Antisecretory actions of a novel vasoactive intestinal polypeptide (VIP) antagonist in human and rat small intestine

Banks, Matthew; Farthing, M. J. G.; Robberecht, Patrick; Burleigh, David

doi:10.1038/sj.bjp.0706128

Cited by 46 publications

(49 citation statements)

References 35 publications

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“…These results are similar to observations in the guinea-pig (Furness et al 2003) and suggest that the VIP/NPY/calretinin/TH neurons are secretomotor neurons. This accords with retrograde tracing studies that have shown that NPY-immunoreactive submucosal neurons project to the mucosa of the mouse small intestine (Van Nassauw et al 2000) and is consistent with VIP being a primary transmitter of secretomotor neurons, as has been demonstrated in other species, including human, rat, guinea-pig and cat Lundgren 2002;Banks et al 2005;Furness 2006). VIP is also a stimulant of secretion in the mouse small intestine (Cox et al 2001), although its role as a secretomotor neurotransmitter has not been directly investigated.…”

Section: Discussionsupporting

confidence: 88%

Identification of neuron types in the submucosal ganglia of the mouse ileum

et al. 2009

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The continuing and even expanding use of genetically modified mice to investigate the normal physiology and development of the enteric nervous system and for the study of pathophysiology in mouse models emphasises the need to identify all the neuron types and their functional roles in mice. An investigation that chemically and morphologically defined all the major neuron types with cell bodies in myenteric ganglia of the mouse small intestine was recently completed. The present study was aimed at the submucosal ganglia, with the purpose of similarly identifying the major neuron types with cell bodies in these ganglia. We found that the submucosal neurons could be divided into three major groups: neurons with vasoactive intestinal peptide (VIP) immunoreactivity (51% of neurons), neurons with choline acetyltransferase (ChAT) immunoreactivity (41% of neurons) and neurons that expressed neither of these markers. Most VIP neurons contained neuropeptide Y (NPY) and about 40% were immunoreactive for tyrosine hydroxylase (TH); 22% of all submucosal neurons were TH/VIP. VIP-immunoreactive nerve terminals in the mucosa were weakly immunoreactive for TH but separate populations of TH- and VIP-immunoreactive axons innervated the arterioles in the submucosa. Of the ChAT neurons, about half were immunoreactive for both somatostatin and calcitonin gene-related peptide (CGRP). Calretinin immunoreactivity occurred in over 90% of neurons, including the VIP neurons. The submucosal ganglia and submucosal arterioles were innervated by sympathetic noradrenergic neurons that were immunoreactive for TH and NPY; no VIP and few calretinin fibres innervated submucosal neurons. We conclude that the submucosal ganglia contain cell bodies of VIP/NPY/TH/calretinin non-cholinergic secretomotor neurons, VIP/NPY/calretinin vasodilator neurons, ChAT/CGRP/somatostatin/calretinin cholinergic secretomotor neurons and small populations of cholinergic and non-cholinergic neurons whose targets have yet to be identified. No evidence for the presence of type-II putative intrinsic primary afferent neurons was found.

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Section: Discussionsupporting

confidence: 88%

Identification of neuron types in the submucosal ganglia of the mouse ileum

et al. 2009

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“…VIP both causes fluid secretion and increases blood flow [96,97], and there is evidence that collaterals from the VIP containing secretomotor neurons innervate arterioles in the submucosa [98]. In human, overproduction of VIP causes the watery diarrhea syndrome [99].…”

Section: Secretomotor and Secretomotor/vasodilator Neurons Controllinmentioning

confidence: 99%

The Enteric Nervous System and Gastrointestinal Innervation: Integrated Local and Central Control

Furness

Callaghan

Rivera

et al. 2014

Advances in Experimental Medicine and Biology

638

648

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The digestive system is innervated through its connections with the central nervous system (CNS) and by the enteric nervous system (ENS) within the wall of the gastrointestinal tract. The ENS works in concert with CNS reflex and command centers and with neural pathways that pass through sympathetic ganglia to control digestive function. There is bidirectional information flow between the ENS and CNS and between the ENS and sympathetic prevertebral ganglia.The ENS in human contains 200-600 million neurons, distributed in many thousands of small ganglia, the great majority of which are found in two plexuses, the myenteric and submucosal plexuses. The myenteric plexus forms a continuous network that extends from the upper esophagus to the internal anal sphincter. Submucosal ganglia and connecting fiber bundles form plexuses in the small and large intestines, but not in the stomach and esophagus. The connections between the ENS and CNS are carried by the vagus and pelvic nerves and sympathetic pathways. Neurons also project from the ENS to prevertebral ganglia, the gallbladder, pancreas and trachea.The relative roles of the ENS and CNS differ considerably along the digestive tract. Movements of the striated muscle esophagus are determined by neural pattern generators in the CNS. Likewise the CNS has a major role in monitoring the state of the stomach and, in turn, controlling its contractile activity and acid secretion, through vago-vagal reflexes. In contrast, the ENS in the small intestine and colon contains full reflex circuits, including sensory neurons, interneurons and several classes of motor neuron, through which muscle activity, transmucosal fluid fluxes, local blood flow and other functions are controlled. The CNS has control of defecation, via the defecation centers in the lumbosacral spinal cord. The importance of the ENS is emphasized by the life-threatening effects of some ENS neuropathies. By contrast, removal of vagal or sympathetic connections with the gastrointestinal tract has minor effects on GI function. Voluntary control of defecation is exerted through pelvic connections, but cutting these connections is not life-threatening and other functions are little affected.

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“…The importance of VIP in CT-induced fl uid secretion is well supported by drug inhibition studies [35,90] . VIP antagonists are effective when given both before and following establishment of the secretory state and able to inhibit LT and ST secretion in addition to their effects on CT [35,90] .…”

Section: Vip Antagonistsmentioning

confidence: 87%

“…However, the 5-HT 3 receptor antagonist, granisetron, reversed fl uid and chloride ion secretion to net absorption [89] . However, LT and ST do not release 5-HT from enterochromaffi n cells in the small intestine and that the secretory state induced by these toxins is not inhibitable by 5-HT receptor antagonists [90] .…”

Section: -Ht Antagonistsmentioning

confidence: 89%

“…VIP antagonists are effective when given both before and following establishment of the secretory state and able to inhibit LT and ST secretion in addition to their effects on CT [35,90] . Specifi c VIP antagonists are not available for use in humans as yet, although evidence from model systems would suggest that this class of drug might have substantial clinical potential.…”

Section: Vip Antagonistsmentioning

confidence: 99%

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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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Antisecretory actions of a novel vasoactive intestinal polypeptide (VIP) antagonist in human and rat small intestine

Cited by 46 publications

References 35 publications

Identification of neuron types in the submucosal ganglia of the mouse ileum

Identification of neuron types in the submucosal ganglia of the mouse ileum

The Enteric Nervous System and Gastrointestinal Innervation: Integrated Local and Central Control

Antisecretory Drugs for Diarrheal Disease

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