Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with prostanoids and sensory neuropeptides in the rat (original) (raw)
Related papers
Actions and interactions of endothelins, prostacyclin and nitric oxide in the gastric mucosa
PubMed, 1993
The modulation of the gastric mucosal microcirculation plays a key role in the maintenance of gastric integrity. Disruption of the balance between the local release of vasodilator and vasoconstrictor mediators could therefore be involved in the pathogenesis of mucosal injury. Thus, the endothelium derived peptide endothelin-1 (ET-1), induces mucosal injury following local administration. In contrast, the vasodilator prostanoids, prostacyclin and PGE2 can protect against gastric damage, while inhibition of endogenous prostanoid formation by cyclo-oxygenase inhibitors augment mucosal damage, including that induced by ET-1. Sensory neuropeptides such as calcitonin gene-related peptide (CGRP) may also play a local protective role, since acute intragastric administration of capsaicin which stimulates neuropeptide release, protects against mucosal injury induced by ET-1, as does local infusion of CGRP. Furthermore, chronic administration of capsaicin which deplete primary sensory neurones augments gastric damage induced by a number of ulcerogens including ET-1. Nitric oxide (NO) synthesized from L-arginine can regulate gastric mucosal blood flow, both under resting conditions and following stimulation of acid secretion. Inhibition of NO biosynthesis alone does not induce acute mucosal injury, yet extensive haemorrhagic damage results from concurrent inhibition of NO formation, cyclo-oxygenase inhibition and depletion of sensory neuropeptides. NO donors can protect against ulceration, although the unregulated release of high levels of NO can lead to mucosal injury. Thus, NO has a critical interactive role with other local protective mediators such as the prostanoids and sensory neuropeptides in the physiological regulation of mucosal integrity.
Role of nitric oxide in indomethacin-induced gastric mucosal dysfunction in the rat
Experimental Physiology, 1999
The present study was undertaken to explore the role of nitric oxide (NO) in the pathogenesis of experimental non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy. We assessed the role of NO inhibition and donation in indomethacin-induced gastric mucosal dysfunction. The stomach was perfused with vehicle (control) for 20 min, followed by indomethacin (10 mg ml-' in 1.25 % sodium bicarbonate, pH 8-4) for 120 min. NG-nitro-L-arginine methyl ester (L-NAME, 5 and 10 mg kg-', '.v. bolus), L-arginine, D-arginine (100 mg kg-1 I.V. bolus, 10 mg kg-' h-', 2 h infusion) and the NO donor glyceryl trinitrate (GTN) were given at the same time (20, 40 and 80 lug kg-l min-', 15 min infusion) as perfusion with indomethacin was started. Epithelial permeability was quantified by measuring blood-to-lumen clearance of 51Cr-labelled EDTA. Indomethacin caused a 20-fold increase in 51Cr-EDTA leakage compared with that of the control group. Treatment with L-NAME or L-arginine did not affect the indomethacin-induced alterations in mucosal permeability. Administration of GTN (20 ug kg-' min-') significantly reduced the indomethacin-induced mucosal dysfunction. By contrast, higher doses of GTN (80 ,tg kg-' min-') exacerbated epithelial dysfunction induced by indomethacin. Elevated levels of carbonyls and myeloperoxidase (MPO) observed after indomethacin administration were significantly reduced, to the control values, when GTN (20 ,ug kg-' mnin-) was administered along with indomethacin.
Role ofl-arginine, a substrate for nitric oxide-synthase, in gastroprotection and ulcer healing
Journal of Gastroenterology, 1997
Nitric oxide (NO) synthesized from L-arginine interacts with prostaglandins (PG) and sensory neuropeptides in the regulation of mucosal integrity, but the role of L-arginine, a substrate for NO-synthase, in gastroprotection and healing of chronic gastric ulcers has been little studied. In this study we compared the effects of intragastric (i.g.) and systemic (i.v.) administration of L-arginine or D-arginine on gastric secretion and acute gastric lesions provoked in rats by i.g. application of 100% ethanol, acidified aspirin (ASA), or the exposure to 3.5 h of water immersion and restraint stress (WRS). In addition, the effects of L-arginine on ulcer healing and the formation of new vessels (angiogenesis) were determined, using monoclonal antibody (MAb E-9). L-arginine (10-200mg/kg i.g.) failed to significantly affect gastric secretion but dose-dependently reduced the gastric lesions induced by 100% ethanol, ASA, and WRS, the doses inhibiting 50% of these lesions being 65, 94, and 72mg/kg, respectively. This protection was accompanied by a significant rise in the gastric blood flow (GBF), whereas L-arginine given i.v. failed to affect the ethanol-lesions and the GBF. D-arginine or the NOrelated amino acids-L-glutamine, L-citrulline, or Lornithine-failed to significantly influence these lesions. Suppression of the generation of mucosal PG by indomethacin or capsaicin-denervation attenuated the protection and hyperemia induced by L-arginine. The inhibition of constitutive NO synthase by L-NNA had no significant effect on the protection afforded by Larginine, but reduced the gastric hyperemia accompanying this protection. L-arginine (150mg/kg per day, i.g.
New Issues about Nitric Oxide and its Effects on the Gastrointestinal Tract
Current Pharmaceutical Design, 2001
Over the last years the important role of nitric oxide (NO) as endogenous modulator of numerous physiological functions has been shown. NO is involved in the regulation of blood flow, maintenance of vascular tone, control of platelet aggregation, and modulation of the activity of the mastocytes. It also plays a key role as neurotransmitter in the central and peripheric nervous system (non adrenergic non colinergic, NANC, neurons), in the nervous control of the cerebral blood flow and in the neuroendocrine regulation or synaptic plasticity. However, NO shows a dual behavior: at physiological concentrations, released through the constitutive synthase (cNOS), it regulates house-keeping functions, whereas its overproduction by the inducible isoenzyme (iNOS) exhibits cytotoxic activity because interacting with reactive species producing peroxinitrites (ONOO • ) and other compounds, which are highly damaging for the tissues.
