Original Article
Nitric Oxide Synthase Activity in Infantile Hypertrophic Pyloric Stenosis
N Engl J Med 1992; 327:511-515August 20, 1992
- Abstract
- Abstract
Background
Hypertrophic pyloric stenosis is a common infantile disorder characterized by enlarged pyloric musculature and gastric-outlet obstruction. Its physio-pathologic mechanism is not known, but a defect in pyloric relaxation (pylorospasm) has been postulated. Nitric oxide is a mediator of relaxation in the mammalian digestive tract, raising the possibility that pylorospasm could be caused by a defect in nitric oxide production. Since neuronal nitric oxide synthase and NADPH diaphorase are identical, we used the NADPH diaphorase histochemical reaction to study the distribution of nitric oxide synthase in pyloric tissue from patients with infantile hypertrophic pyloric stenosis.
Methods
We studied pyloric tissue from nine infants with infantile hypertrophic pyloric stenosis and seven control infants and children. Cryostat sections were processed for NADPH diaphorase histochemical analysis. A polyclonal tau antiserum was used to identify the enteric nervous system by immunohistochemical methods.
Results
NADPH diaphorase activity was restricted to the enteric nervous system and blood vessels. In the pyloric tissues from the control patients, intense diaphorase activity was present in the nerve fibers of the circular musculature, in the neurons and nerve bundles of the myenteric plexus, and in some nerve fibers of the longitudinal musculature. In the pyloric tissues from patients with infantile hypertrophic pyloric stenosis, the enteric nerve fibers in the hypertrophied circular musculature were enlarged and distorted and did not contain diaphorase activity, whereas the activity in the myenteric plexus and the longitudinal musculature was preserved.
Conclusions
We suggest that a lack of nitric oxide synthase in pyloric tissue is responsible for pylorospasm in infantile hypertrophic pyloric stenosis. (N Engl J Med 1992;327:511–5.)
Media in This Article
Figure 1
Histochemical Localization of Activity of NADPH Diaphorase, Also Known as Nitric Oxide Synthase, and Tau Immunofluorescence Staining of Pyloric Tissue.Article Activity
- Article
HYPERTROPHIC pyloric stenosis classically occurs within a few weeks after birth. Typically, affected infants present with bile-free vomitus, metabolic alkalosis, and dehydration. The identification of an enlarged pylorus (the pyloric "olive") by palpation, ultrasonography, or radiology is pathognomonic of this disorder, and it is safely and effectively treated by pyloromyotomy.1 A defect in pyloric relaxation has been thought to be responsible for the gastric-outlet obstruction.1
Nitric oxide, initially identified as the endothelium-derived relaxing factor,2 has been found in the past few years to be a pluripotent molecule involved in multiple functions, including neurotransmission.3 4 5 6 7 In animals, nitric oxide is an important mediator of relaxation of the esophagus,8 stomach,9 , 10 intestine,11 12 13 and colon,14 but whether it has similar actions in humans is not known. The enzyme NADPH diaphorase can be detected with histochemical techniques in subpopulations of neurons in the central nervous system and the myenteric plexus,15 , 16 but its functional importance remained obscure until it was recognized to be a nitric oxide synthase.17 Simultaneously, nitric oxide synthase in brain and endothelial tissues was purified, cloned, and localized by immunohistochemical techniques.18 , 19 Finally, immunohistochemical and histochemical studies demonstrated that the activity of nitric oxide synthase and that of NADPH diaphorase in brain and peripheral tissues were identical.20 For these reasons, we used the NADPH diaphorase histochemical reaction to study the distribution of nitric oxide synthase in the pylorus of normal infants and children and of infants with infantile hypertrophic pyloric stenosis.
Methods
We obtained full-thickness muscle-biopsy specimens from nine patients (eight boys and one girl, with an age range of 2 to 7 weeks) with infantile hypertrophic pyloric stenosis who underwent pyloromyotomy and from seven patients (five boys and two girls, with an age range of 1 day to 13 years) without pyloric disease. The control tissue from three patients was obtained at autopsy performed less than six hours after death and during routine pyloroplasty at the time of surgery for gastroesophageal reflux in the remaining four. This study was approved by our institutional ethics committee, and permission to obtain and use the tissue was received from the parents of each patient.
The tissue was fixed in fresh 4 percent paraformaldehyde solution in phosphate buffer for 48 hours at 4°C and then cryopreserved in graded solutions of sucrose (10, 20, and 30 percent; 24 hours each), embedded in Tissue-Tek OCT compound (Miles, Elkhart, Ind.), snap-frozen in 2-methyl butane that had been cooled in dry ice, and stored at -80°C. Some fresh specimens were also snap-frozen immediately, without fixation. Cryostat sections 20 μm thick were mounted on slides coated with 0.1 percent poly-L-lysine (Sigma, St. Louis) and stored at -20°C until use. Sections of fresh tissue were fixed in 4 percent paraformaldehyde for one hour immediately before use.
