Pyloric Sphincter Dysfunction in nNOS−/− and W/Wv Mutant Mice: Animal Models of Gastroparesis and Duodenogastric Reflux

Sivarao, Digavalli V.; Mashimo, Hiroshi; Goyal, Raj K.

doi:10.1053/j.gastro.2008.06.039

Cited by 60 publications

(60 citation statements)

References 32 publications

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“…Unexpectedly, ICC depletion showed no effect on both components of the IJP, whereas disruption of NO/CO signalling in ICC by Prkg1 deletion blocks selectively the NO/COdependent sIJP. These findings are in line with data from mice lacking intramuscular ICC (W/W v mice) or the gene encoding nNOS 29,30 . The lower oesophageal sphincter and the pyloric sphincter are hypotensive, with normal nitrergic relaxation in W/W v mice due to the selective lack of excitatory cholinergic input from enteric neurons (loss of EJP, unaffected IJP, for comparison see Fig.…”

Section: Discussionsupporting

confidence: 90%

“…These data provide the first genetic in vivo evidence for an essential role of ICC in excitatory neurotransmission to smooth muscle cells in acute ICC-depleted adult animals and support findings in W/W v germline mutant mice that display reduced excitatory neurotransmission and a hypotensive lower oesophageal and pyloric sphincter 12,13,16,29,30 .…”

Section: Icc Depletion Blocks Excitatory Enteric Neurotransmissionsupporting

confidence: 81%

“…Taken together, our results may explain and resolve the apparently contradictory findings in W/W v and nNOS KO models, which are the basis of the long-lasting controversy on how NO released from enteric neurons relaxes the smooth musculature 9,12,29,30,42 .…”

Section: Discussionsupporting

confidence: 59%

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Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity

et al. 2013

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The enteric nervous system contains excitatory and inhibitory neurons, which control contraction and relaxation of smooth muscle cells as well as gastrointestinal motor activity. Little is known about the exact cellular mechanisms of neuronal signal transduction to smooth muscle cells in the gut. Here we generate a c-Kit CreERT2 knock-in allele to target a distinct population of pacemaker cells called interstitial cells of Cajal. By genetic loss-of-function studies, we show that interstitial cells of Cajal, which generate spontaneous electrical slow waves and thus rhythmic contractions of the smooth musculature, are essential for transmission of signals from enteric neurons to gastrointestinal smooth muscle cells. Interstitial cells of Cajal, therefore, integrate excitatory and inhibitory neurotransmission with slow-wave activity to orchestrate peristaltic motor activity of the gut. Impairment of the function of interstitial cells of Cajal causes severe gastrointestinal motor disorders. The results of our study show at the genetic level that these disorders are not only due to loss of slow-wave activity but also due to disturbed neurotransmission.

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Section: Discussionsupporting

confidence: 90%

Section: Icc Depletion Blocks Excitatory Enteric Neurotransmissionsupporting

confidence: 81%

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Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity

et al. 2013

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“…Neuronal nitric oxide synthase-deficient (nNOS −/− ) mice and diabetic animals (eg, Streptozotocin treated rats, nonobese diabetic [NOD] mice, and ob/ob mouse model of obesity) are well-known animal models of GP. [19][20][21][22] The results observed in ICC deficient mice or rats were contradictory. They have been used both as a model of duodenogastric reflux based on the presence of a hypotensive pyloric sphincter, as well as delayed gastric emptying mimicking GP.…”

Section: Gastroparesis and Interstitial Cells Of Cajal In Animal Modelsmentioning

confidence: 99%

“…They have been used both as a model of duodenogastric reflux based on the presence of a hypotensive pyloric sphincter, as well as delayed gastric emptying mimicking GP. 19,23 Ultrastructural changes of ICC as well as ICC depletion have been observed in diabetic animal models. Two recent studies by Chen et al 24,25 showed that diabetes induced by streptozotocin in rats delays gastric emptying, decreases contractions of the antral strips, and decreases ICC-IM, ICC-MP, and ICC-SM counts in the antrum.…”

Section: Gastroparesis and Interstitial Cells Of Cajal In Animal Modelsmentioning

confidence: 99%

Is Interstitial Cells of Cajal‒opathy Present in Gastroparesis?

Bashashati

McCallum

2015

J Neurogastroenterol Motil

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Gastroparesis (GP), defined as delayed gastric emptying in the absence of any mechanical obstruction, is a challenging clinical condition, mainly because of limited treatment options. Studies in animal models of delayed gastric emptying as well as patients with gastroparesis revealed depletion or ultrastructural changes of interstitial cells of Cajal (ICC) in the gastric tissue, recently termed ICC-opathy. ICC are the pacemakers of the gastrointestinal tract and are involved in the transmission of the neuronal signaling to the smooth muscles. Therefore, lack of ICC could be one explanation of delayed gastric emptying in gastroparetic patients. How frequently ICC changes are observed in gastroparesis is not yet clear. In this review, the data on gastric ICC counts and morphology in animal models and patients with gastroparesis are discussed.

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Neurochemical phenotypes of myenteric neurons in the rhesus monkey

Noorian

Taylor

Annerino

et al. 2011

J of Comparative Neurology

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Understanding the neurochemical composition of the enteric nervous system (ENS) is critical for elucidating neurological function in the gastrointestinal (GI) tract in health and disease. Despite their status as the closest models of human neurological systems, relatively little is known about enteric neurochemistry in nonhuman primates. We describe neurochemical coding of the enteric nervous system, specifically the myenteric plexus, of the rhesus monkey (Macaca mulatta) by immunohistochemistry and directly compare it to human tissues. There are considerable differences in the myenteric plexus along different segments of the monkey GI tract. While acetylcholine neurons make up the majority of myenteric neurons in the stomach (70%), they are a minority in the rectum (47%). Conversely, only 22% of gastric myenteric neurons express nitric oxide synthase (NOS) compared to 52% in the rectum. Vasoactive intestinal peptide (VIP) is more prominent in the stomach (37%) versus the rest of the GI tract (10%), and catecholamine neurons are rare (1%). There is significant coexpression of NOS and VIP in myenteric neurons that is more prominent in the proximal GI tract. Taken as a whole, these data provide insight into the neurochemical anatomy underlying GI motility. While overall similarity to other mammalian species is clear, there are some notable differences between the ENS of rhesus monkeys, humans, and other species that will be important to take into account when evaluating models of human diseases in animals.

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Pyloric Sphincter Dysfunction in nNOS−/− and W/Wv Mutant Mice: Animal Models of Gastroparesis and Duodenogastric Reflux

Abstract: Background and & Aims-Nitrergic nerves and interstitial cells of Cajal (ICC) have been implicated in the regulation of pyloric motility. The purpose of these studies was to define their roles in pyloric function in vivo.

Cited by 60 publications

References 32 publications

Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity

Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity

Is Interstitial Cells of Cajal‒opathy Present in Gastroparesis?

Neurochemical phenotypes of myenteric neurons in the rhesus monkey

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