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Abstract
Gastroparesis is a neurogastrointestinal disorder of motility in which patients experience symptoms of nausea, vomiting, bloating, early satiety, postprandial fullness, upper abdominal discomfort or pain, and delayed gastric emptying of solids based on scintigraphy or stable isotope breath test when mechanical obstruction has been excluded. Symptoms of gastroparesis may result from diverse pathophysiological mechanisms, including antroduodenal hypomotility, pylorospasm, increased gastric accommodation, and visceral hypersensitivity. The most common etiologies of gastroparesis are idiopathic, diabetic, and postsurgical, and less frequent causes are neurodegenerative disorders (Parkinson's disease), myopathies (scleroderma, amyloidosis), medication-induced (glucagon-like peptide-1 agonists and opioid agents), and paraneoplastic syndrome. This review addresses pharmacologic management of gastroparesis including prokinetic and antiemetic agents, pharmacologic agents targeting the pylorus, and effects of neuromodulators. SIGNIFICANCE STATEMENT: Gastroparesis is a neurogastrointestinal motility disorder characterized by delayed gastric emptying without mechanical obstruction with numerous upper gastrointestinal symptoms, including nausea and vomiting. The management of gastroparesis involves nutritional support, medications, and procedures. The only Food and Drug Administration-approved medication for gastroparesis is metoclopramide. This article reviews the pharmacology and efficacy of all classes of antiemetics or prokinetic effects used in gastroparesis. There is still a considerable unmet need for efficacious medications specifically for the treatment of gastroparesis, especially in refractory cases.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Kara J Jencks
- Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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2
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Athavale ON, Di Natale MR, Avci R, Clark AR, Furness JB, Cheng LK, Du P. Mapping the rat gastric slow-wave conduction pathway: bridging in vitro and in vivo methods, revealing a loosely coupled region in the distal stomach. Am J Physiol Gastrointest Liver Physiol 2024; 327:G254-G266. [PMID: 38860855 PMCID: PMC11427108 DOI: 10.1152/ajpgi.00069.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 06/04/2024] [Accepted: 06/10/2024] [Indexed: 06/12/2024]
Abstract
Rhythmic electrical events, termed slow waves, govern the timing and amplitude of phasic contractions of the gastric musculature. Extracellular multielectrode measurement of gastric slow waves can be a biomarker for phenotypes of motility dysfunction. However, a gastric slow-wave conduction pathway for the rat, a common animal model, is unestablished. In this study, the validity of extracellular recording was demonstrated in vitro with simultaneous intracellular and extracellular recordings and by pharmacological inhibition of slow waves. The conduction pathway was determined by in vivo extracellular recordings while considering the effect of motion. Slow-wave characteristics [means (SD)] varied regionally having higher amplitude in the antrum than the distal corpus [1.03 (0.12) mV vs. 0.75 (0.31) mV; n = 7; P = 0.025 paired t test] and faster propagation near the greater curvature than the lesser curvature [1.00 (0.14) mm·s-1 vs. 0.74 (0.14) mm·s-1; n = 9 GC, 7 LC; P = 0.003 unpaired t test]. Notably, in some subjects, separate wavefronts propagated near the lesser and greater curvatures with a loosely coupled region occurring in the area near the distal corpus midline at the interface of the two wavefronts. This region had either the greater or lesser curvature wavefront propagating through it in a time-varying manner. The conduction pattern suggests that slow waves in the rat stomach form annular wavefronts in the antrum and not the corpus. This study has implications for interpretation of the relationship between slow waves, the interstitial cells of Cajal network structure, smooth muscles, and gastric motility.NEW & NOTEWORTHY Mapping of rat gastric slow waves showed regional variations in their organization. In some subjects, separate wavefronts propagated near the lesser and greater curvatures with a loosely coupled region near the midline, between the wavefronts, having a varying slow-wave origin. Furthermore, simultaneous intracellular and extracellular recordings were concordant and independent of movement artifacts, indicating that extracellular recordings can be interpreted in terms of their intracellular counterparts when intracellular recording is not possible.