Histochemical staining for NADPH diaphorase was performed by a published procedure16 with slight modifications. The slides were incubated in a solution of 10 mM sodium phosphate buffer containing 2.5 mM NADPH (Sigma), 1 mM nitroblue tetrazolium (Sigma), and 10 percent dimethyl sulfoxide at 37°C for 15 to 90 minutes.
The sections were then processed for immunofluorescence with a polyclonal tau antiserum, in order to label the enteric nervous system. Tau is a family of microtubule-associated proteins of the neuronal cytoskeleton,21 and the antiserum is known to react with cells of the enteric nervous system in infants.22 The B19 tau antiserum used was a generous gift from Dr. J. P. Brion (Brussels, Belgium). It was raised in a rabbit with use of purified bovine tau proteins and has been tested for immunoreactivity against total human brain proteins and purified tau by Western blotting and against tau synthetic peptides by enzyme-linked immunosorbent assay.21 The sections were incubated for one hour with a 5 percent solution of normal porcine serum (Dakopatts, Glostrup, Denmark) in 0.01 M TRIS-buffered saline (pH 7.6) containing 0.1 percent Triton X-100. The sections were then incubated overnight at room temperature with the antiserum at a dilution of 1:500, rinsed in TRIS-buffered saline, and incubated for one hour at room temperature with fluorescein-coupled porcine antirabbit immunoglobulin (Dakopatts) at a dilution of 1:30. After rinsing with TRIS-buffered saline, the sections were mounted in glycerol containing 20 percent Gelvatol (Monsanto, St. Louis) and 10 percent triethylenediamine (Janssen Chimica, Beerse, Belgium) as an antibleaching agent and examined under an Axiophot Zeiss microscope equipped with epifluorescence.
To provide a negative control in the immunohistochemical studies, the primary antibody was omitted. In the histochemical studies, NADPH was omitted to provide a negative control. We verified that NADPH diaphorase staining was always present in histologically or immunohistologically identified structures. The substitution of NADH (NADH diaphorase) for NADPH in the histochemical protocol resulted in a nonspecific pattern of staining, clearly different from that of the NADPH diaphorase reaction (data not shown). The reactivity of tissue with the tau antiserum was not altered by previous histochemical staining for NADPH diaphorase. The diaphorase reaction was observed only in tau-positive neuronal structures and in blood vessels. The dense blue deposit of the diaphorase reaction sometimes masked the fluorescent signal in the cell bodies of some enteric neurons, but this problem was not encountered in nerve fibers. Fixed tissue compared favorably with fresh tissue in terms of histologic preservation and immunohistologic labeling of the enteric nervous system. The pattern of histochemical staining for NADPH diaphorase was identical in the fresh and the fixed materials. However, a better signal-to-noise ratio was achieved with fixed tissue, although the optimal incubation time was longer (75 minutes, vs. 30 minutes for fresh tissue).
Results
Normal Pylorus
The patterns of immunofluorescence staining of the enteric nervous system with the tau antiserum and of NADPH diaphorase activity were similar in the pyloric tissues from all the control patients. Numerous NADPH diaphorase—positive structures were seen in all the sections (Fig. 1Figure 1
Histochemical Localization of Activity of NADPH Diaphorase, Also Known as Nitric Oxide Synthase, and Tau Immunofluorescence Staining of Pyloric Tissue.A). Many thin nerve fibers were present in the circular (internal) smooth musculature, most of which displayed intense NADPH diaphorase activity (Fig. 1B). In the myenteric plexus, a subgroup of neurons and nerve bundles also showed strong NADPH diaphorase activity. In the longitudinal (external) smooth musculature, the nerve fibers appeared less numerous than in the circular layer, and only some of them showed NADPH diaphorase activity. In the submucosal plexus, NADPH diaphorase—positive neuronal cell bodies were present, whereas positive nerve fibers were seldom seen. Diaphorase activity was frequently seen in the nerve bundles connecting the submucosal plexus and the myenteric plexus. The blood vessels and a subgroup of cells, mainly located at the bottom of the villi of the pyloric mucosa, also contained NADPH diaphorase activity (data not shown).Infantile Hypertrophic Pyloric Stenosis
Only the musculature and the myenteric plexus could be investigated in the biopsy specimens from the patients with infantile hypertrophic pyloric stenosis. The results were similar in all nine patients. The most striking difference between these tissues and the control tissues was that no NADPH diaphorase activity could be detected in the nerves within the hypertrophied circular musculature (Fig. 1C). With the tau antiserum, grossly abnormal, dilated, and tortuous nerve fibers were labeled that lacked NADPH diaphorase activity (Fig. 1D). A few thin, normal-looking nerve fibers identified with the tau antiserum showed weak NADPH diaphorase activity (Fig. 1D). Some NADPH diaphorase—positive nerve bundles connecting the myenteric plexus and submucosal plexus were seen in the connective tissue between the hypertrophied muscle bundles. In contrast, NADPH diaphorase activity was preserved in the myenteric plexus and the longitudinal muscular layer.
