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Effects of nitric oxide on gastric acid secretion in human gastric mucosa: functional and morphological studies
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, Faculty of Health Sciences.
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hydrochloric acid (HCI) is secreted in high amounts by parietal cells in the human gastric mucosa and the resulting low pH constitutes an important factor for creating a suitable environment for the digestion. The normal gastric mucosa is equipped with an arsenal of protective mechanisms against the extreme chemical environment which the gastric acid creates. There are situations when the barrier function of the gastric mucosa is disrupted and gastric acid becomes potentially deleterious. Understanding the regulatory mechanisms by which the secretion of gastric acid is controlled under physiological conditions may improve future treatment in peptic ulcers, gastritis and other gastric inflammatory disorders.

Nitric oxide (NO) has previously been found to regulate gastric acid secretion in animals. Immunohistochemical investigation of normal human gastric mucosa revealed that hitherto unknown endocrine cells in the oxyntic mucosa express nitric oxide synthase (NOS). These cells were found located in close contact with parietal cells, which suggests a paracrine effect of NO on parietal cell function.

Functional studies of the effects of exogenous and endogenous NO on stimulated gastric acid secretion were performed on isolated human gastric glands. Indirect determination of gastric acid secretion by using the 14C-labeled aminopyrine (AP) technique was used. Stimulation was induced by administration of histamine or db-cAMP. Secretagogue-induced AP-accumulation in gastric glands treated with NO-donor was significantly decreased compared with untreated glands. This indicates that exogenously administered NO inhibits stimulated gastric acid secretion in humans. Inhibition of endogenous NO-production by the use of NOS-inhibitors caused an increase in AP-accumulation, which suggests that NO released from cells within the glandular epithelium exerts a physiological effect in acting as an inhibitor of stimulated gastric acid secretory activity in humans.

Further functional and morphological investigations showed that exogenously administered cGMP induced a concentration-dependent inhibition of AP-accumulation in isolated human gastric glands similar to that induced by NO-donors. When soluble guanylate cyclase (sGC), a common target enzyme for NO, was blocked NO failed to induce inhibition. Biochemical analysis of the cGMP concentrations in isolated gastric glands after treatment with NO-donor revealed that inhibition of AP-accumulation due to NO is accompanied by an increase in glandular cGMP content. This increase was localized by immunohistochemistry to the parietal cells. These results indicates that NO inhibits secretagogue-induced gastric acid secretion in isolated human gastric glands via activation of sGC, which results in an increased concentration of cGMP in the parietal cells.

In order to determine the cGMP-dependent mechanisms leading to diminished output of gastric acid, parietal cells were investigated with emphasis on the cytological transformations associated with stimulation of acid secretion. Isolated human gastric glands were treated with NO-donor prior to administration of histamine. The cytoskeletal rearrangement as well as the translocation and incorporation of H+/K+-ATPase into the apical membrane was studied using con focal and electron microscopy techniques. Results showed that histamine-induced F-actin rearrangement as well as the translocation of H+/K+-ATPase rich tubulovesicles to the canalicular membrane, and their fusion with the same, was unaffected by NO. The secretory canaliculi, which swell to great size as a result of histamine-treatment, were however small and unexpanded in response to treatment with NO-donor. The unexpanded canaliculi reflected the NO-induced inhibition of secretion of HCI observed in the functional studies.

In conclusion, these results show that NO may be a physiological regulator of stimulated gastric acid secretion in humans and that this inhibition is a cGMP-dependent mechanisms which diminishes output of HCI from parietal cells without affecting stimuli-induced cytological transformations.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2005. , 86 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 925
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-31122Local ID: 16856ISBN: 91-85497-61-4 (print)OAI: oai:DiVA.org:liu-31122DiVA: diva2:251945
Public defence
2005-12-15, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-01Bibliographically approved
List of papers
1. Morphological support for paracrine inhibition of gastric acid secretion by nitric oxide in humans
Open this publication in new window or tab >>Morphological support for paracrine inhibition of gastric acid secretion by nitric oxide in humans
2001 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, Vol. 36, no 10, 1016-1021 p.Article in journal (Refereed) Published
Abstract [en]

Background: Functional studies have shown that nitric oxide (NO) inhibits gastric acid secretion in a variety of species, including man. We have performed a morphological study with the intention of localizing the endothelial NO synthase (eNOS) in the human gastric mucosa.

Methods: Fifteen healthy subjects voluntarily participated in the study, and mucosal biopsies were obtained from the cardia, corpus and antrum. The presence and localization of eNOS were studied using immunohistochemical techniques.

Results: eNOS-immunoreactivity (eNOS-IR) is found in surface mucous cells of cardia, corpus and antrum. Unique to the oxyntic mucosa is the presence of eNOS-IR in 'endocrine-like' cells, found in close contact with parietal cells.

Conclusions: eNOS-IR cells in close apposition to parietal cells provide morphological support for paracrine inhibition of gastric acid secretion by NO.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-24926 (URN)10.1080/003655201750422594 (DOI)9331 (Local ID)9331 (Archive number)9331 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-01Bibliographically approved
2. Nitric oxide-an endogenous inhibitor of gastric acid secretion in isolated human gastric glands
Open this publication in new window or tab >>Nitric oxide-an endogenous inhibitor of gastric acid secretion in isolated human gastric glands
2004 (English)In: BMC Gastroenterology, ISSN 1471-230X, Vol. 4, no 16Article in journal (Refereed) Published
Abstract [en]

Background

Endothelial nitric oxide synthase (eNOS) has previously been detected in the glandular part of the human gastric mucosa. Furthermore, nitric oxide (NO) has been shown to influence gastric secretion in various animal models. The present study was conducted to investigate the influence of exogenously and endogenously derived NO on histamine- and cAMP-stimulated gastric acid secretion in isolated human oxyntic glands.