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Affiliation(s)
- Omkar N Athavale
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Madeleine R Di Natale
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
- Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria, Australia
| | - Recep Avci
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Alys R Clark
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - John B Furness
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
- Department of Anatomy & Physiology, University of Melbourne, Parkville, Victoria, Australia
| | - Leo K Cheng
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Peng Du
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
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3
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Tovbis D, Yoo PB. Vagus nerve stimulation in bursts can efficiently modulate gastric contractions and contraction frequency at varying gastric pressures. Neurogastroenterol Motil 2024; 36:e14815. [PMID: 38735698 DOI: 10.1111/nmo.14815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 03/25/2024] [Accepted: 04/26/2024] [Indexed: 05/14/2024]
Abstract
OBJECTIVE There has been recent clinical interest in the use of vagus nerve stimulation (VNS) for treating gastrointestinal disorders as an alternative to drugs or gastric electrical stimulation. However, effectiveness of burst stimulation has not been demonstrated. We investigated the ability of bursting and continuous VNS to influence gastric and pyloric activity under a range of stimulation parameters and gastric pressures. The goals of this study were to determine which parameters could optimally excite or inhibit gastric activity. MATERIALS AND METHODS Data were collected from 21 Sprague-Dawley rats. Under urethane anesthesia, a rubber balloon was implanted into the stomach, connected to a pressure transducer and a saline infusion pump. A pressure catheter was inserted at the pyloric sphincter and a bipolar nerve cuff was implanted onto the left cervical vagus nerve. The balloon was filled to 15 cmH2O. Stimulation trials were conducted in a consistent order; the protocol was then repeated at 25 and 35 cmH2O. The nerve was then transected and stimulation repeated to investigate directionality of effects. RESULTS Bursting stimulation at the bradycardia threshold caused significant increases in gastric contraction amplitude with entrainment to the bursting frequency. Some continuous stimulation trials could also cause increased contractions but without frequency changes. Few significant changes were observed at the pylorus, except for frequency entrainment. These effects could not be uniquely attributed to afferent or efferent activity. SIGNIFICANCE Our findings further elucidate the effects of different VNS parameters on the stomach and pylorus and provide a basis for future studies of bursting stimulation for gastric neuromodulation.
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Affiliation(s)
- D Tovbis
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - P B Yoo
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada
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4
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Athavale ON, Avci R, Clark AR, Di Natale MR, Wang X, Furness JB, Liu Z, Cheng LK, Du P. Neural regulation of slow waves and phasic contractions in the distal stomach: a mathematical model. J Neural Eng 2024; 20:066040. [PMID: 38100816 PMCID: PMC10765034 DOI: 10.1088/1741-2552/ad1610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 11/06/2023] [Accepted: 12/15/2023] [Indexed: 12/17/2023]
Abstract
Objective.Neural regulation of gastric motility occurs partly through the regulation of gastric bioelectrical slow waves (SWs) and phasic contractions. The interaction of the tissues and organs involved in this regulatory process is complex. We sought to infer the relative importance of cellular mechanisms in inhibitory neural regulation of the stomach by enteric neurons and the interaction of inhibitory and excitatory electrical field stimulation.Approach.A novel mathematical model of gastric motility regulation by enteric neurons was developed and scenarios were simulated to determine the mechanisms through which enteric neural influence is exerted. This model was coupled to revised and extended electrophysiological models of gastric SWs and smooth muscle cells (SMCs).Main results.The mathematical model predicted that regulation of contractile apparatus sensitivity to intracellular calcium in the SMC was the major inhibition mechanism of active tension development, and that the effect on SW amplitude depended on the inhibition of non-specific cation currents more than the inhibition of calcium-activated chloride current (kiNSCC= 0.77 vs kiAno1= 0.33). The model predicted that the interaction between inhibitory and excitatory neural regulation, when applied with simultaneous and equal intensity, resulted in an inhibition of contraction amplitude almost equivalent to that of inhibitory stimulation (79% vs 77% decrease), while the effect on frequency was overall excitatory, though less than excitatory stimulation alone (66% vs 47% increase).Significance.The mathematical model predicts the effects of inhibitory and excitatory enteric neural stimulation on gastric motility function, as well as the effects when inhibitory and excitatory enteric neural stimulation interact. Incorporation of the model into organ-level simulations will provide insights regarding pathological mechanisms that underpin gastric functional disorders, and allow forin silicotesting of the effects of clinical neuromodulation protocols for the treatment of these disorders.