Digestive Diseases and Sciences, 2002
l-Arginine (l-arg) exhibits multiple biological properties and plays an important role in the regulation of different functions in pathological conditions. Many of these effects could be achieved on this amino acid serving as a substrate for the enzyme nitric oxide synthase (NOS). At the gastrointestinal level, recent reports revealed its protective activities involving a hyperemic response increasing the gastric blood flow. The aim of this study was to characterize the relationship between NOS activity/expression and prostaglandin changes (PGs) in rats gastric mucosa, with l-arg associated resistance to the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen (IBP). The protective effect of oral l-arg (100 mg/kg body wt), administerred together with IBP (100 mg/kg body wt, per os), was evident enough 90 min after drug administration, although a significant protection persisted for more than 6 hr. Pretreatment with NG-nitro-l-arginine (l-NNA) (40 mg/kg body wt, intraperitoneally), a competitive inhibitor of constitutive NOS, partly altered the protection afforded by the amino acid. In contrast, no changes could be observed after inducible NOS inhibition [aminoguanidine (AG) 50 mg/Kg body wt, intraperitoneally). l-arg, plus IBP, produced a significant increase of the cyclic GMP (cGMP) response in tissue samples from rat stomach, 90 min and 6 h after drug administration. iNOS activity and mRNA expression were higher in IBP-treated rats, and no differences were observed in inducible responses in the l-arg plus IBP group. No variations in the cNOS activity and expression were found among the different groups of animals assayed. The measurement of mucosal PGE2 content confirmed that biosynthesis of the eicosanoid is maintained by l-arg for over 90 min after IBP, while a total inhibition was observed 6 hr later. The mechanisms of the l-arg protective effect on the damaged induced by IBP could be explained by the different period after drug administration. The early phase is mediated by cyclooxygenase/prostaglandins pathway (COX/PGs) although NO liberated by cNOS and the guanylate cyclase/cGMP pathway could be also relevant. The later phase implicates inhibition of the iNOS/NO response.
Pharmacological Research, 2001
Gastric ulceration was induced in rats by i.p. injection of the non-steroidal anti-inflammatory drug (NSAID), indomethacin (IND) (30 mg kg −1 ). Pyloric ligation was carried out in each animal before injection to enable collection of the gastric juice. Three hours later, the animals were killed and their stomachs were removed. In the gastric juice, the amounts of mucin, pepsin and HCl were assessed. Gastric mucosa were scrapped for the determination of nitric oxide (NO) (as nitrite) after evaluation of the gastric ulcer index.
British Journal of Pharmacology, 1993
The protective or damaging actions on the gastric mucosa, of locally infused nitrovasodilators that donate nitric oxide (NO), have been investigated in the pentobarbitone‐anaesthetized rat. Local intra‐arterial infusion of endothelin‐1 (ET‐1; 5 pmol kg−1 min−1 for 10 min) induced extensive, macroscopically apparent, haemorrhagic injury to the rat gastric mucosa. This damage was dose‐dependently reduced by concurrent local intra‐arterial infusion of glyceryl trinitrate (GTN; 10–40 μg kg−1 min−1) which liberates NO on metabolic transformation, or the nitrosothiol, S‐nitroso‐N‐acetyl‐penicillamine (SNAP, 2.5–10 μg kg−1 min−1) which spontaneously liberates NO. Local infusion of higher doses of SNAP (20 and 40 μg kg−1 min−1, i.a.) did not, however, significantly protect against mucosal injury induced by ET‐1. Furthermore, local infusion alone of these higher doses of SNAP, as well as sodium nitroprusside (10–40 μg kg−1 min−1, i.a.) which also spontaneously liberates NO, induced significa...
Neuronal nitric oxide in the gut
Journal of Gastroenterology and Hepatology, 1993
Motility of the gastrointestinal tract is directly controlled by enteric inhibitory and excitatory motor neurons that innervate the layers of smooth muscle. Inhibitory motor neurons mediate receptive and accommodative relaxations and control the opening of sphincters, thus playing an important role in normal gut motility, Recent studies have demonstrated that nitric oxide (NO) is an important neurotransmitter released by inhibitory motor neurons in animal and human gut. Antagonists of nitric oxide synthase (NOS), the synthetic enzyme for NO, reduce the effectiveness of transmission from inhibitory motor neurons. Exogenous NO mimics inhibitory nerve activation, and a variety of compounds that affect the availability of endogenously produced NO modulate relaxations of gastrointestinal smooth muscle. It is clear, however, that NO is unlikely to be the only transmitter released by enteric inhibitory motor neurons: several other substances such as vasoactive intestinal polypeptide (VIP), or related peptides, and adenosine triphosphate (ATP) are also likely to contribute to nerve-mediated inhibition. The identification of NO as a major inhibitory neurotransmitter to gastrointestinal smooth muscle fills an important gap in our understanding of the physiological control of motility and opens up a wide range of new experimental possibilities. It may eventually lead. to the development of new drugs for motility disorders. It should be noted, however, that NO is important in the brain, in cardiovascular control, in blood cell function and in many other organ systems, suggesting that it may be difficult to achieve specific pharmacological intervention targeted on inhibitory neurotransmission in the gut, without undesirable side effects.