Discussion
Hypertrophic pyloric stenosis is a common disorder of the gastrointestinal tract in infants. It is characterized by gastric-outlet obstruction associated with hypertrophy,23 hyperplasia,24 or both of the circular musculature of the pylorus. Although it has been recognized for more than two centuries,1 its physiopathologic mechanism is not known. A defect of pyloric relaxation (pylorospasm) has been postulated,25 , 26 but no manometric studies in infantile hypertrophic pyloric stenosis have been reported. Clinical observations indicate that the hypertrophic pylorus can be easily intubated27 and that the extent of muscular hypertrophy does not correlate with the patient's age or the duration of symptoms.28 These observations favor the hypothesis that the disorder is a disturbance of pyloric contractility.
Immunohistochemical staining of the enteric nervous system with tau antiserum has, to our knowledge, been reported only in the intestine.22 Since the pattern of staining of the pylorus in normal subjects was very similar to the pattern obtained by other methods, immunostaining with tau antiserum may be considered a good marker of the enteric nervous system.22 In infantile hypertrophic pyloric stenosis, the abnormal appearance of the nerve fibers labeled with tau antiserum also corresponds closely with the appearance of the enlarged fibers filled with various types of organelles observed by electron microscopy.29
We found that the activity of NADPH diaphorase (which is identical to that of nitric oxide synthase) normally present in many nerve fibers of the pyloric musculature was selectively absent from the hypertrophied circular musculature of patients with infantile hypertrophic pyloric stenosis, whereas the activity was preserved in the myenteric plexus and the longitudinal layer. These results confirm that the peptidergic inhibitory innervation of the circular muscular layer is decreased in infantile hypertrophic pyloric stenosis.30 Moreover, since nitric oxide has an important role in the relaxation of enteric smooth musculature,8 9 10 11 12 13 14 these results suggest that the nitric oxide synthase in the enteric nerves of the smooth musculature is also involved in the relaxation of the pylorus and that the lack of this enzyme in infantile hypertrophic pyloric stenosis may account for the defect in relaxation of the pyloric sphincter — the old concept of pylorospasm — and leads to the clinical syndrome of gastric-outlet obstruction.
Supported by a grant (3.4523–86) from the Fondation de la Recherche Scientifique Médicale and by grants from the Fondation Médicale Reine Elisabeth, Pôle d'Attraction Interuniversitaire, and the Fondation Erasme. Dr. Mailleux and Dr. Schiffmann are senior research assistants of the Fonds National de la Recherche Scientifique (Belgium).
We are indebted to Drs. M. Dassonville, C. Lerminiaux, and E. Van Der Veken for their cooperation in obtaining the pyloric-biopsy specimens; to Ms. M. Authelet and Mr. J.-L. Conreur for skillful technical assistance; and to Ms. M. Ludgate for editorial advice.
Source Information
From the Laboratory of Neuropathology and Neuropeptide Research (J.-M.V., P.M., S.N.S., J.-J.V.) and the Department of Surgery (J.-M.V.), Erasme Academic Hospital; the Department of Pediatric Surgery, University Children's Hospital (M.-H.D.L.); and the Faculty of Medicine, Université Libre de Bruxelles (J.-M.V., P.M., S.N.S., J.-J.V., M.-H.D.L.) — all in Brussels, Belgium. Address reprint requests to Dr. Vanderwinden at the Laboratory of Neuropathology and Neuropeptide Research, Université Libre de Bruxelles, Campus Erasme, CP 601, 808 route de Lennik, 1070 Brussels, Belgium.