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Affiliation(s)
- Omkar N Athavale
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Recep Avci
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Alys R Clark
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Madeleine R Di Natale
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- Department of Anatomy & Physiology, University of Melbourne, Parkville, VIC, Australia
| | - Xiaokai Wang
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States of America
| | - John B Furness
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
- Department of Anatomy & Physiology, University of Melbourne, Parkville, VIC, Australia
| | - Zhongming Liu
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States of America
| | - Leo K Cheng
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Peng Du
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
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5
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Abstract
Propulsion of contents in the gastrointestinal tract requires coordinated functions of the extrinsic nerves to the gut from the brain and spinal cord, as well as the neuromuscular apparatus within the gut. The latter includes excitatory and inhibitory neurons, pacemaker cells such as the interstitial cells of Cajal and fibroblast-like cells, and smooth muscle cells. Coordination between these extrinsic and enteric neurons results in propulsive functions which include peristaltic reflexes, migrating motor complexes in the small intestine which serve as the housekeeper propelling to the colon the residual content after digestion, and mass movements in the colon which lead to defecation.
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Affiliation(s)
- Gary M Mawe
- Department of Neurological Sciences, The University of Vermont, Burlington, Vermont
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada, Reno, School of Medicine, Reno, Nevada
| | - Michael Camilleri
- Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, Minnesota
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Jaffey DM, McAdams JL, Baronowsky EA, Black D, Powley TL. Vagal preganglionic axons arborize in the myenteric plexus into two types: nitrergic and non-nitrergic postganglionic motor pools? Am J Physiol Regul Integr Comp Physiol 2023; 324:R305-R316. [PMID: 36622086 PMCID: PMC9942884 DOI: 10.1152/ajpregu.00260.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/16/2022] [Accepted: 01/03/2023] [Indexed: 01/10/2023]
Abstract
Vagal preganglionic neurons innervate myenteric ganglia. These autonomic efferents are distributed so densely within the ganglia that it has been impractical to track individual vagal axons through the myenteric plexus with tracer labeling. To evaluate whether vagal efferent axons evidence selectivity, particularly for nitrergic or non-nitrergic myenteric neurons within the plexus, we limited the numbers and volumes of brainstem dextran biotin tracer injections per animal. Reduced labeling and the use of immunohistochemistry generated cases in which some individual axons could be distinguished and traced in three dimensions (Neurolucida) within and among successive (up to 46) myenteric ganglia. In the myenteric plexus of all stomach regions, the majority (∼86%) of vagal efferents were organized into two distinct subtypes. One subtype (∼24% of dextran-labeled efferents, designated "primarily nitrergic") selectively contacted and linked-both within and between ganglia-nitric oxide synthase positive (nNOS+) neurons into presumptive motor modules. A second subtype (∼62% of efferents, designated "primarily non-nitrergic") appeared to selectively contact and link-both within and between ganglia-non-nitrergic enteric neurons into a second type of effector ensemble. A third candidate type (∼14% of labeled preganglionics), appeared to lack "nitrergic selectivity" and to contact both nNOS+ and nNOS- enteric neurons. In addition to the quantitative assessment of the efferent axons in stomach, qualitative observations of the proximal duodenum indicated similar selective vagal efferent projections, in proportions comparable with those evaluated in the stomach. Limited injections of tracer, three-dimensional (3-D) tracing of individual axons, and histochemistry of myenteric neurons might distinguish additional efferent phenotypes.NEW & NOTEWORTHY The present study highlights the following: 1) one type of vagal efferent axon selectively innervates nitrergic upper gastrointestinal myenteric neurons; 2) a second type of vagal efferent selectively innervates non-nitrergic gastrointestinal myenteric neurons; and 3) the two types of vagal efferents might modulate peristalsis reciprocally and cooperatively.
