An intrinsic neural pathway for long intestino-intestinal inhibitory reflexes

Frantzides, Constantinos; Sarna, Sushil K.; Matsumoto, Teiji; Lang, Ivan M.; Condon, Robert E.

doi:10.1016/0016-5085(87)90006-0

Cited by 36 publications

(15 citation statements)

References 26 publications

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“…Cholinesterase inhibitors that accumulate ACh at the neuromuscular junction also stimulate nonpropagating RPCs for the same reason. However, as noted above, the accumulation of ACh at the neuroeffector junction may also stimulate GMCs, which are highly propulsive irrespective of the slow waves (17,32).…”

Section: Strategies In the Selection Of Molecular And Pharmacologicalmentioning

confidence: 85%

“…The sustained accumulation of ACh stimulates different signaling pathways for excitationcontraction coupling in circular smooth muscle cells than those stimulated by short-duration release of ACh that generates RPCs (6,58). For example, neostigmine, a cholinesterase inhibitor, stimulates colonic GMCs by accumulating ACh at the neuroeffector junction (17,32). In a physiological setting, the slow excitatory postsynaptic junctional potentials (sEPSPs) may release ACh at the neuromuscular junction for a longer duration resulting in its accumulation and stimulation of GMCs.…”

Section: Types Of Gut Contractions Their Regulatory Mechanisms and mentioning

confidence: 99%

“…First, most evidence indicates that excessive release or accumulation of ACh at the neuroeffector junction stimulates GMCs (17,32,55). The excessive release of ACh may be due to the stimulation of slow EPSPs that can generate a long series of action potentials lasting longer than 10 s (50, 79).…”

Section: Strategies In the Selection Of Molecular And Pharmacologicalmentioning

confidence: 99%

“…Systemic administration of guanethidine also transiently generates GMCs by blocking the inhibitory effect of norepinephrine on the release of ACh at the presynaptic terminals (77). Likewise, systemic or close intra-arterial administration of anticholinesterase neostigmine stimulates GMCs (17,32). In all these cases, the GMCs propagate distally and produce mass movements.…”

Section: Strategies In the Selection Of Molecular And Pharmacologicalmentioning

confidence: 99%

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Molecular, functional, and pharmacological targets for the development of gut promotility drugs

Sarna

2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Molecular, functional, and pharmacological targets for the development of gut promotility drugs. Am J Physiol Gastrointest Liver Physiol 291: G545-G555, 2006. First published March 24, 2006 doi:10.1152/ajpgi.00122.2006.-The science of gastrointestinal motility has made phenomenal advances during the last fifty years. Yet, there is a paucity of effective promotility drugs to treat functional bowel disorders that affect 10 -29% of the U.S. population. A part of the reason for the lack of effective drugs is our limited understanding of the etiology of these diseases. In the absence of this information, mostly an ad hoc approach has been used to develop the currently available drugs, which are modestly effective or effective in only a subset of the patients with functional bowel disorders. This review discusses a grounds-up approach for development of the next generation of promotility drugs. The approach is based on our current understanding of 1) the different types of contractions that produce overall motility function of mixing and orderly net distal propulsion in major gut organs, 2) the regulatory mechanisms of these contractions, 3) which receptors and intracellular signaling molecules could be targeted to stimulate specific types of contractions to accelerate or retard transit, and 4) the strengths and limitations of animal models and experimental approaches that could screen potential promotility drugs for their efficacy in human gut propulsion in functional bowel disorders. smooth muscle; slow waves; enteric neurons; excitation-contraction coupling; peristaltic reflex; irritable bowel syndrome; prokinetic agents; gastroparesis; functional bowel disorders THE SCIENCE OF GASTROINTESTINAL MOTILITY has made phenomenal advances during the last fifty years. Our understanding of the individual regulatory mechanisms of motility function [excitation-contraction coupling in smooth muscle cells; enteric motor, sensory, and interneurons; enteric neurotransmitters, neuromodulators, and hormones; extrinsic neurons including spinal cord and central nervous system (CNS)] has matured (7, 18 -20, 26, 28, 39, 42, 53, 54, 57, 59, 60, 76, 78). However, significant gaps remain in our understanding of how and when the inputs from these mechanisms integrate to produce the normal mixing and propulsive motor functions of the gut; defects in these regulatory mechanisms result in motility dysfunction in diseases such as irritable bowel syndrome, inflammatory bowel disease, gastroparesis, and gastroesophageal reflux. Finally, our understanding of which receptors and intracellular signaling molecules in circular smooth muscle cells and enteric neurons could be targeted to normalize function in motility disorders is still rudimentary.Most currently available promotility drugs or those under development seem to have their origins in a known physiological or pharmacological effect or in their established role in a different system. For example, CCK receptor antagonists (loxiglumide and deloxyglumide) are thought to be potential promotil...

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Section: Strategies In the Selection Of Molecular And Pharmacologicalmentioning

confidence: 85%

Section: Types Of Gut Contractions Their Regulatory Mechanisms and mentioning

confidence: 99%

Section: Strategies In the Selection Of Molecular And Pharmacologicalmentioning

confidence: 99%

Section: Strategies In the Selection Of Molecular And Pharmacologicalmentioning

confidence: 99%

See 2 more Smart Citations

Molecular, functional, and pharmacological targets for the development of gut promotility drugs

Sarna

2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The IIIR is activated by contraction or distension of the intestine and results in inhibition of the intestine at a distal site mediated by the mesenteric nerves. 27 While this study was not designed to investigate the IIIR, the effects of cutting the mesenteric nerves on the IIIR were observed. It was found that transection of the mesenteric nerves significantly eliminated the absence of non-RGC contractions during the propagation of the RGC at the sites where the mesenteric nerve was transected, ie, 50 to 80 cm from the pylorus, and for 10 cm aborad of the transection.…”

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confidence: 99%

The Role of Central and Enteric Nervous Systems in the Control of the Retrograde Giant Contraction

Lang

2016

J Neurogastroenterol Motil

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Background/AimsThe role of the enteric (ENS) and central (CNS) nervous systems in the control of the retrograde giant contraction (RGC) associated with vomiting is unknown. MethodsThe effects of myotomy or mesenteric nerve transection (MNT) on apomorphine-induced emesis were investigated in 18 chronically instrumented dogs ResultsNeither surgery affected the RGC orad of the surgical site or the velocity of the RGC over the entire small intestine. Myotomy blocked the RGC for 17 ± 5 cm aborad of the myotomy, and the velocity of the RGC from 100 to 70 cm from the pylorus slowed (18.1 ± 3.0 to 9.0 ± 0.8 cm/sec) such that the RGC orad and aborad of the myotomy occurred simultaneously. After MNT, the RGC was unchanged up to 66 ± 6 cm from the pylorus, and the sequence of the RGC across the denervated intestine was unaltered. The velocity of the RGC from 100 to 70 cm from the pylorus increased from 12.8 ± 1.6 to 196 ± 116 cm/sec. After myotomy or MNT, the percent occurrence and magnitude of the RGC across the intestine 100 to 70 cm from the pylorus decreased. ConclusionsThe CNS activates the RGC 10 to 20 cm aborad of its innervation of the intestine and controls the RGC sequence. On the other hand, the ENS plays a role in initiation and generation of the RGC.

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