- References
References
1
Hayes 2
Palmer
CrossRef | Web of Science | Medline3
Collier
CrossRef | Web of Science | Medline4
Moncada
CrossRef | Web of Science | Medline5
Crossin
CrossRef | Web of Science | Medline6
Snyder
CrossRef | Web of Science | Medline7
Garthwaite
CrossRef | Web of Science | Medline8
Tottrup
Web of Science | Medline9
Li
CrossRef | Web of Science | Medline10
Desai
CrossRef | Web of Science | Medline11
Gustafsson
CrossRef | Web of Science | Medline12
Bult
CrossRef | Web of Science | Medline13
Shuttleworth
CrossRef | Web of Science | Medline14
Dalziel
Web of Science | Medline15
Hope
CrossRef | Web of Science | Medline16
Branchek
CrossRef | Web of Science | Medline17
Hope
CrossRef | Web of Science | Medline18
Bredt
CrossRef | Web of Science | Medline19
Bredt
CrossRef | Web of Science | Medline20
Dawson
CrossRef | Web of Science | Medline21
Brion
Web of Science | Medline22
Tam
Web of Science | Medline23
Tam
Medline24
Dieler
CrossRef | Web of Science | Medline25
Lehmann
CrossRef26
Lynn
Web of Science | Medline27
Yamashiro
CrossRef | Web of Science | Medline28
Ukabiala
CrossRef | Web of Science | Medline29
Dieler
CrossRef | Web of Science | Medline30
Wattchow
Web of Science | Medline
- Citing Articles (92)
Citing Articles
1
Clara Song, Jeffrey S. Upperman, Victoria Niklas. 2012. Structural Anomalies of the Gastrointestinal Tract. , 979-993.
CrossRef2
L. R Rivera, D. P. Poole, M. Thacker, J. B. Furness. (2011) The involvement of nitric oxide synthase neurons in enteric neuropathies. Neurogastroenterology & Motility 23:11, 980-988
CrossRef3
Alexandre Serra, Katrin Schuchardt, Jon Genuneit, Clothilde Leriche, Guido Fitze. (2011) Genomic variants in the coding region of neuronal nitric oxide synthase (NOS1) in infantile hypertrophic pyloric stenosis. Journal of Pediatric Surgery 46:10, 1903-1908
CrossRef4
Michal Zalecki. (2011) Localization and neurochemical characteristics of the extrinsic sympathetic neurons projecting to the pylorus in the domestic pig. Journal of Chemical Neuroanatomy
CrossRef5
Eileen Rodriguez–Tapia, James J. Galligan. (2011) A New Player in Neuromuscular Transmission in the Gastrointestinal Tract. Gastroenterology 140:2, 397-400
CrossRef6
Gregory Hammer, Steven Hall, Peter J. Davis. 2011. Anesthesia for General Abdominal, Thoracic, Urologic, and Bariatric Surgery. , 745-785.
CrossRef7
Judith D. Ranells, Jane D. Carver, Russell S. Kirby. (2011) Infantile Hypertrophic Pyloric Stenosis: Epidemiology, Genetics, and Clinical Update. Advances in Pediatrics 58:1, 195-206
CrossRef8
Malolan S. Rajagopalan, Brandon Stone, Jean-Claude Rwigema, Umar Salimi, Michael W. Epperly, Julie Goff, Darcy Franicola, Tracy Dixon, Shaonan Cao, Xichen Zhang, Bettina M. Buchholz, Anthony J. Bauer, Serah Choi, Christopher Bakkenist, Hong Wang, Joel S. Greenberger. (2010) Intraesophageal Manganese Superoxide Dismutase-Plasmid Liposomes Ameliorates Novel Total-Body and Thoracic Radiation Sensitivity of NOS1 −/− Mice. Radiation Research 174:3, 297-312
CrossRef9
Christina Panteli. (2009) New insights into the pathogenesis of infantile pyloric stenosis. Pediatric Surgery International 25:12, 1043-1052
CrossRef10
Marlene M. Hao, Heather M. Young. (2009) Development of enteric neuron diversity. Journal of Cellular and Molecular Medicine 13:7, 1193-1210
CrossRef11
AGA Brouwers, CMJA Waals-van de Wal. (2009) Hypertrophic pyloric stenosis and pulmonary hypertension in a neonate. A common mechanism?. Acta Paediatrica 98:6, 1064-1065
CrossRef12
DHANPAT JAIN. 2009. Neuromuscular Disorders of the GI Tract. , 125-143.