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Affiliation(s)
- D M Jaffey
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana
| | - J L McAdams
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana
| | - E A Baronowsky
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana
| | - D Black
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana
| | - T L Powley
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana
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Analysis of Regional Variations of the Interstitial Cells of Cajal in the Murine Distal Stomach Informed by Confocal Imaging and Machine Learning Methods. Cell Mol Bioeng 2022; 15:193-205. [PMID: 35401841 PMCID: PMC8938532 DOI: 10.1007/s12195-021-00716-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 11/24/2021] [Indexed: 01/05/2023] Open
Abstract
Introduction The network of Interstitial Cells of Cajal (ICC) plays a plethora of key roles in maintaining, coordinating, and regulating the contractions of the gastrointestinal (GI) smooth muscles. Several GI functional motility disorders have been associated with ICC degradation. This study extended a previously reported 2D morphological analysis and applied it to 3D spatial quantification of three different types of ICC networks in the distal stomach guided by confocal imaging and machine learning methods. The characterization of the complex changes in spatial structure of the ICC network architecture contributes to our understanding of the roles that different types of ICC may play in post-prandial physiology, pathogenesis, and/or amelioration of GI dsymotility- bridging structure and function. Methods A validated classification method using Trainable Weka Segmentation was applied to segment the ICC from a confocal dataset of the gastric antrum of a transgenic mouse, followed by structural analysis of the segmented images. Results The machine learning model performance was compared to manually segmented subfields, achieving an area under the receiver-operating characteristic (AUROC) of 0.973 and 0.995 for myenteric ICC (ICC-MP; n = 6) and intramuscular ICC (ICC-IM; n = 17). The myenteric layer in the distal antrum increased in thickness (from 14.5 to 34 μm) towards the lesser curvature, whereas the thickness decreased towards the lesser curvature in the proximal antrum (17.7 to 9 μm). There was an increase in ICC-MP volume from proximal to distal antrum (406,960 ± 140,040 vs. 559,990 ± 281,000 μm3; p = 0.000145). The % of ICC volume was similar for ICC-LM and for ICC-CM between proximal (3.6 ± 2.3% vs. 3.1 ± 1.2%; p = 0.185) and distal antrum (3.2 ± 3.9% vs. 2.5 ± 2.8%; p = 0.309). The average % volume of ICC-MP was significantly higher than ICC-IM at all points throughout sample (p < 0.0001). Conclusions The segmentation and analysis methods provide a high-throughput framework of investigating the structural changes in extended ICC networks and their associated physiological functions in animal models.
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8
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Abstract
Gastroparesis is characterized by symptoms suggestive of, and objective evidence of, delayed gastric emptying in the absence of mechanical obstruction. This review addresses the normal emptying of solids and liquids from the stomach and details the myogenic and neuromuscular control mechanisms, including the specialized function of the pyloric sphincter, that result in normal emptying, based predominantly on animal research. A clear understanding of fundamental mechanisms is necessary to comprehend derangements leading to gastroparesis, and additional research on human gastric muscles is needed. The section on pathophysiology of gastroparesis considers neuromuscular diseases that affect nonsphincteric gastric muscle, disorders of the extrinsic neural control, and pyloric dysfunction that lead to gastroparesis. The potential cellular basis for gastroparesis is attributed to the effects of oxidative stress and inflammation, with increased pro-inflammatory and decreased resident macrophages, as observed in full-thickness biopsies from patients with gastroparesis. Predominant diagnostic tests involving measurements of gastric emptying, the use of a functional luminal imaging probe, and high-resolution antral duodenal manometry in characterizing the abnormal motor functions at the gastroduodenal junction are discussed. Management is based on supporting nutrition; dietary interventions, including the physical reduction in particle size of solid foods; pharmacological agents, including prokinetics and anti-emetics; and interventions such as gastric electrical stimulation and pyloromyotomy. These are discussed briefly, and comment is added on the potential for individualized treatments in the future, based on optimal gastric emptying measurement and objective documentation of the underlying pathophysiology causing the gastroparesis.
