Nitric Oxide Synthase Activity in Infantile Hypertrophic Pyloric Stenosis

Vanderwinden, Jean Marie; Mailleux, Pierre; Schiffmann, Serge N.; Vanderhaeghen, J J; Laet, M H De

doi:10.1056/nejm199208203270802

Cited by 328 publications

(127 citation statements)

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“…Taken together, these results suggest an undersupply of the thickened pyloric smooth muscle with NO in IHPS patients. Because nNOS is expressed in the human enteric nervous system but not in enteric smooth muscle cells (9,30), the reduced abundance of nNOS mRNA transcripts normalized against ubiquitous housekeeping genes most likely reflects hypertrophy and hyperplasia of enteric smooth muscle cells leading to a relative decrease of enteric neurons in tissue specimen of IHPS patients when compared with controls. Therefore, expression of nNOS mRNA was assessed further by normalization against PGP9.5, a marker for general neural tissue (Fig.…”

Section: Quantitative Expression Patterns Of Nnos First-exon Mrna Varmentioning

confidence: 99%

“…Recent evidence suggested a reduced expression of neuronal nitric oxide synthase (nNOS) in IHPS, because the pyloric circular muscle layer shows decreased staining of nNOS-positive neurons (9) and decreased expression of nNOS mRNA normalized against GAPDH (10). Additionally, genetic-linkage analysis suggests the nNOS gene as a susceptibility locus for hereditary IHPS (11).…”

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Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis

Saur

Vanderwinden

Seidler

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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103

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Infantile hypertrophic pyloric stenosis (IHPS), characterized by enlarged pyloric musculature and gastric-outlet obstruction, is associated with altered expression of neuronal nitric oxide synthase (nNOS). Here we have studied molecular mechanisms by which nNOS gene expression is altered in pyloric tissues of 16 infants with IHPS and 9 controls. A significant decreased expression of total nNOS mRNA was found by quantitative RT-PCR in IHPS after normalization against GAPDH, which predominantly affected exon 1c with a reduction of 88% compared with controls (P < 0.001). After normalization against the neuronal-specific gene PGP9.5, expression of exon 1c was still decreased (P < 0.001), whereas expression of exon 1f was increased significantly (P ‫؍‬ I nfantile hypertrophic pyloric stenosis (IHPS), with an incidence of 1-5 per 1,000 live births in whites and a marked preponderance of males to females (4:1), is the most frequent disorder requiring surgery in the first year of life (1). A genetic contribution toward the etiology of IHPS is well established with familiar aggregation, a concordance rate of 25-40% in monogenetic twins, a recurrence risk of 10% for males and 2% for females born after an affected child, and a ratio of risk of 18 for first-degree relatives compared with the general population (2).IHPS is characterized by hypertrophy and hyperplasia of the circular muscle layer of the pylorus, leading to persistent vomiting 2-12 weeks after birth (3, 4). Defective pyloric relaxation and increased pyloric smooth muscle mass have been suggested to be responsible for gastric-outlet obstruction. In most cases, surgical pyloromyotomy is the treatment of choice, but conservative management has sometimes been used successfully (5, 6). Within a few months, hypertrophy resolves and no permanent functional or morphological abnormalities have been detected after healing (5,7,8).Recent evidence suggested a reduced expression of neuronal nitric oxide synthase (nNOS) in IHPS, because the pyloric circular muscle layer shows decreased staining of nNOS-positive neurons (9) and decreased expression of nNOS mRNA normalized against GAPDH (10). Additionally, genetic-linkage analysis suggests the nNOS gene as a susceptibility locus for hereditary IHPS (11). In addition to decreased nNOS expression, other abnormalities have been described, such as a reduced amount of interstitial cells of Cajal (12) NO, generated by nNOS, is a major inhibitory transmitter in the gut. It is involved in the intrinsic and extrinsic inhibitory innervation of the pyloric muscle (14), and genetic deletion of nNOS␣ in mice causes a phenotype closely resembling IHPS with delayed gastric emptying, enlargement of the stomach, and hypertrophy of the muscle layer of the antrum (15, 16). Furthermore, deletion of cGMP-dependent kinase I, the downstream target of the NO͞cGMP signaling pathway, leads to a similar phenotype with pyloric stenosis, delayed gastric emptying, and thickened pyloric muscle (17). Additional evidence for an important role of the NO͞cGMP...

