Role of nitric oxide in intestinal water and electrolyte transport

Mourad, Fadi H.; Turvill, James; Farthing, M. J. G.

doi:10.1136/gut.44.2.143

Cited by 64 publications

(43 citation statements)

References 60 publications

(35 reference statements)

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“…The VIP antagonist [4Cl-D -Phe 6 Leu 17 ] VIP converted fl uid secretion in rat jejunum to net absorption [35] . We have confi rmed this effect on CT-induced secretion and have also provided evidence that VIPergic nerves may also be the fi nal effector pathway for LT and ST secretion [36] . Sigma receptors are found widely in the neurons of the ENS.…”

Section: The Enteric Nervous Systemmentioning

confidence: 78%

Antisecretory Drugs for Diarrheal Disease

Farthing

2006

Dig Dis

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Acute diarrhea is a major cause of morbidity and mortality worldwide. Infants and pre-school children are the most vulnerable in whom there are 2–3 million deaths each year as a result of the associated dehydration and acidosis. Although oral rehydration therapy has reduced mortality during the past 30 years ago, the search for agents that will directly inhibit intestinal secretory mechanisms and thereby reduce faecal losses in patients with high-volume watery diarrhea has continued for more than 20 years. A variety of potential targets for antisecretory agents have been explored which include loci within the enterocyte (the chloride channel, calcium-calmodulin) and other sites such as enteric nerves and endogenous mediators (such as 5-HT, prostaglandins). Although the potential of calcium-calmodulin inhibition has as yet not been realised, preliminary studies suggest that there are chloride channel blockers under development that will find a place in the management of secretory diarrheas. Recent work has highlighted the importance of neurohumoral mechanisms in the pathogenesis of acute diarrhea. Potentiation of the effects of endogenous enkephalin activity by enkephalinase inhibition has already produced a safe, effective anti-secretory drug, racecadotril. Speculative early work indicates that there may be a role for antagonists of 5-HT, substance P, and VIP receptors. There now seems to be a real possibility that antisecretory therapy will become more widely available in the future.

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Section: The Enteric Nervous Systemmentioning

confidence: 78%

Antisecretory Drugs for Diarrheal Disease

Farthing

2006

Dig Dis

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“…NO 2 Ϫ /NO 3 Ϫ determination and Western blot experiments contributed to clarifying the mechanisms of NO production and its role in response to cAMP-mediated ion secretion. The increased NO 2 Ϫ /NO 3 Ϫ production in response to CT or to 8Br-cAMP indicates that NO synthesis by the enterocyte is increased in response to stimulated secretion. NO overproduction was associ- …”

Section: Discussionmentioning

confidence: 99%

“…In physiologic conditions, the basal cNOS activity is implicated in the regulation of the proabsorptive tone in the intestine, but whether this is the result of a direct effect on the enterocyte, or involves a neurologic control of intestinal blood flow, is still not clear (2,3). On the contrary, an overproduction of NO by iNOS in pathologic conditions, such as inflammatory intestinal diseases, results in net ion secretion (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”

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confidence: 99%

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Nitric Oxide Produced by the Enterocyte Is Involved in the Cellular Regulation of Ion Transport

