Inflammatory modulation of muscarinic receptor activation in canine ileal circular muscle cells

Shi, X-Z.; Sarna, S. K.

doi:10.1053/gast.1997.v112.pm9041248

Cited by 40 publications

(46 citation statements)

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“…ACh acts mainly on muscarinic M 3 receptors on circular smooth muscle cells (72) and VIP acts on VPAC 2 receptors (45), and NO permeates through the membrane to activate soluble guanylyl cylase. The M 3 and VPAC 2 are G proteincoupled receptors through which they activate multiple intracellular signaling pathways (Fig.…”

Section: Selection Of Enteric Neurons And/or Circular Smooth Muscle Cmentioning

confidence: 99%

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: Selection Of Enteric Neurons And/or Circular Smooth Muscle Cmentioning

confidence: 99%

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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“…We can only speculate as to the nature of this mediator [e.g., neuropeptide Y (23), somatostatin (6), prostaglandin D 2 (30)], but it is apparent that cholinergic control of colonic ion transport is more complex than simple interaction of ACh with epithelial M 3 receptors. Perturbation of the cholinergic system is not uncommon in inflammatory conditions (12,29,39), and it is clear that the DSS-induced colitis has resulted in dysfunctional cholinergic muscarinic receptors on the epithelium. This could be the result of reduced receptor expression, altered receptor affinity, or failure of the intracellular signaling pathway.…”

Section: Fluorescence Micrographs Of Inos and Glial Fibrillatory Acmentioning

confidence: 99%

Dextran sodium sulfate-induced colitis reveals nicotinic modulation of ion transport via iNOS-derived NO

Green¹,

Ho²,

Sharkey³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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. Dextran sodium sulfate-induced colitis reveals nicotinic modulation of ion transport via iNOS-derived NO. Am J Physiol Gastrointest Liver Physiol 287: G706 -G714, 2004. First published April 15, 2004 10.1152/ajpgi.00076.2004.-In normal colon, ACh elicits a luminally directed Cl Ϫ efflux from enterocytes via activation of muscarinic receptors. In contrast, in the murine model of dextran sodium sulfate (DSS)-induced colitis, an inhibitory cholinergic ion transport event due to nicotinic receptor activation has been identified. The absence of nicotinic receptors on enteric epithelia and the ability of nitric oxide (NO) to modulate ion transport led us to hypothesize that NO mediated the cholinergic nicotinic receptor-induced changes in ion transport. Midportions of colon from control and DSS-treated mice were examined for inducible NO synthase (iNOS) expression by RT-PCR and immunofluorescence or mounted in Ussing chambers for assessment of cholinergic-evoked changes in ion transport (i.e., shortcircuit current) with or without pretreatment with pharmacological inhibitors of NO production. iNOS mRNA and protein levels were increased throughout the tissue from DSS-treated mice and, notably, in the myenteric plexus, where the majority of iNOS immunoreactivity colocalized with the enteric glial cell marker glial fibrillary acidic protein. The drop in short-circuit current evoked by the cholinomimetic carbachol in tissue from DSS-treated mice was prevented by selective inhibitors of iNOS activity {N 6 -(1-iminoethyl)-lysine HCl and N- [3-(aminomethyl)benzyl]acetamidine} or an NO scavenger [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide] or by removal of the myenteric plexus. Thus, in this model of colitis, a "switch" occurs from muscarinic to nicotinic receptor-dominated control of cholinergic ion transport. The data indicate a novel pathway involving activation of nicotinic receptors on myenteric neurons, resulting in release of NO from neurons or enteric glia and, ultimately, a dampening of stimulated epithelial Cl Ϫ secretion that would reduce secretory diarrhea.short-circuit current; chloride; inflammatory bowel disease WATER MOVEMENT between the gut lumen and the interstitium is critically important for hydrating the surface of the enteric epithelium, providing the medium for contact digestion and nutrient absorption, and reducing the contact of pathogens and potentially noxious bacterial or environmental toxins with the enterocytes. This key function of the epithelium is accomplished by the coordinated activity of ion channels, cotransporters, and energy-dependent ion pumps that are asymmetrically arranged in the cell membrane of the polarized epithelium: this allows for vectorial ion transport, creating the driving forces for directed water movements (2). Many intrinsic and extrinsic agents influence epithelial ion transport, including neurotransmitters (e.g., ACh), biogenic amines, nu-