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Section: Quantitative Expression Patterns Of Nnos First-exon Mrna Varmentioning

confidence: 99%

mentioning

confidence: 99%

Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis

Saur

Vanderwinden

Seidler

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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103

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“…Non-adrenergic, noncholinergic (NANC) innervation to the pylorus is predominantly inhibitory and mediates relaxation of the sphincter (Anuras et al 1974). A high density of NOSimmunopositive nerve cells and fibres has been demonstrated in the pylorus (Ekblad et al 1994), and significant reduction of NOS activity of the pylorus has been demonstrated in infantile hypertrophic pyloric stenosis (Vanderwinden et al 1992). It has been shown that transgenic mice with homozygous depletion of the nNOS gene develop grossly enlarged stomachs with hypertrophy of the pyloric sphincter (Huang et al 1993).…”

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confidence: 99%

Gastric distension‐induced pyloric relaxation: central nervous system regulation and effects of acute hyperglycaemia in the rat

Ishiguchi

Nakajima

Sone

et al. 2001

The Journal of Physiology

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Pyloric sphincter tone plays an important role in the regulation of gastric emptying. Non-adrenergic, noncholinergic (NANC) innervation to the pylorus is predominantly inhibitory and mediates relaxation of the sphincter (Anuras et al. 1974). A high density of NOSimmunopositive nerve cells and fibres has been demonstrated in the pylorus (Ekblad et al. 1994), and significant reduction of NOS activity of the pylorus has been demonstrated in infantile hypertrophic pyloric stenosis (Vanderwinden et al. 1992). It has been shown that transgenic mice with homozygous depletion of the nNOS gene develop grossly enlarged stomachs with hypertrophy of the pyloric sphincter (Huang et al. 1993). Thus, gastric outlet obstruction is associated with the lack of NO-generating neurons in the pylorus. Previous studies have shown that NO biosynthesis inhibitors delay Gastric distension-induced pyloric relaxation: central nervous system regulation and effects of acute hyperglycaemia in the rat 1. The pylorus plays an important role in the regulation of gastric emptying. In addition to the autonomic neuropathy associated with long-standing diabetes, acute hyperglycaemia per se has effects on gastric emptying. In this study, the role of the central nervous system in modulating the effects of hyperglycaemia on gastric distension-induced pyloric relaxation was investigated.2. Gastric distension-induced pyloric relaxation was significantly reduced by subdiaphragmatic vagotomy, hexamethonium (20 mg kg _1 ) and N G -nitro-L-arginine methyl ester (L-NAME; 10 mg kg _1 ), a nitric oxide synthase (NOS) biosynthesis inhibitor, in anaesthetized rats. In contrast, neither splanchnectomy nor guanethidine (5 mg kg _1 ) had an effect. 8. Taken together, these findings suggest that gastric distension-induced pyloric relaxation is mediated via a vago-vagal reflex and NO release. Acute hyperglycaemia stimulates hypothalamic NPY release, which, acting through the Y1 receptor, inhibits gastric distensioninduced pyloric relaxation in rats exposed to acute elevations in blood glucose concentrations.

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“…Les poissons du nord de l'Atlantique, incluant les limandes (flets), les éperlans, les harengs, les lycodes, les chaboisseaux et les morues, fabriquent des PAG ainsi que des glycoprotéines antigel de cinq types différents, qui sont non homologues et remarquablement diverses en terme de séquence et de structure [1]. Les limandes plie rouge (Pleuronectes americanus) fabriquent une PAG découverte il y a plus de 30 ans [2]. Cette PAG (de «type I ») est composée d'une simple hélice α amphipatique de 33 acides aminés [3] qui se lie à la face pyramidale de la glace [4] via une surface riche en résidus alanine et complé-mentaire de celle du réseau cristallin de la glace.…”

Section: Pourquoi Les Limandes Vivant Dans L'atlantique Nord Ne Gèlenunclassified

Sténose du pylore et nNOS

Labie

Tamouza

2004

Med Sci (Paris)

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> La sténose hypertrophique du pylore est un accident relativement fréquent chez le nourrisson de race blanche (1,5/1000 naissances), à prédominance masculine nette (4:1). C'est la cause la plus fré-quente de chirurgie au cours de la première année de vie. L'hypertrophie musculaire qui en est responsable ne se développe que dans les semaines qui suivent la naissance et les troubles sont très vite améliorés par une pyloromyotomie. Des études familiales ont, depuis longtemps, fait suspecter une composante génétique [1]. Ce spasme du pylore avec défaut de relaxation avait, par ailleurs, fait envisager un déficit en monoxyde d'azote (NO) dont le rôle comme médiateur de relaxation au niveau du tube digestif est connu. Les premiers arguments indirects en faveur de ce déficit remontent à 1992 [2]. L'hypothèse a été confirmée plus récem-ment par un premier travail effectué sur des biopsies chirurgicales prélevées chez six nourrissons et comparées à des prélè-vements témoins effectués à différents niveaux du tube digestif. De fait, les auteurs ont montré dans les prélève-ments de sténose une diminution signifi-

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Nitric Oxide Synthase Activity in Infantile Hypertrophic Pyloric Stenosis

Abstract: We suggest that a lack of nitric oxide synthase in pyloric tissue is responsible for pylorospasm in infantile hypertrophic pyloric stenosis.

Cited by 328 publications

References 26 publications

Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis

Single-nucleotide promoter polymorphism alters transcription of neuronal nitric oxide synthase exon 1c in infantile hypertrophic pyloric stenosis

Gastric distension‐induced pyloric relaxation: central nervous system regulation and effects of acute hyperglycaemia in the rat

Sténose du pylore et nNOS

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