CrossRef13
Digavalli V. Sivarao, Hiroshi Mashimo, Raj K. Goyal. (2008) Pyloric Sphincter Dysfunction in nNOS−/− and W/Wv Mutant Mice: Animal Models of Gastroparesis and Duodenogastric Reflux. Gastroenterology 135:4, 1258-1266
CrossRef14
Cynthia L. Leaphart, Kate Borland, Timothy D. Kane, David J. Hackam. (2008) Hypertrophic pyloric stenosis in newborns younger than 21 days: remodeling the path of surgical intervention. Journal of Pediatric Surgery 43:6, 998-1001
CrossRef15
P. E. Meissner, G. Engelmann, J. Troeger, O. Linderkamp, W. Nuetzenadel. (2006) Conservative treatment of infantile hypertrophic pyloric stenosis with intravenous atropine sulfate does not replace pyloromyotomy. Pediatric Surgery International 22:12, 1021-1024
CrossRef16
Thambipillai Sri Paran, Udo Rolle, Prem Puri. (2006) Enteric nervous system and developmental abnormalities in childhood. Pediatric Surgery International 22:12, 945-959
CrossRef17
Francesca Capon, Ashley Reece, Rathi Ravindrarajah, Eddie Chung. (2006) Linkage of Monogenic Infantile Hypertrophic Pyloric Stenosis to Chromosome 16p12-p13 and Evidence for Genetic Heterogeneity. The American Journal of Human Genetics 79:2, 378-382
CrossRef18
k. korenaga, m.-a. micci, g. taglialatela, p. j. pasricha. (2006) Suppression of nNOS expression in rat enteric neurones by the receptor for advanced glycation end-products. Neurogastroenterology and Motility 18:5, 392-400
CrossRef19
Greg Hammer, Steven Hall, Peter J. Davis. 2006. Anesthesia for General Abdominal, Thoracic, Urologic, and Bariatric Surgery. , 685-722.
CrossRef20
N. E. Diamant. (2005) Gastrointestinal sphincters: up and down and ups and downs. Neurogastroenterology and Motility 17:s1, 1-2
CrossRef21
d. ramkumar, k. s. schulze. (2005) The pylorus. Neurogastroenterology and Motility 17:s1, 22-30
CrossRef22
Toshiyuki TANAKA, Akiyoshi MIZUMOTO, Zen ITOH. (2005) Effects of Nitric Oxide Synthase Inhibitor on the Digestive System Measured by Simultaneous Monitoring of Gastric Motility, Gastric Emptying Activity and Postprandial Pancreaticobiliary Secretion in Dogs. Experimental Animals 54:4, 309-317
CrossRef23
Henry P. Parkman, William L. Hasler, Robert S. Fisher. (2004) American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis. Gastroenterology 127:5, 1592-1622
CrossRef24
Steven L. Blumer, William B. Zucconi, Harris L. Cohen, Richard J. Scriven, Thomas K. Lee. (2004) The Vomiting Neonate: A Review of the ACR Appropriateness Criteria and Ultrasound’s Role in the Workup of Such Patients. Ultrasound Quarterly 20:3, 79-89
CrossRef25
M. M. Tiao, K. D. Yang, J. W. Lin, Y. J. Jong. (2004) P0558 THE CONTRIBUTION OF LIPOPOLYSACCHARIDE-INDUCED INTUSSUSCEPTION AND INTESTINAL NITRIC OXIDE SYNTHASE ACTIVITY. Journal of Pediatric Gastroenterology and Nutrition 39:Supplement 1, S269
CrossRef26
R. De Giorgio, S. Guerrini, G. Barbara, C. Cremon, V. Stanghellini, R. Corinaldesi. (2004) New insights into human enteric neuropathies. Neurogastroenterology and Motility 16:s1, 143-147
CrossRef27
Alice AO Bricola, Simone A Teixeira, Iara MS De Luca, Marcelo N Muscara, Fernando MF Abdala, Catarina S Porto, Angelina Zanesco, Edson Antunes, Gilberto De Nucci. (2003) Upregulation of muscarinic receptors by long-term nitric oxide inhibition in the rat ileum. Clinical and Experimental Pharmacology and Physiology 30:3, 168-173
CrossRef28
Patrick Vallance. (2003) Nitric oxide: therapeutic opportunities. Fundamental and Clinical Pharmacology 17:1, 1-10
CrossRef29
Christine L. Frissora. (2002) A new look at irritable bowel syndrome [IBS]: A neuroenteric disorder. Comprehensive Therapy 28:3, 222-231
CrossRef30
Yvan Vandenplas, Eric Hassall. (2002) Mechanisms of Gastroesophageal Reflux and Gastroesophageal Reflux Disease. Journal of Pediatric Gastroenterology and Nutrition 35:2, 119-136
CrossRef31