Methods

Oxyntic glands were isolated from human gastric biopsies and were subsequently pre-treated with NO donors and nitric oxide synthase inhibitors and then exposed to histamine or dibutyryl-cAMP (db-cAMP). The secretory response of the glands was determined as accumulation of [14C]aminopyrine.

Results

The histamine- or db-cAMP-induced acid secretion was attenuated by L-arginine, a known source of endogenous NO, and also by the NO-donors sodium nitroprusside (SNP) and S-nitroso-N-acetyl-penicillamine (SNAP). Pre-treatment with either of the NOS inhibitors NG-nitro-L-arginine methyl ester (L-NAME) or NG-nitro-L-arginine (L-NNA) enhanced the secretory response.

Conclusion

Our results show that NO inhibits gastric acid secretion in isolated human gastric glands, and that there is endogenous formation of NO within the glandular epithelium in the vicinity of the parietal cells.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-22394 (URN)10.1186/1471-230X-4-16 (DOI)1604 (Local ID)1604 (Archive number)1604 (OAI)
Available from: 2009-10-07 Created: 2009-10-07 Last updated: 2012-10-01Bibliographically approved
3. Nitric oxide inhibits gastric acid secretion by increasing intraparietal cell levels of cGMP in isolated human gastric glands
Open this publication in new window or tab >>Nitric oxide inhibits gastric acid secretion by increasing intraparietal cell levels of cGMP in isolated human gastric glands
Show others...
2005 (English)In: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 289, no 6, G1061-G1066 p.Article in journal (Refereed) Published
Abstract [en]

We have previously identified cells containing the enzyme nitric oxide (NO) synthase (NOS) in the human gastric mucosa. Moreover, we have demonstrated that endogenous and exogenous NO has been shown to decrease histamine-stimulated acid secretion in isolated human gastric glands. The present investigation aimed to further determine whether this action of NO was mediated by the activation of guanylyl cyclase (GC) and subsequent production of cGMP. Isolated gastric glands were obtained after enzymatic digestion of biopsies taken from the oxyntic mucosa of healthy volunteers. Acid secretion was assessed by measuring [14C]aminopyrine accumulation, and the concentration of cGMP was determined by radioimmunoassay. In addition, immunohistochemistry was used to examine the localization of cGMP in mucosal preparations after stimulation with the NO donor S-nitroso-N-acetylpenicillamine (SNAP). SNAP (0.1 mM) was shown to decrease acid secretion stimulated by histamine (50 μM); this effect was accompanied by an increase in cGMP production, which was histologically localized to parietal cells. The membrane-permeable cGMP analog dibuturyl-cGMP (db-cGMP; 0.1–1 mM) dose dependently inhibited acid secretion. Additionally, the effect of SNAP was prevented by preincubating the glands with the GC inhibitor 4H-8-bromo-1,2,4-oxadiazolo[3,4-d]benz[b][1,4]oxazin-1-one (10 μM). We therefore suggest that NO in the human gastric mucosa is of physiological importance in regulating acid secretion. Furthermore, the results show that NO-induced inhibition of gastric acid secretion is a cGMP-dependent mechanism in the parietal cell involving the activation of GC.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-31485 (URN)10.1152/ajpgi.00230.2005 (DOI)17277 (Local ID)17277 (Archive number)17277 (OAI)
Available from: 2009-10-09 Created: 2009-10-09 Last updated: 2012-10-01Bibliographically approved
4. Effect of nitric oxide on histamine-induced cytological transformations in parietal cells in isolated human gastric glands
Open this publication in new window or tab >>Effect of nitric oxide on histamine-induced cytological transformations in parietal cells in isolated human gastric glands
2007 (English)In: Digestive Diseases and Sciences, ISSN 0163-2116, E-ISSN 1573-2568, Vol. 52, no 1, 126-136 p.Article in journal (Refereed) Published
Abstract [en]

Previous studies have shown that nitric oxide (NO) inhibits histamine-induced gastric acid secretion in isolated human gastric glands. NO synthase has been found to be present in the human oxyntic mucosa and has been suggested to serve as a paracrine regulator of gastric acid secretion. Histamine stimulation of parietal cells induces cytoskeletal rearrangements, recruitment of H +/K +-ATPase-rich tubulovesicles to the apical membrane and expansion of intracellular canaliculi. The aim of the present study was thus to investigate (i) the effect of an NO donor on histamine-induced cytological transformations and (ii) the influence of increased [Ca 2+] i on NO-induced morphological changes in human parietal cells. Human gastric glands were isolated and subjected to the NO donor SNAP prior to histamine administration. [Ca 2+] i was increased by photolysis of the caged Ca 2+ compound NP-EGTA. The distribution of F-actin, ezrin, and H +/K +-ATPase was assessed by confocal microscopy. Ultrastructural analysis was performed using transmission electron microscopy. SNAP did not influence the histamine-induced translocation of F-actin, ezrin, and H +/K +-ATPase but prevented an increase in the canalicular size. Elevation of [Ca 2+] i in resting cells was found to mimic histamine-induced intraparietal cell transformations; however, NO-induced parietal cell morphology was unaffected by a rise in [Ca 2+] i. These results indicate that NO inhibits secretion of fluid into the canalicular lumen without affecting membrane recruitment and that this effect is Ca 2+-insensitive. © 2006 Springer Science+Business Media, Inc.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-40472 (URN)10.1007/s10620-006-9439-z (DOI)53339 (Local ID)53339 (Archive number)53339 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2012-10-01Bibliographically approved

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