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Affiliation(s)
- Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Kenton M. Sanders
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV
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9
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Huizinga JD, Hussain A, Chen JH. Generation of Gut Motor Patterns Through Interactions Between Interstitial Cells of Cajal and the Intrinsic and Extrinsic Autonomic Nervous Systems. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1383:205-212. [PMID: 36587159 DOI: 10.1007/978-3-031-05843-1_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
The musculature of the gastrointestinal tract is a vast network of collaborating excitable cell types. Embedded throughout are the interstitial cells of Cajal (ICC) intertwined with enteric nerves. ICC sense external stimuli such as distention, mediate nerve impulses to smooth muscle cells, and provide rhythmic excitation of the musculature. Neural circuitry involving both the intrinsic and extrinsic autonomic nervous systems, in collaboration with the ICC, orchestrate an array of motor patterns that serve to provide mixing of content to optimize digestion and absorption, microbiome homeostasis, storage, transit, and expulsion. ICC are specialized smooth muscle cells that generate rhythmic depolarization to the musculature and so provide the means for peristaltic and segmenting contractions. Some motor patterns are purely myogenic, but a neural stimulus initiates most, further depolarizing the primary pacemaker cells and the musculature and/or initiating transient pacemaker activity in stimulus-dependent secondary ICC pacemaker cells. From stomach to rectum, ICC networks rhythmically provide tracks along which contractions advance.
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Affiliation(s)
- Jan D Huizinga
- McMaster University, Farncombe Family Digestive Health Research Institute, Department of Medicine, Division of Gastroenterology, Hamilton, ON, Canada.
| | - Amer Hussain
- McMaster University, Farncombe Family Digestive Health Research Institute, Department of Medicine, Division of Gastroenterology, Hamilton, ON, Canada
| | - Ji-Hong Chen
- McMaster University, Farncombe Family Digestive Health Research Institute, Department of Medicine, Division of Gastroenterology, Hamilton, ON, Canada
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10
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O'Grady G, Gharibans AA, Du P, Huizinga JD. The gastric conduction system in health and disease: a translational review. Am J Physiol Gastrointest Liver Physiol 2021; 321:G527-G542. [PMID: 34549598 DOI: 10.1152/ajpgi.00065.2021] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Gastric peristalsis is critically dependent on an underlying electrical conduction system. Recent years have witnessed substantial progress in clarifying the operations of this system, including its pacemaking units, its cellular architecture, and slow-wave propagation patterns. Advanced techniques have been developed for assessing its functions at high spatiotemporal resolutions. This review synthesizes and evaluates this progress, with a focus on human and translational physiology. A current conception of the initiation and conduction of slow-wave activity in the human stomach is provided first, followed by a detailed discussion of its organization at the cellular and tissue level. Particular emphasis is then given to how gastric electrical disorders may contribute to disease states. Gastric dysfunction continues to grow in their prevalence and impact, and while gastric dysrhythmia is established as a clear and pervasive feature in several major gastric disorders, its role in explaining pathophysiology and informing therapy is still emerging. New insights from high-resolution gastric mapping are evaluated, together with historical data from electrogastrography, and the physiological relevance of emerging biomarkers from body surface mapping such as retrograde propagating slow waves. Knowledge gaps requiring further physiological research are highlighted.