et al. 2003

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The role of nitric oxide (NO) in the intestinal basal ion transport and under conditions of enterotoxin-induced ion secretion is controversial. Namely it is not clear whether NO enhances or counteracts intestinal ion secretion and whether the effects on transport result from a direct interaction with the enterocyte. The cell origin of NO is also unclear. We have tested the hypothesis that NO produced by the enterocyte directly regulates ion transport processes either in basal condition or in response to cholera toxin-induced secretion. Electrical variables reflecting transepithelial ion transport were measured in Caco-2 cell monolayers mounted in Ussing chambers exposed to the NO synthase inhibitor N-nitro-L-arginine methyl ester, in the presence or absence of cholera toxin. cAMP concentrations were also measured. NO release was determined by nitrite-nitrate concentration. NO synthase activities were assayed by Western blot analysis. N-nitro-L-arginine methyl ester had a secretory effect, as judged by increased basal short-circuit current and cAMP concentration. It also increased cholera toxin-induced electrical response and cAMP production. Either cholera toxin or the cAMP analog 8-bromo-cAMP induced a rapidly progressive and Ca 2ϩ -dependent increase in NO concentration, suggesting a homeostatic up-regulation of the constitutive form of NO synthase.Western blot analysis showed an increase in constitutive NO synthase enzyme isoform. These results indicate that the enterocyte regulates its own ion transport processes, either in basal condition or in the presence of active secretion, through the activation of a constitutive NO synthase-NO pathway, functioning as a braking force of cAMP-induced ion secretion. Intestinal water and electrolyte transepithelial transport is under a complex control by several agents including neurotransmitters, hormones, or paracrine agents (1). There is evidence that NO takes part in the intestinal ion transport processes with an effect that involves the enteric nervous system, the suppression of prostaglandin formation, and the opening of K ϩ channels (2, 3). NO is a gas with a half-life of less than 5 s, rapidly degrading to nitrite and nitrate in the presence of oxygen and water. NO is produced by a number of cells, including neuronal cells, and released in various organs. Being soluble in both water and lipids, it freely passes into adjacent target cells (2,4). NO is generated from L-arginine by a family of enzymes, NOS, whose activity can be stereospecifically inhibited by L-but not by D-arginine analogs (5). Two NOS are constantly active in the intestine and are termed cNOS. They include the neuronal NOS (NOS 1) and the endothelial NOS (NOS 3). Both are Ca 2ϩ /calmodulin-dependent, produce small amounts of NO in short burst, and are involved in several homeostatic processes. A third NOS form, which is Ca 2ϩ /calmodulin-independent, is activated by various signal molecules, including proinflammatory cytokines. This latter form, termed iNOS (NOS 2), requires at least 2 h to be act...

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“…NO production has been found to be increased in IBD and experimental colitis (33,35,43), but its role in the pathogenesis or in the associated diarrhea has not been elucidated. The effect of NO on intestinal fluid transport has been controversial, with many studies showing a proabsorptive and/or a prosecretory effect (21,40). Whether the release of NO in colitis would affect fluid and nutrient absorption in a distant part of the intestine has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory effect of experimental colitis on fluid absorption in rat jejunum: role of the enteric nervous system, VIP, and nitric oxide

Mourad¹,

Barada²,

Rached³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Impairment of small intestinal absorption has been described in patients with ulcerative colitis and in animal models of experimental colitis. The pathophysiology of this dysfunction has not been elucidated. The aim of this study was to investigate the effect of chemical colitis on jejunal fluid absorption and determine the role of the enteric nervous system and some putative neurotransmitters. In a rat model of iodoacetamide-induced colitis, jejunal net fluid absorption was evaluated by the in vivo single-pass perfusion technique. The effects of 1) tetrodotoxin (TTX), 2) benzylalkonium chloride (BAC), 3) capsaicin, 4) vasoactive intestinal polypeptide (VIP) antagonism, 5) nitric oxide (NO) synthase (NOS) inhibition, and 6) 5-hydroxytryptamine type 3 and 4 (5-HT3 and 5-HT4) receptor antagonism on the changes in fluid movement were investigated. A significant decrease in jejunal net fluid absorption was found 2 and 4 days after colitis induction: 26 (SD 14) and 28 (SD 19) μl·min−1·g dry intestinal wt−1, respectively [ P < 0.0002 compared with sham rats at 61 (SD 6.5) μl·min−1·g dry intestinal wt−1]. No histological changes were evident in jejunal sections. TTX and BAC reversed this decrease in fluid absorption: 54 (SD 13) and 44 (SD 14) μl·min−1·g dry intestinal wt−1 ( P = 0.0005 and P = 0.019, respectively, compared with colitis). Ablation of capsaicin-sensitive primary afferent fibers had a partial effect: 45 (SD 5) μl·min−1·g dry intestinal wt−1 ( P = 0.001 and P = 0.003 compared with colitis and sham, respectively). Constitutive and neuronal NOS inhibition and VIP antagonism returned jejunal net fluid absorption to normal values: 66 (SD 19), 61 (SD 5), and 56 (SD 14) μl·min−1·g dry intestinal wt−1, respectively. 5-HT3 and 5-HT4 receptor antagonism had no effect. Chemical colitis is associated with a significant decrease in jejunal net fluid absorption. This decrease is neurally mediated and involves VIP- and NO-related mechanisms.

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Role of nitric oxide in intestinal water and electrolyte transport

Cited by 64 publications

References 60 publications

Antisecretory Drugs for Diarrheal Disease

Antisecretory Drugs for Diarrheal Disease

Nitric Oxide Produced by the Enterocyte Is Involved in the Cellular Regulation of Ion Transport

Inhibitory effect of experimental colitis on fluid absorption in rat jejunum: role of the enteric nervous system, VIP, and nitric oxide

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