Role of nitric oxide in the gastric cytoprotection induced by central vagal stimulation

doi:10.1016/0014-2999(93)90913-3

European Journal of Pharmacology

Volume 240, Issues 2–3, 24 August 1993, Pages 299-301

https://doi.org/10.1016/0014-2999(93)90913-3 Get rights and content

Abstract

The role of nitric oxide (NO) in the vagal cholinergic-mediated cytoprotective effect of intracisternal (i.c.) injection of the stable thyrotropin-releasing hormone (TRH) analog, RX 77368, was investigated in conscious rats. RX 77368 (1.5 ng i.c.) reduced by 88% gastric hemorrhagic lesions induced by oral administration of ethanol (60%). L-N^G-Nitro-arginine methyl ester (L-NAME, 3 mg/kg i.v.), an inhibitor of NO synthase, abolished the cytoprotection provided by i.c. RX 77368. The effect of L-NAME was reversed by L- but not D-arginine. These results suggest that the L-arginine-nitric oxide pathway is involved in the cytoprotective effect of i.c. TRH analog, probably through the modulation of gastric mucosal blood flow.

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Cited by (39)

Effects of centrally injected glucagon-like peptide-2 on gastric mucosal blood flow in rats: Possible mechanisms
2015, Peptides
Citation Excerpt :
Thus NO does not mediates the GMBF-increasing effect of i.c.v. GLP-2. This was quite surprising, since many neuropeptides produce central effects on GMBF via NO [37,45–47]. There may be several other pathways independent from NO, which may increase GMBF.
“Glucagon-like peptide-2” (GLP-2) is a peptide that is released from the enteroendocrine L cells in response to food in the gastrointestinal tract. Peripheral injection of GLP-2 has been shown to increase gastrointestinal blood flow, but effects of central GLP-2 on any vascular bed has not been studied yet. The aim of this study is to investigate the effects of various doses of intracerebroventricularly (i.c.v.)-injected GLP-2 on gastric mucosal blood flow (GMBF) and contribution of calcitonin gene related peptide (CGRP), nitric oxide synthase-nitric oxide (NOS-NO) and cyclooxygenase-prostaglandin (COX-PG) systems to the possible effect. The gastric chamber technique was used to determine GMBF. Urethane anesthesia was used throughout the recording procedure. Male Wistar rats were treated with GLP-2 (100, 150 ve 200 ng/10 μl; i.c.v.) or saline (10 μl; i.c.v.) in order to find out the effective dose of i.c.v. GLP-2 on GMBF. Then, CGRP receptor antagonist CGRP-(8-37) (10 μg/kg; s.c.), NOS inhibitor NG-nitro-l-arginine methyl ester (l-NAME; 30 mg/kg; s.c.) or COX inhibitor indomethacin (5 mg/kg; i.p.) was injected before the effective dose of i.c.v. GLP-2. GMBF was measured continuously for 35 min following GLP-2 and recorded every fifth minute. Non-parametric Kruskal–Wallis test was used for statistical analysis. Differences were considered to be significant at p < 0.05. GMBF increased rapidly following 100 ng GLP-2 injection and did not fall to the basal levels during 35 min. Other doses of i.c.v. GLP-2 did not produce any significant difference in GMBF. CGRP receptor antagonist, CGRP-(8-37) (10 μg/kg; s.c.) and COX inhibitor indomethacin (5 mg/kg; i.p.) significantly prevented the increase in GMBF due to GLP-2 (100 ng; i.c.v.), while l-NAME (30 mg/kg; s.c.) was ineffective. None of the drugs produced a significant change in GMBF when administered alone. Thus we suggest that, i.c.v. GLP-2 increases GMBF and CGRP and endogenous prostaglandins but not NO, contribute to this effect.
Investigation of the mechanisms involved in the central effects of glucagon-like peptide-1 on ethanol-induced gastric mucosal lesions
2005, Regulatory Peptides
The aim of this study was to investigate the effects of intracerebroventricularly injected glucagon-like peptide-1 (GLP-1) on ethanol-induced gastric mucosal damage and to elucidate the mechanisms involved. Absolute ethanol was administered through an orogastric cannula 5 min before GLP-1 (1 μg/10 μl) injection. One hour later, the rats were decapitated, their stomachs were removed and scored for mucosal damage. GLP-1 inhibited the ethanol-induced gastric mucosal damage by 92%. Centrally injected atropine sulphate, a muscarinic receptor antagonist (5 μg/10 μl), prevented the gastroprotective effect of GLP-1, while mecamylamine, a nicotinic receptor antagonist (25 μg/10 μl), was ineffective. Peripherally injected atropine methyl nitrate (1 mg/kg) did not change the effect of GLP-1, but mecamylamine (5 mg/kg) blocked it. Cysteamine, a somatostatin depletor (280 mg/kg, s.c.), did not affect the protective activity of GLP-1, while inhibition of nitric oxide (NO) synthesis by l-NAME (3 mg/kg, i.v.) significantly abolished the protective effect of GLP-1 on ethanol-induced gastric mucosal lesions. We conclude that central muscarinic and peripheral nicotinic cholinergic receptors and NO, but not somatostatin, contribute to the protective effect of intracerebroventricularly injected GLP-1 on ethanol-induced gastric mucosal damage.