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Affiliation(s)
- Gregory O'Grady
- Department of Surgery, The University of Auckland, Auckland, New Zealand.,Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
| | - Armen A Gharibans
- Department of Surgery, The University of Auckland, Auckland, New Zealand.,Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
| | - Peng Du
- Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand
| | - Jan D Huizinga
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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Huizinga JD, Hussain A, Chen JH. Interstitial cells of Cajal and human colon motility in health and disease. Am J Physiol Gastrointest Liver Physiol 2021; 321:G552-G575. [PMID: 34612070 DOI: 10.1152/ajpgi.00264.2021] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Our understanding of human colonic motility, and autonomic reflexes that generate motor patterns, has increased markedly through high-resolution manometry. Details of the motor patterns are emerging related to frequency and propagation characteristics that allow linkage to interstitial cells of Cajal (ICC) networks. In studies on colonic motor dysfunction requiring surgery, ICC are almost always abnormal or significantly reduced. However, there are still gaps in our knowledge about the role of ICC in the control of colonic motility and there is little understanding of a mechanistic link between ICC abnormalities and colonic motor dysfunction. This review will outline the various ICC networks in the human colon and their proven and likely associations with the enteric and extrinsic autonomic nervous systems. Based on our extensive knowledge of the role of ICC in the control of gastrointestinal motility of animal models and the human stomach and small intestine, we propose how ICC networks are underlying the motor patterns of the human colon. The role of ICC will be reviewed in the autonomic neural reflexes that evoke essential motor patterns for transit and defecation. Mechanisms underlying ICC injury, maintenance, and repair will be discussed. Hypotheses are formulated as to how ICC dysfunction can lead to motor abnormalities in slow transit constipation, chronic idiopathic pseudo-obstruction, Hirschsprung's disease, fecal incontinence, diverticular disease, and inflammatory conditions. Recent studies on ICC repair after injury hold promise for future therapies.
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Affiliation(s)
- Jan D Huizinga
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Amer Hussain
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Ji-Hong Chen
- Division of Gastroenterology, Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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12
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Chen QC, Jiang Z, Zhang JH, Cao LX, Chen ZQ. Xiangbinfang granules enhance gastric antrum motility via intramuscular interstitial cells of Cajal in mice. World J Gastroenterol 2021; 27:576-591. [PMID: 33642830 PMCID: PMC7901053 DOI: 10.3748/wjg.v27.i7.576] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/24/2020] [Accepted: 01/13/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Interdigestive migrating motor complexes (MMC) produce periodic contractions in the gastrointestinal tract, but the exact mechanism of action still remains unclear. Intramuscular interstitial cells of Cajal (ICC-IM) participate in gastrointestinal hormone and neuromodulation, but the correlation between ICC-IM and MMC is also unclear. We found that xiangbinfang granules (XBF) mediated the phase III contraction of MMC. Here, the effects of XBF on gastric antrum motility in W/Wv mice and the effects of ICC-IM on gastric antrum MMC are reported.
AIM To observe the effects of ICC-IM on gastric antrum motility and to establish the mechanism of XBF in promoting gastric antrum motility.
METHODS The density of c-kit-positive ICC myenteric plexus (ICC-MP) and ICC-IM in the antral muscularis of W/Wv and wild-type (WT) mice was examined by confocal microscopy. The effects of XBF on gastric antrum slow waves in W/Wv and WT mice were recorded by intracellular amplification recording. Micro-strain-gauge force transducers were implanted into the gastric antrum to monitor the MMC and the effect of XBF on gastric antrum motility in conscious W/Wv and WT mice.