R. M. Abel, C. J. Dore, A. E. Bishop, P. Facer, J. M. Polak, L. Spitz. (2002) A Quantitative Study of the Neural Changes Underlying Pyloric Stenosis in Dogs. Anatomia, Histologia, Embryologia: Journal of Veterinary Medicine Series C 31:3, 139-143
CrossRef32
Juan V Esplugues. (2002) NO as a signalling molecule in the nervous system. British Journal of Pharmacology 135:5, 1079-1095
CrossRef33
AC Dick, J Ardill, SR Potts, JA Dodge. (2001) Gastrin, somatostatin and infantile hypertrophic pyloric stenosis. Acta Paediatrica 90:8, 879-882
CrossRef34
Tadashi Ishiguchi, Masaharu Nakajima, Hirohito Sone, Hitoshi Tada, Arno K. Kumagai, Toku Takahashi. (2001) Gastric distension-induced pyloric relaxation: central nervous system regulation and effects of acute hyperglycaemia in the rat. The Journal of Physiology 533:3, 801-813
CrossRef35
T Goto. (2001) CSF glutamate/GABA concentrations in pyridoxine-dependent seizures: etiology of pyridoxine-dependent seizures and the mechanisms of pyridoxine action in seizure control. Brain and Development 23:1, 24-29
CrossRef36
Crystal C. Watkins, Akira Sawa, Samie Jaffrey, Seth Blackshaw, Roxanne K. Barrow, Solomon H. Snyder, Christopher D. Ferris. (2000) Insulin restores neuronal nitric oxide synthase expression and function that is lost in diabetic gastropathy. Journal of Clinical Investigation 106:3, 373-384
CrossRef37
Dieter Saur, Heidi Paehge, Volker Schusdziarra, Hans–Dieter Allescher. (2000) Distinct expression of splice variants of neuronal nitric oxide synthase in the human gastrointestinal tract. Gastroenterology 118:5, 849-858
CrossRef38
Cristina Giaroni, Fabrizio De Ponti, Marco Cosentino, Sergio Lecchini, Gianmario Frigo. (1999) Plasticity in the enteric nervous system. Gastroenterology 117:6, 1438-1458
CrossRef39
Jean-Marie Vanderwinden, J
ri J. Rumessen. (1999) Interstitial cells of Cajal in human gut and gastrointestinal disease. Microscopy Research and Technique 47:5, 344-360
CrossRef40
Maria-Giuliana Vannucchi. (1999) Receptors in interstitial cells of Cajal: Identification and possible physiological roles. Microscopy Research and Technique 47:5, 325-335
CrossRef41
Otto Louis-Jacques, Jay A. Perman. (1999) Disorders of the stomach and duodenum in children. Current Opinion in Gastroenterology 15:6, 516
CrossRef42
L Ny, K Persson, B Larsson, J Chan, L.M Weiss, M Wittner, H Huang, H.B Tanowitz. (1999) Localization and activity of nitric oxide synthases in the gastrointestinal tract of Trypanosoma cruzi-infected mice. Journal of Neuroimmunology 99:1, 27-35
CrossRef43
H Fischer. (1999) Expression of constitutive nitric oxide synthase in rat and human gastrointestinal tract. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1450:3, 414-422
CrossRef44
TAKAHARU OUE, PREM PURI. (1999) Smooth Muscle Cell Hypertrophy versus Hyperplasia in Infantile Hypertrophic Pyloric Stenosis. Pediatric Research 45:6, 853-857
CrossRef45
Marie-Reine Losser, Didier Payen. (1999) Nitric oxide and the gastrointestinal tract. Current Opinion in Critical Care 5:2, 151
CrossRef46
SATISH RATTAN, WATARU TAMURA. (1998) Role of Galanin in the Gastrointestinal Sphincters a. Annals of the New York Academy of Sciences 863:1 GALANIN, 143-155
CrossRef47
Sean M. Ward, Gerard Morris, Lee Reese, Xuan-Yu Wang, Kenton M. Sanders. (1998) Interstitial cells of Cajal mediate enteric inhibitory neurotransmission in the lower esophageal and pyloric sphincters. Gastroenterology 115:2, 314-329
CrossRef48
Joseph Levy. (1998) Immunonutrition: the pediatric experience. Nutrition 14:7-8, 641-647
CrossRef49
Barry Alexander. (1998) The Role of Nitric Oxide in Hepatic Metabolism. Nutrition 14:4, 376-390
CrossRef50
Christian P. Braegger, Marcus Schwöbel, Jakob von Känel, Ernst R. Werner, Beat Thöny, Nenad Blau. (1997) Tetrahydrobiopterin in the Treatment of Infantile Hypertrophic Pyloric Stenosis. Biochemical and Molecular Medicine 62:1, 101-105
CrossRef51
Henry P Parkman, Anthony P Pagano, James P Ryan. (1997) PACAP and VIP inhibit pyloric muscle through VIP/PACAP-preferring receptors. Regulatory Peptides 71:3, 185-190
