Inducible nitric oxide synthase is involved in acid-induced gastric hyperemia in rats and mice

Phillipson, Mia; Henriksnäs, Johanna; Holstad, Maria; Sandler, Stellan; Holm, Lena

doi:10.1152/ajpgi.00432.2002

Cited by 27 publications

(24 citation statements)

References 36 publications

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“…Thus the involvement of iNOS in mucus secretion was studied, and a thinner mucus layer with a lower rate of accumulation in iNOS-deficient mice was determined. This observation supported the gastroprotective role of epithelial iNOS that has been previously suggested (29). These results also explained why the mucus was not affected by L-NNA pretreatment (in a concentration efficient in increasing blood pressure, Refs.…”

Section: Discussionsupporting

confidence: 89%

“…Constitutively expressed iNOS is present in the surface epithelial cells in the mouse corpus (29). Thus the involvement of iNOS in mucus secretion was studied, and a thinner mucus layer with a lower rate of accumulation in iNOS-deficient mice was determined.…”

Section: Discussionmentioning

confidence: 99%

“…Constitutively expressed iNOS in the gastric epithelium has been identified (29), and, in the present study, its role in mucus secretion was investigated by pretreating rats with the iNOSspecific inhibitor L-NIL (10 mg/kg iv bolus followed by 3 mg/kg per h continuous intravenous infusion). After 40 min with L-NIL and the first mucus removal, the firmly adherent mucus layer decreased (49 Ϯ 1 m) compared with untreated (72 Ϯ 4 m) and L-NNA-treated (64 Ϯ 6 m) rats.…”

Section: Inos-derived Not Nnos-derived No Increases Mucus Accumulatmentioning

confidence: 98%

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The gastric mucus layers: constituents and regulation of accumulation

Phillipson¹,

Johansson²,

Henriksnäs³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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The mucus layer continuously covering the gastric mucosa consists of a loosely adherent layer that can be easily removed by suction, leaving a firmly adherent mucus layer attached to the epithelium. These two layers exhibit different gastroprotective roles; therefore, individual regulation of thickness and mucin composition were studied. Mucus thickness was measured in vivo with micropipettes in anesthetized mice [isoflurane; C57BL/6, Muc1−/−, inducible nitric oxide synthase (iNOS)−/−, and neuronal NOS (nNOS)−/−] and rats (inactin) after surgical exposure of the gastric mucosa. The two mucus layers covering the gastric mucosa were differently regulated. Luminal administration of PGE2increased the thickness of both layers, whereas luminal NO stimulated only firmly adherent mucus accumulation. A new gastroprotective role for iNOS was indicated since iNOS-deficient mice had thinner firmly adherent mucus layers and a lower mucus accumulation rate, whereas nNOS did not appear to be involved in mucus secretion. Downregulation of gastric mucus accumulation was observed in Muc1−/− mice. Both the firmly and loosely adherent mucus layers consisted of Muc5ac mucins. In conclusion, this study showed that, even though both the two mucus layers covering the gastric mucosa consist of Muc5ac, they are differently regulated by luminal PGE2and NO. A new gastroprotective role for iNOS was indicated since iNOS−/− mice had a thinner firmly adherent mucus layer. In addition, a regulatory role of Muc1 was demonstrated since downregulation of gastric mucus accumulation was observed in Muc1−/− mice.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Inos-derived Not Nnos-derived No Increases Mucus Accumulatmentioning

confidence: 98%

See 1 more Smart Citation

The gastric mucus layers: constituents and regulation of accumulation

Phillipson¹,

Johansson²,

Henriksnäs³

et al. 2008

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In a recent study, we (29) showed that the hyperemia induced by luminal acid was absent or substantially reduced in iNOS knockout mice. Our results also suggested that iNOS was constitutively expressed in surface epithelial cells.…”