RESULTS In the gastric antrum of W/Wv mice, c-kit immunoreactivity was significantly reduced, and no ICC-IM network was observed. Spontaneous rhythmic slow waves also appeared in the antrum of W/Wv mice, but the amplitude of the antrum slow wave decreased significantly in W/Wv mice (22.62 ± 2.23 mV vs 2.92 ± 0.52 mV, P < 0.0001). MMCs were found in 7 of the 8 WT mice but no complete MMC cycle was found in W/Wv mice. The contractile frequency and amplitude index of the gastric antrum were significantly increased in conscious WT compared to W/Wv mice (frequency, 3.53 ± 0.18 cpm vs 1.28 ± 0.12 cpm; amplitude index, 23014.26 ± 1798.65 mV·20 min vs 3782.16 ± 407.13 mV·20 min; P < 0.0001). XBF depolarized smooth muscle cells of the gastric antrum in WT and W/Wv mice in a dose-dependent manner. Similarly, the gastric antrum motility in WT mice was significantly increased after treatment with XBF 5 mg (P < 0.05). Atropine (0.1 mg/kg) blocked the enhancement of XBF in WT and W/Wv mice completely, while tetrodotoxin (0.05 mg/kg) partially inhibited the enhancement by XBF.
CONCLUSION ICC-IM participates in the regulation of gastric antrum MMC in mice. XBF induces MMC III-like contractions that enhance gastric antrum motility via ICC-IM in mice.
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Affiliation(s)
- Qi-Cheng Chen
- The Research Team of TCM Applications of Perioperative, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong Province, China
| | - Zhi Jiang
- The Research Team of TCM Applications of Perioperative, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong Province, China
| | - Jun-Hong Zhang
- Department of Research Public Service Center, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong Province, China
| | - Li-Xing Cao
- The Research Team of TCM Applications of Perioperative, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong Province, China
| | - Zhi-Qiang Chen
- The Research Team of TCM Applications of Perioperative, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Traditional Chinese Medicine, Guangzhou 510120, Guangdong Province, China
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13
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Parsons SP, Huizinga JD. Nitric Oxide Is Essential for Generating the Minute Rhythm Contraction Pattern in the Small Intestine, Likely via ICC-DMP. Front Neurosci 2021; 14:592664. [PMID: 33488345 PMCID: PMC7817771 DOI: 10.3389/fnins.2020.592664] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 11/25/2020] [Indexed: 12/16/2022] Open
Abstract
Nitrergic nerves have been proposed to play a critical role in the orchestration of peristaltic activities throughout the gastrointestinal tract. In the present study, we investigated the role of nitric oxide, using spatiotemporal mapping, in peristaltic activity of the whole ex vivo mouse intestine. We identified a propulsive motor pattern in the form of propagating myogenic contractions, that are clustered by the enteric nervous system into a minute rhythm that is dependent on nitric oxide. The cluster formation was abolished by TTX, lidocaine and nitric oxide synthesis inhibition, whereas the myogenic contractions, occurring at the ICC-MP initiated slow wave frequency, remained undisturbed. Cluster formation, inhibited by block of nitric oxide synthesis, was fully restored in a highly regular rhythmic fashion by a constant level of nitric oxide generated by sodium nitroprusside; but the action of sodium nitroprusside was inhibited by lidocaine indicating that it was relying on neural activity, but not rhythmic nitrergic nerve activity. Hence, distention-induced activity of cholinergic nerves and/or a co-factor within nitrergic nerves such as ATP is also a requirement for the minute rhythm. Cluster formation was dependent on distention but was not evoked by a distention reflex. Block of gap junction conductance by carbenoxolone, dose dependently inhibited, and eventually abolished clusters and contraction waves, likely associated, not with inhibition of nitrergic innervation, but by abolishing ICC network synchronization. An intriguing feature of the clusters was the presence of bands of rhythmic inhibitions at 4-8 cycles/min; these inhibitory patches occurred in the presence of tetrodotoxin or lidocaine and hence were not dependent on nitrergic nerves. We propose that the minute rhythm is generated by nitric oxide-induced rhythmic depolarization of the musculature via ICC-DMP.