CrossRef52
G. Stacher, Ute Weber. (1997) Störungen der Ösophagus- und Magenmotilität bei Kindern. European Surgery 29:2, 80-84
CrossRef53
DIETER BLOTTNER. (1997) NITRIC OXIDE AND FIBROBLAST GROWTH FACTOR IN AUTONOMIC NERVOUS SYSTEM: SHORT- AND LONG-TERM MESSENGERS IN AUTONOMIC PATHWAY AND TARGET-ORGAN CONTROL. Progress in Neurobiology 51:4, 423-438
CrossRef54
Henrik H. Iversen, Fredrik Celsing, Anna M. Leone, Lars E. Gustafsson, N. Peter Wiklund. (1997) Nerve-induced release of nitric oxide in the rabbit gastrointestinal tract as measured by in vivo microdialysis. British Journal of Pharmacology 120:4, 702-706
CrossRef55
A. M. Holschneider, D. Schulten. (1997) Motilitätsstörungen des Anorektums. Coloproctology 19:1, 14-27
CrossRef56
IM Rogers. (1997) The enigma of pyloric stenosis. Some thoughts on the aetiology. Acta Paediatrica 86:1, 6-9
CrossRef57
Colin D. Rudolph. (1996) Medical Treatment of Idiopathic Hypertrophic Pyloric Stenosis: Should We Marinate or Slice the “Olive”?. Journal of Pediatric Gastroenterology & Nutrition 23:4, 399-401
CrossRef58
A. J. GODKIN, A. J. DE BELDER, L. VILLA, A. WONG, J. E. BEESLEY, S. P. KANE, J. F. MARTIN. (1996) Expression of nitric oxide synthase in ulcerative colitis. European Journal of Clinical Investigation 26:10, 867-872
CrossRef59
L. GROSSI, M. FALCUCCI, D. LAPENNA, L. MARZIO. (1996) Effect of nitric oxide on propagated clusters of spontaneous motor waves in an ex vivo rabbit intestinal preparation. Neurogastroenterology & Motility 8:3, 201-205
CrossRef60
Akira Nagita, Jun Yamaguchi, Kanji Amemoto, Atsushi Yoden, Takeshi Yamazaki, Makoto Mino. (1996) Management and Ultrasonographic Appearance of Infantile Hypertrophic Pyloric Stenosis with Intravenous Atropine Sulfate. Journal of Pediatric Gastroenterology & Nutrition 23:2, 172-177
CrossRef61
A. C. Dick, J. A. Dodge. (1996) Confusion Surrounding Nitric Oxide Synthase/NADPH-Diaphorase. Journal of Pediatric Gastroenterology & Nutrition 23:2, 204
CrossRef62
W. M. SUN, S. DORAN, TH. LINGENFELSER, G. S. HEBBARD, J. E. MORLEY, J. DENT, M. HOROWITZ. (1996) Effects of glyceryl trinitrate on the pyloric motor response to intraduodenal triglyceride infusion in humans. European Journal of Clinical Investigation 26:8, 657-664
CrossRef63
K Altdorfer. (1996) Nitric oxide synthase-containing nerve elements in the pylorus of the cat. Neuroscience Letters 212:3, 195-198
CrossRef64
Epstein, Franklin H., , Goyal, Raj K., Hirano, Ikuo, . (1996) The Enteric Nervous System. New England Journal of Medicine 334:17, 1106-1115
Full Text65
RH Regev, T Dolfin, S Katz. (1996) Transient gastric outlet obstruction and tetralogy of Fallot: a true association or a coincidental finding?. Acta Paediatrica 85:4, 514-515
CrossRef66
Chandar Singaram, Ashok SenGupta. (1996) HISTOPATHOLOGY OF THE ENTERIC NEUROPATHIES. Gastroenterology Clinics of North America 25:1, 183-201
CrossRef67
Manju Chandra, Hope Maddix, Melinda McVicar. (1996) Transient Urodynamic Dysfunction of Infancy. The Journal of Urology673-677
CrossRef68
Manju Chandra, Hope Maddix, Melinda McVicar. (1996) Transient Urodynamic Dysfunction of Infancy: Relationship to Urinary Tract Infections and Vesicoureteral Reflux. The Journal of Urology 155:2, 673-677
CrossRef69
Ted M. Dawson, M.D., Ph.D, Valina L. Dawson, Ph.D. (1996) NITRIC OXIDE SYNTHASE: Role as a Transmitter/Mediator in the Brain and Endocrine System. Annual Review of Medicine 47:1, 219-227
CrossRef70
M. G. Davies, G. J. Fulton, P.-O. Hagen. (1995) Clinical biology of nitric oxide. British Journal of Surgery 82:12, 1598-1610
CrossRef71
Rebecca A. Schroeder, Paul C. Kuo. (1995) Nitric Oxide. Anesthesia & Analgesia 81:5, 1052-1059
CrossRef72
Camillo Cortesini, Fabio Cianchi, Aldo Infantino, Mario Lise. (1995) Nitric oxide synthase and VIP distribution in enteric nervous system in idiopathic chronic constipation. Digestive Diseases and Sciences 40:11, 2450-2455