Central and peripheral regulation of gastric acid secretion by peptide YY
2002, Peptides
Citation Excerpt :
However, when the DVC neurons are stimulated with subthreshold doses of these stimuli that do not change acid secretion or motility, gastric protection against ulcerations was observed. It has been established that stimulating DVC-induced gastric protection is mediated by vagal-cholinergic pathways and gastric calcitonin gene-related peptide (CGRP) and L-arginine/nitric oxide (NO)-dependent gastric vasodilation [42,43,45,46,80]. A similar pattern of this dose-related distinction in gastric response was also observed in the central actions of PYY.
Peptide YY (PYY) released postprandially from the ileum and colon displays a potent inhibition of cephalic and gastric phases of gastric acid secretion through both central and peripheral mechanisms. To modulate vagal regulation of gastric functions, circulating PYY enters the brain through the area postrema and the nucleus of the solitary tract, where it exerts a stimulatory action through PYY-preferring Y1-like receptors, and an inhibitory action through Y2 receptors. In the gastric mucosa, PYY binds to Y1 receptors in the enterochromaffin-like cells to inhibit gastrin-stimulated histamine release and calcium signaling via a pertussis toxin-sensitive pathway.
Intracerebroventricular injection of clonidine releases β-endorphin to induce mucosal protection in the rat
2000, Neuropharmacology
The possibility that the endogenous opioid system could be involved in the central nervous system (CNS)-mediated gastroprotective effect of clonidine was investigated. Intracerebroventricularly (i.c.v.) injected clonidine (470 pmol/rat) inhibited the gastric mucosal lesions induced by (orally administered) acidified ethanol in a significant manner in the rat. The gastroprotective effect of the centrally administered clonidine was antagonised by i.c.v. or intracisternally (i.c.) administered presynaptic alpha-2 adrenoceptor antagonist, yohimbine; the non-selective opioid receptor antagonist, naloxone; and the delta opioid receptor antagonist naltrindole. These results suggest that an interaction between central alpha-2 adrenoceptors and endogenous opioid systems is involved in mediating the mucosal protective effect. β-endorphin antiserum (i.c.) also antagonised the gastroprotection induced by intracerebroventricularly injected clonidine indicating that β-endorphin release is likely to be a key factor in the gastroprotective effect of clonidine. Furthermore, the i.c.v. or i.c. injection of beta-endorphin produced a potent gastroprotection in the picomolar range. The mucosal protective effect of clonidine was abolished after vagotomy indicating that the central effect may be conveyed to the periphery by vagal efferents. Since atropine (1 mg/kg i.v.) failed to modify, but hexamethonium (10 mg/kg i.v.) antagonised the gastroprotective effect of clonidine, it would appear that in the periphery nicotinic, but not muscarinic, cholinergic receptors are likely to be involved in the mucosal protective effect of clonidine. In conclusion, clonidine (i.c.v.) induces gastroprotective action by releasing an endogenous opioid substance — most likely β-endorphin — in the rat. The clonidine-induced central gastroprotection requires the integrity of vagal pathway; cholinergic nicotinic — but not muscarinic — receptors might mediate the effect in the periphery.
Vagus-mediated activation of mucosal mast cells in the stomach: Effect of ketotifen on gastric mucosal lesion formation and acid secretion induced by a high dose of intracisternal TRH analogue
2000, Journal of Physiology Paris