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“…Smooth muscle cells were isolated according to the methods described before (23)(24)(25). Briefly, colon tissue was thoroughly washed in ice-cold 0.9% saline to clear the debris, and then placed in ice-cold oxygenated N-2-hydroxyethylpiperazine-N'-2-ethane-sulphonic acid (HEPES) buffer on ice.…”

Section: Protocol For In Vivo Measurementsmentioning

confidence: 99%

Inflammation Inhibits Muscarinic Signaling in In Vivo Canine Colonic Circular Smooth Muscle Cells

Jadcherla

2002

Pediatr Res

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We investigated the effects of experimental colitis on the muscarinic signaling properties and contractile behavior of canine colonic circular smooth muscle. The hypotheses that inflammation 1) inhibits in vivo muscarinic receptor mediated contractions, and 2) alters receptor density or receptor-binding affinities were tested. Muscarine was infused close-intra-arterially in seven conscious dogs during normal and experimental colitis states. Colonic circular muscle contractions were recorded via surgically attached strain gauge transducers. Muscarine stimulated phasic contractions in a dose-dependent manner, whereas colitis was inhibited. The inhibitory concentration 50% dose of M 3 receptor inhibitor was several times lower than that of M 1 , M 2 , and M 4 inhibitors during normal and colitis. However, inflammation induced a significant leftward shift in the circular muscle inhibitory dose-response curve of M 2 inhibitor. Muscarinic receptor density and binding analyses in isolated circular muscle cells was done in normal and colitis states. Inflammation significantly decreased maximum binding from 4082 fmol/mg to 2708 fmol/mg, whereas affinity constant remained unaffected. The conclusions were that 1) spontaneous and muscarine-activated in vivo phasic contractile activity of colonic circular muscle cells is primarily mediated by M 3 receptors; 2) inflammation was associated with a shift in M 2 receptor potency, due chiefly to a decrease in receptor density; and 3) this inhibitory effect was seen in normal and inflamed states, suggesting the importance of M 2 receptor. These findings suggest that changes in muscarinic response during colitis may contribute to the abnormal motility seen with inflammatory bowel disease. ACh, the principal neurotransmitter of the enteric nervous system, is released not only as a result of parasympathetic activation, but also in response to many other gastrointestinal peptides (1). Atropine (nonselective muscarinic antagonist), when administered intravenously or close-intra-arterially (arterial) completely blocks all spontaneous smooth muscle contractions in the gut (1-3). In the gastrointestinal system, muscarinic receptors play a significant role in coordination of peristalsis and propulsion of luminal contents (4).The muscarinic receptors in the gut are localized at presynaptic, postsynaptic, and prejunctional and postjunctional sites (5). These receptors on smooth muscle cells mediate contractions by G-protein coupled mechanisms, whereas those at presynaptic and prejunctional sites modulate the release of ACh by negative feedback. The activation of muscarinic receptors at postsynaptic sites stimulates postsynaptic excitatory and inhibitory neurons to release neurotransmitters. The physiologic mechanisms by which muscarinic receptors stimulate in vivo colonic circular muscle contractions are not completely understood.

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Inflammatory modulation of muscarinic receptor activation in canine ileal circular muscle cells

Cited by 40 publications

References 1 publication

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

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

Dextran sodium sulfate-induced colitis reveals nicotinic modulation of ion transport via iNOS-derived NO

Inflammation Inhibits Muscarinic Signaling in In Vivo Canine Colonic Circular Smooth Muscle Cells

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