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Nitric oxide inhibits gastric acid secretion by increasing intraparietal cell levels of cGMP in isolated human gastric glands
Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för biomedicin och kirurgi, Kirurgi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för medicin och vård, Farmakologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för biomedicin och kirurgi, Cellbiologi. Linköpings universitet, Hälsouniversitetet.
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2005 (Engelska)Ingår i: American Journal of Physiology - Gastrointestinal and Liver Physiology, ISSN 0193-1857, E-ISSN 1522-1547, Vol. 289, nr 6, s. G1061-G1066Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
2005. Vol. 289, nr 6, s. G1061-G1066
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-31485DOI: 10.1152/ajpgi.00230.2005Lokalt ID: 17277OAI: oai:DiVA.org:liu-31485DiVA, id: diva2:252308
Tillgänglig från: 2009-10-09 Skapad: 2009-10-09 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
Ingår i avhandling
1. Effects of nitric oxide on gastric acid secretion in human gastric mucosa: functional and morphological studies
Öppna denna publikation i ny flik eller fönster >>Effects of nitric oxide on gastric acid secretion in human gastric mucosa: functional and morphological studies
2005 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Linköping: Linköping University Electronic Press, 2005. s. 86
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 925
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:liu:diva-31122 (URN)16856 (Lokalt ID)91-85497-61-4 (ISBN)16856 (Arkivnummer)16856 (OAI)
Disputation
2005-12-15, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Svenska)
Opponent
Tillgänglig från: 2009-10-09 Skapad: 2009-10-09 Senast uppdaterad: 2012-10-01Bibliografiskt granskad

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Berg, AnnaRedéen, StefanGrenegård, MagnusEricson, Ann-CharlottSjöstrand, Sven-Erik

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