TRH analogue, RX 77368, injected intracisternally (i.c.) at high dose (3 μg/rat) produces gastric mucosal lesion formation through vagal-dependent pathway. The gastric mucosal hyperemia induced by i.c. RX 77368 was shown to be mediated by muscarinic vagal efferent fibres and mast cells. Furthermore, electrical vagal stimulation was observed to induce gastric mucosal mast cell degranulation. The aim of the study was to assess the influence of ketotifen, a mast cell stabilizer, on RX 77368-induced gastric lesion formation and gastric acid secretion. RX 77368 (3 μg, i.c.) or vehicle (10 μL, i.c.) was delivered 240 min prior to the sacrifice of the animals. Ketotifen or vehicle (0.9% NaCl, 0.5 mL) was injected intraperitoneally (i.p.) at a dose of 10 mg.kg^–1 30 min before RX 77368 injection. The extent of mucosal damage was planimetrically measured by a video image analyzer (ASK Ltd., Budapest) device. In the gastric acid secretion studies, the rats were pretreated with ketotifen (10 mg.kg^–1, i.p.) or vehicle (0.9% NaCl, 0.5 mL, i.p.), 30 min later pylorus-ligation was performed and RX 77368 (3 μg, i.c.) or vehicle (0.9% NaCl, 10 μL, i.c.) was injected. The rats were killed 240 min after i.c. injection, and the gastric acid secretion was measured through the titration of gastric contents with 0.1 N NaOH to pH 7.0. RX 77368 (3 μg, i.c.) resulted in a gastric mucosal lesion formation involving 8.2% of the corpus mucosa (n = 7). Ketotifen elicited an 85% inhibition on the development of mucosal lesions (n = 7, P < 0.001) whereas ketotifen alone had no effect on the lesion formation in the mucosa (n = 7). The RX 77368 induced increase of gastric acid secretion was not influenced by ketotifen pretreatment in 4-h pylorus-ligated animals. Central vagal activation induced mucosal lesion formation is mediated by the activation of mucosal mast cells in the stomach. Mast cell inhibition by ketotifen does not influence gastric acid secretion induced by i.c. TRH analogue in 4-h pylorus-ligated rats.
Nonsteroidal anti-inflammatory drugs
2000, Medical Clinics of North America
Citation Excerpt :
Nitric oxide has been found to exert many of the same functions as endogenous prostaglandins and may play a critical role in maintaining gastroduodenal mucosal integrity. In experimental animals, nitric oxide reduces gastroduodenal mucosal injury induced by ethanol and other irritants.26,27,41 In a clinical trial, nitric oxide–flurbiprofen was found to induce fewer gastric erosions than the parent drug.12
Nonsteroidal anti-inflammatory drugs (NSAIDs) have become one of the most commonly used medications in Western nations since the introduction of the first NSAID, aspirin, about 1 century ago. It is estimated that more than 70 million NSAID prescriptions and more than 30 billion of over-the-counter aspirin, ibuprofen, ketoprofen, and naproxen preparations are sold annually in the United States.38, 44 NSAIDs are generally well tolerated; however, their use frequently is limited by adverse gastrointestinal effects ranging from dyspepsia to serious complications, such as bleeding or perforation from gastric or duodenal ulcers.
Although adverse effects of NSAIDs occur only in a few individuals, the widespread use of NSAIDs has resulted in a substantial number of affected persons who experience serious gastrointestinal complications. It is estimated that 10% to 20% of NSAID users report dyspeptic symptoms, and 5% to 15% of rheumatoid arthritis patients taking NSAIDs are expected to discontinue medications because of dyspepsia.36, 59 A prospective study from the Arthritis, Rheumatism, and Aging Medical Information System (ARAMIS) has showed that the rate of NSAID-related gastrointestinal complications requiring hospitalization was 6 times higher in patients with rheumatoid arthritis who were taking NSAIDs than in those who were not.⁶¹ Despite a decline in the rate of hospitalization from NSAID-related gastrointestinal disorders, the mortality of hospitalized patients remains about 5% to 10%.2, 60 In 1997, the estimated death rate from NSAID-related complications in patients with arthritis was equivalent to that from acquired immunodeficiency syndrome (AIDS).58, 61 The medical costs related to NSAID-associated gastrointestinal complications have been reported to exceed $2 billion annually.⁶⁹

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Short communicationRole of nitric oxide in the gastric cytoprotection induced by central vagal stimulation

Abstract

Gastroentorology

Life Sci.

Biochem. Biophys. Res. Commun.

Gastroenterology

Gastroenterology

Peptidergic sensory neurons in the control of vascular functions: mechanisms and significance in the cutaneous and splanchnic vascular beds

Rev. Physiol. Biochem. Pharmacol.

Role of calcitonin gene-related peptide (CGRP) in the regulation of gastric acid secretion and mucosal integrity in the rat

Gastroenterology

Antiulcerogenic actions of endothelium-derived relaxing factor (EDRF)

Exp. Ulcer

Short communication
Role of nitric oxide in the gastric cytoprotection induced by central vagal stimulation