Urinary bladder-urethral sphincter dysfunction in mice with targeted disruption of neuronal nitric oxide synthase models idiopathic voiding disorders in humans

Burnett, Arthur L.; Calvin, David; Chamness, Shelly L.; Liu, Jian‐Xiang; Nelson, Randy J.; Klein, Sabra L.; Dawson, Valina L.; Dawson, Ted M.; Snyder, Solonion H.

doi:10.1038/nm0597-571

Cited by 143 publications

(100 citation statements)

References 15 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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). Interestingly, eNOS immunoreactivity was observed in endothelium of submucosa blood vessels and in urothelium of the urethra, whereas nNOS expression was restricted to nerve fibers throughout the inner lamina propria and muscular layer, thereby supporting an exclusive control of urethral muscle relaxation by nNOS (5).…”

Section: Discussionmentioning

confidence: 99%

“…Micturition behavior was assessed as described by Burnett et al (5). Briefly, animals were housed individually in hanging stainless cages for 14 h before the experiment and provided with food and water ad libitum.…”

Section: Methodsmentioning

confidence: 99%

“…Nitric oxide (NO), the key neurotransmitter of the nonadrenergic, noncholinergic nerves of the peripheral nervous system, is produced by the neuronal isoform of NO synthase (nNOS). In the lower urinary tract, nNOS is mainly expressed in nerves located in the muscular and inner lamina propria layers of the urethral wall and only sparsely present in the detrusor muscle (5,14). In line with the ubiquitous relaxing effect of NO (20), variations in local NO production are suspected to play a physiological role in urethral sphincter relaxation during micturition (18).…”

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confidence: 99%

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

Gamé¹,

Allard²,

Escourrou³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Gamé X, Allard J, Escourrou G, Gourdy P, Tack I, Rischmann P, Arnal J-F, Malavaud B. Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression. Am J Physiol Regul Integr Comp Physiol 294: R851-R857, 2008. First published January 9, 2008 doi:10.1152/ajpregu.00467.2007.-Estrogens are known to modulate lower urinary tract (LUT) trophicity and neuronal nitric oxide synthase (nNOS) expression in several organs. The aim of this study was to explore the effects of endogenous and supraestrus levels of 17␤-estradiol (E2) on LUT and urethral nNOS expression and function. LUT function and histology and urethral nNOS expression were studied in adult female mice subjected either to sham surgery, surgical castration, or castration plus chronic E2 supplementation (80 g ⅐ kg Ϫ1 ⅐ day Ϫ1 , i.e., pregnancy level). The micturition pattern was profoundly altered by long-term supraestrus levels of E2 with decreased frequency paralleled by increased residual volumes higher than those of ovariectomized mice. Urethral resistance was increased twofold in E2-treated mice, with no structural changes in urethra, supporting a pure tonic mechanism. Acute nNOS inhibition by 7-nitroindazole decreased frequency and increased residual volumes in ovariectomized mice but had no additive effect on the micturition pattern of long-term supraestrus mice, showing that longterm supraestrus E2 levels and acute inhibition of nNOS activity had similar functional effects. Finally, E2 decreased urethral nNOS expression in ovariectomized mice. Long-term supraestrus levels of E2 increased urethral tone through inhibition of nNOS expression, whereas physiological levels of E2 had no effect. estrogen; neurourology; urethra UP TO 50% OF WOMEN ARE REPORTED to suffer from urinary incontinence or overactive bladder (22). Lower urinary tract function is intimately interrelated to physiological estradiol (E 2 ) variations, as illustrated by the transitory increase in urethral pressure at the peak of E 2 secretion at midcycle (32), its gradual increase during pregnancy (15), and the prevalence of urinary bothers after menopause (6).In woman, estrogen therapy has been shown to prevent postmenopausal cystitis (8) and urinary atrophy and overactive bladder (6). Moreover, clinical data suggest that estrogens partly improve lower urinary tract functioning by improving local trophicity (13). However, regarding urinary incontinence, estrogens either failed to show any effect on stress urinary incontinence (24) or actually increased (in a large multicentric study) the incidence and severity of all types of urinary incontinence (12).The intricate relationship between urine storage and micturition involves a reciprocal balance in the muscle tone of bladder and urethra, which are under spinal and supraspinal controls. Autonomic regulation of the lower urinary tract physiology is driven by all three components of the autonomic nervous system. Nitric oxide (NO), the key neurotransmitter of the nonadrenergic, noncholinergic nerves ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Gamé¹,

