on the increased urethral resistances observed in E 2 -treated mice.…”

“…Sutherland et al showed that gene inactivation of nNOS in female mice resulted in a profound decrease of overall NOS activity in bladder and urethra, indicating that it accounts for most of the NOS activity in the lower urinary tract. Increased bladder weight and maximal bladder pressure at leakage suggested that nNOS disruption resulted in increased uretral resistances, which did not however translate into measurable alterations of the voiding patterns (28). In male animals, however, targeted disruption of the nNOS gene resulted in dysfunctional bladder outlet (5).…”

“…Although nNOS was shown to be the major NOS isoform in the lower urinary tract (5), its gene invalidation did not affect bladder strip contractility or relaxation after chemical and electrical stimulations (28), suggesting that the reported effects on urodynamics and micturition were secondary to alterations of urethral resistances (5,18,28). We therefore focused on the dynamic control of urethral resistances by E 2 through the nNOS pathway.…”

“…Sutherland et al (28) and Burnett et al (5) previously emphasized the key role of the nNOS subtype on lower urinary function. Sutherland et al showed that gene inactivation of nNOS in female mice resulted in a profound decrease of overall NOS activity in bladder and urethra, indicating that it accounts for most of the NOS activity in the lower urinary tract.…”

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

“…Supporting the hypothesis that the bladder changes were caused by disturbances in outflow relaxation, the decrease in tension produced by low-frequency stimulation of nerves of isolated urethral preparations from wild-type controls was absent in preparations from nNOS-deficient mice. In contrast to these findings, Sutherland et al (1997), investigating female nNOSdeficient mice with voiding, urodynamic, and muscle strip testing, as well as histological examination, found no marked differences between these animals and normal controls. NO-mediated smooth muscle relaxation is mediated by cGMP through activation of cGMP-dependent protein kinase I (PKG; cGKI).…”