CrossRef73
David A. Wattchow, Simon J.H. Brookes, Marcello Costa. (1995) The morphology and projections of retrogradely labeled myenteric neurons in the human intestine. Gastroenterology 109:3, 866-875
CrossRef74
Siu-Chun G. Hui, Tak-Yuen Chan. (1995) Mechanisms mediating NG-nitro-l-arginine methyl ester-induced hypophagia in mice. European Journal of Pharmacology 283:1-3, 141-150
CrossRef75
Chandar Singaram, Mark A. Sweet, Eric A. Gaumnitz, Alan J. Cameron, Michael Camilleri. (1995) Peptidergic and nitrinergic denervation in congenital esophageal stenosis. Gastroenterology 109:1, 275-281
CrossRef76
Richard B. Lynn, Suzanne L. Sankey, Sushanta Chakder, Satish Rattan. (1995) Colocalization of NADPH-diaphorase staining and VIP immunoreactivity in neurons in opossum internal anal sphincter. Digestive Diseases and Sciences 40:4, 781-791
CrossRef77
Romain A. Lefebvre. (1995) Nitric Oxide in the Peripheral Nervous System. Annals of Medicine 27:3, 379-388
CrossRef78
Ilkka Pörsti, Ilari Paakkari. (1995) Nitric Oxide-based Possibilities for Pharmacotherapy. Annals of Medicine 27:3, 407-420
CrossRef79
P. C. A. KAM, G. GOVENDER. (1994) Nitric oxide: basic science and clinical applications. Anaesthesia 49:6, 515-521
CrossRef80
Mark J. S. Miller, Upender K. Munshi, Halina Sadowska-Krowicka, Jane L. Kakkis, Xiao-Jing Zhang, Sandra Eloby-Childress, David A. Clark. (1994) Inhibition of calcium-dependent nitric oxide synthase causes ileitis and leukocytosis in guinea pigs. Digestive Diseases and Sciences 39:6, 1185-1192
CrossRef81
E. Änggård. (1994) Nitric oxide: mediator, murderer, and medicine. The Lancet 343:8907, 1199-1206
CrossRef82
Hiroyuki Kobayashi, D. Sean O'Briain, Prem Puri. (1994) Defective cholinergic innervation in pyloric muscle of patients with hypertrophic pyloric stenosis. Pediatric Surgery International 9:5-6, 338-341
CrossRef83
Johannes J. Bogers, Jean-Pierre Timmermans, Dietrich W. Scheuermann, Paul A. Pelckmans, Bernd Mayer, Eric A. van Marck. (1994) Localization of nitric oxide synthase in enteric neurons of the porcine and human ileocaecal junction. Annals of Anatomy - Anatomischer Anzeiger 176:2, 131-135
CrossRef84
Jean-Pierre Timmermans, Martine Barbiers, Dietrich W. Scheuermann, Johannes J. Bogers, Dirk Adriaensen, Eva Fekete, Bernd Mayer, Eric A. Marck, Marie H. A. Groodt-Lasseel. (1994) Nitric oxide synthase immunoreactivity in the enteric nervous system of the developing human digestive tract. Cell & Tissue Research 275:2, 235-245
CrossRef85
V. Barrios, M.J.M. Urrutia, M. Hernández, R. Lama, M.D. García-Nuvo, A. Hernanz, E. Arilla. (1994) Serum gastrin level and gastric somatostatin content and binding in long-term pyloromyotomized children. Life Sciences 55:4, 317-325
CrossRef86
Epstein, Franklin H., , Moncada, SalvadorHiggs, Annie. (1993) The L-Arginine-Nitric Oxide Pathway. New England Journal of Medicine 329:27, 2002-2012
Full Text87
SIMON J. H. BROOKES. (1993) Neuronal nitric oxide in the gut. Journal of Gastroenterology and Hepatology 8:6, 590-603
CrossRef88
Paul L. Huang, Ted M. Dawson, David S. Bredt, Solomon H. Snyder, Mark C. Fishman. (1993) Targeted disruption of the neuronal nitric oxide synthase gene. Cell 75:7, 1273-1286
CrossRef89
F. MEARIN, M. MOURELLE, F. GUARNER, A. SALAS, V. RTVEROS-MORENO, S. MONCADA, J.-R. MALAGELADA. (1993) Patients with achalasia lack nitric oxide synthase in the gastro-oesophageal junction. European Journal of Clinical Investigation 23:11, 724-728
CrossRef90
Janet Treasure, Jane Tiller. (1993) The Aetiology of Eating Disorders—its Biological Basis. International Review of Psychiatry 5:1, 23-32
CrossRef91
(1992) Nitric Oxide Synthesis in Infantile Hypertrophic Pyloric Stenosis. New England Journal of Medicine 327:23, 1690-1691
Full Text92
Milla, Peter J., . (1992) Gastric-Outlet Obstruction in Children. New England Journal of Medicine 327:8, 558-560
Full Text
- Letters