Allard²,

Escourrou³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…These mice displayed increased frequency of micturition. 20 In another study, blockade of the NO pathway influenced the function of the lower urinary tract, as studied by cystometry in conscious rats and in vitro, in isolated muscle strips from the rat detrusor and urethra. 21 The theory that NO has a role in the development of LUTS is further supported by the characterization and functional relevance of PDE isoenzymes in the human prostate, urethra and bladder wall.…”

Section: Luts and Ed: Pathophysiological Correlationsmentioning

confidence: 99%

Association of lower urinary tract symptoms and erectile dysfunction: pathophysiological aspects and implications for clinical management

2011

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There is strong evidence from multiple epidemological studies that lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) are correlated, independent of age or comorbidities as diabetes or hypertension. Although a direct causal relationship is not established yet, four pathophysio logical mechanisms can explain the relationship. These include alteration in nitric oxide bioavailability, a1-adrenergic receptor hyperactivity, pelvic atherosclerosis and sex hormones. This association has different clinical implications on the management of both disorders. Men seeking care for one condition should always be screened for complaints of the other condition. Sexual function should be assessed and discussed with the patient when choosing the appropriate management strategy for LUTS, as well as when evaluating the patient's response to treatment. Multiple large clinical trials have shown an improvement in LUTS after phosphodiesterase-5 (PDE5)-inhibitor treatment. PDE5 inhibitors show promise as a future treatment for LUTS, either in conjunction with existing therapies or as a primary treatment. There may be a potential therapeutic role for testosterone in LUTS treatment in cases of testosterone deficiency that needs to be investigated. Much further investigation is required, but it is evident that the association between LUTS and ED is fundamental for future therapies and possible preventative strategies.

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Colocalization of nitric oxide synthase and some neurotransmitters in the intramural ganglia of the guinea pig urinary bladder

Zhou

Ling

1998

J. Comp. Neurol.

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The distribution of nitrergic neurons was investigated by using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry and nitric oxide synthase (NOS) immunohistochemistry in wholemount preparations of the urinary bladder in guinea pigs. Both NADPH-d+ and NOS+ neurons were located predominantly in the bladder base. Double staining showed that 70.9% of the NADPH-d+ neurons coexpressed NOS. Acetylcholinesterase histochemistry revealed that a majority of the intramural neurons were reactive, and about half of them (51.4%) were double labelled for NOS. Tyrosine hydroxylase-positive neurons were also distributed mainly in the bladder base but in a neuronal population that was separate from the preponderant NADPH-d+ neurons. Vasoactive intestinal polypeptide immunoreactivity was also detected in the some of intramural ganglion cells, in which 21.3% of them coexpressed NADPH-d. Calcitonin gene-related peptide and substance P immunoreactivities were confined to nerve fibers, often in close association with NADPH-d+ cells or extended along the blood vessels. These results have demonstrated the colocalization of NADPH-d and NOS in the majority of intramural ganglion cells. Many of the nitrergic neurons are apparently cholinergic, indicating that they are parasympathetic postganglionic neurons, and this underscores NO as the major neuromodulator in the parasympathetic nerves in the bladder walls. The localization of vasoactive intestinal polypeptide in nitrergic neurons suggests that the peptide may complement NO for regulation of micturition reflex. The close relationship of NADPH-d-reactive intramural neurons with calcitonin gene-related peptide and substance P fibers, most probably derived from dorsal root ganglion cells, suggests that NO released from the local neurons may exert its influence on the sensory neural pathways in the urinary bladder.

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Urinary bladder-urethral sphincter dysfunction in mice with targeted disruption of neuronal nitric oxide synthase models idiopathic voiding disorders in humans

Cited by 143 publications

References 15 publications

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

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

Association of lower urinary tract symptoms and erectile dysfunction: pathophysiological aspects and implications for clinical management

Colocalization of nitric oxide synthase and some neurotransmitters in the intramural ganglia of the guinea pig urinary bladder

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