Section: Discussionmentioning

confidence: 88%

“…Blood flow is also important in removing backdiffusing hydrogen ions, toxic waste products, accumulated oxygen metabolites, and other inflammatory mediators (17). We have shown in previous studies (29,35) that luminal acid alone induces hyperemia without any macroscopic lesions. Furthermore, we have suggested that epithelial inducible nitric oxide (NO) synthase (iNOS) is involved in the hyperemic response to acid, possibly signaling to afferent nerves, leading to a blood flow increase.…”

mentioning

confidence: 79%

Impaired mucus-bicarbonate barrier inHelicobacter pylori-infected mice

Henriksnäs

Phillipson²,

Storm³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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To resist the harsh intrinsic milieu, several lines of defense exist in the stomach. The aim of this study was to investigate the effect of the gastric pathogen Helicobacter pylori on these mechanisms in vivo. We used FVB/N mice expressing human ␣-1,3/4-fucosyl transferase (producing Lewis b epitopes) and inoculated with H. pylori 1. Mice were anesthetized with isoflurane or Hypnorm-midazolam, the stomach was exteriorized, and the surface of the corpus mucosa was exposed. Mucus thickness was measured with micropipettes, juxtamucosal pH (pHjm) was measured with pH-sensitive microelectrodes, blood flow was measured with laser-Doppler flowmetry, and mRNA levels of the bicarbonate transporter SLC26A9 were quantified with real-time PCR. The increase in mucosal blood flow seen in response to luminal acid (pH 1.5) in control animals (140 Ϯ 9% of control) was abolished in infected mice. The firmly adherent mucus layer was significantly thinner in infected mice (31 Ϯ 2 m) than in control mice (46 Ϯ 5 m), and no mucus accumulation occurred in infected mice. pHjm decreased significantly more on exposure to luminal acid in infected mice (luminal pH 1.5, pH jm 2.4 Ϯ 0.7) than in control mice (pHjm 6.4 Ϯ 0.5). Despite reduced pHjm, SLC26A9 mRNA expression was significantly, by increased 1.9-fold, in infected mice. The reduction in pH jm by infection with H. pylori might be due to a reduced firmly adherent mucus layer, increased mucus permeability to H ϩ , and/or inhibition of bicarbonate transport. The upregulation of SLC26A9 in H. pylori-infected epithelium might be a result of continuous inhibition of the transporter, e.g., by ammonium, a H. pylori product, which has been previously shown to inhibit SLC26A9. juxtamucosal pH; blood flow; laser-Doppler flowmetry; permeability

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The Gastrointestinal Circulation: Physiology and Pathophysiology

Granger

Holm

Kvietys

2015

Comprehensive Physiology

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The gastrointestinal (GI) circulation receives a large fraction of cardiac output and this increases following ingestion of a meal. While blood flow regulation is not the intense phenomenon noted in other vascular beds, the combined responses of blood flow, and capillary oxygen exchange help ensure a level of tissue oxygenation that is commensurate with organ metabolism and function. This is evidenced in the vascular responses of the stomach to increased acid production and in intestine during periods of enhanced nutrient absorption. Complimenting the metabolic vasoregulation is a strong myogenic response that contributes to basal vascular tone and to the responses elicited by changes in intravascular pressure. The GI circulation also contributes to a mucosal defense mechanism that protects against excessive damage to the epithelial lining following ingestion of toxins and/or noxious agents. Profound reductions in GI blood flow are evidenced in certain physiological (strenuous exercise) and pathological (hemorrhage) conditions, while some disease states (e.g., chronic portal hypertension) are associated with a hyperdynamic circulation. The sacrificial nature of GI blood flow is essential for ensuring adequate perfusion of vital organs during periods of whole body stress. The restoration of blood flow (reperfusion) to GI organs following ischemia elicits an exaggerated tissue injury response that reflects the potential of this organ system to generate reactive oxygen species and to mount an inflammatory response. Human and animal studies of inflammatory bowel disease have also revealed a contribution of the vasculature to the initiation and perpetuation of the tissue inflammation and associated injury response.

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Inducible nitric oxide synthase is involved in acid-induced gastric hyperemia in rats and mice

Cited by 27 publications

References 36 publications

The gastric mucus layers: constituents and regulation of accumulation

The gastric mucus layers: constituents and regulation of accumulation

Impaired mucus-bicarbonate barrier inHelicobacter pylori-infected mice

The Gastrointestinal Circulation: Physiology and Pathophysiology

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