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Affiliation(s)
- Sean P. Parsons
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
| | - Jan D. Huizinga
- Department of Medicine and School of Biomedical Engineering, Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada
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14
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Mah SA, Avci R, Cheng LK, Du P. Current applications of mathematical models of the interstitial cells of Cajal in the gastrointestinal tract. WIREs Mech Dis 2020; 13:e1507. [PMID: 33026190 DOI: 10.1002/wsbm.1507] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 08/31/2020] [Accepted: 09/04/2020] [Indexed: 12/25/2022]
Abstract
The interstitial cells of Cajal (ICC) form interconnected networks throughout the gastrointestinal (GI) tract. ICC act as the pacemaker cells that initiate the rhythmic bioelectrical slow waves and intermediary between the GI musculature and nerves, both of which are critical to GI motility. Disruptions to the number of ICC and the integrity of ICC networks have been identified as a key pathophysiological mechanism in a number of clinically challenging GI disorders. The current analyses of ICC generally rely on either functional recordings taken directly from excised tissue or morphological analysis based on images of labeled ICC, where the structural-functional relationship is investigated in an associative manner rather than mechanistically. On the other hand, computational physiology has played a significant role in facilitating our understanding of a number of physiological systems in both health and disease, and investigations in the GI field are beginning to incorporate several mathematical models of the ICC. The main aim of this review is to present the major modeling advances in GI electrophysiology, in order to introduce a multi-scale framework for mathematically quantifying the functional consequences of ICC degradation at both cellular and tissue scales. The outcomes will inform future investigators utilizing modeling techniques in their studies. This article is categorized under: Metabolic Diseases > Computational Models.
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Affiliation(s)
- Sue Ann Mah
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Recep Avci
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Leo K Cheng
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - Peng Du
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand.,Department of Engineering Science, University of Auckland, Auckland, New Zealand
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15
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Wang X, Zhang S, Pasricha PJ, Chen JDZ. Ameliorating effects of sacral neuromodulation on gastric and small intestinal dysmotility mediated via a sacral afferent-vagal efferent pathway. Neurogastroenterol Motil 2020; 32:e13837. [PMID: 32189439 DOI: 10.1111/nmo.13837] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 02/04/2020] [Accepted: 02/18/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIMS In a recent study of sacral nerve stimulation (SNS) for colonic inflammation, a possible spinal-vagal pathway was implicated. The aim of this study was to provide evidence for such a pathway by investigating the effects of SNS on dysmotility of the stomach and duodenum that are not directly innervated by the sacral efferents. METHODS Twenty-seven rats were chronically implanted with wire electrodes for SNS and gastrointestinal slow waves. SNS was performed in several acute sessions to investigate its effects on gastric/duodenal slow waves and emptying/transit impaired by glucagon and rectal distention (RD). RESULTS (a) SNS increased the percentage of normal gastric slow waves impaired by glucagon (from 53.9% to 77.0%, P < .0001) and RD (from 64% to 78%, P = .037). This improvement was abolished by atropine. (b) Similar effects were observed with SNS on duodenal slow waves, which was also blocked by atropine. (c) SNS normalized delayed gastric emptying induced by glucagon (control: 61.3%, glucagon: 44.3%, glucagon + SNS: 65.8%) and RD (control: 61.3%, RD: 46.7%, RD + SNS: 64.3%). It also normalized small intestinal transit delayed by RD (P = .001, RD + SNS vs RD; P = .9, RD + SNS vs control). (4) Both glucagon and RD induced an increase in the sympathovagal ratio (P = .007, glucagon vs baseline; P < .001, RD vs baseline) and SNS decreased the ratio (P = .006, glucagon + SNS vs glucagon; P = .04, RD + SNS vs RD). CONCLUSIONS Neuromodulation of the sacral nerve improves gastric and small intestinal pacemaking activity and transit impaired by glucagon and RD by normalizing the sympathovagal balance via a retrograde neural pathway from the sacral nerve to vagal efferents.
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Affiliation(s)
- Ximeng Wang
- Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Shengai Zhang
- Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Pankaj J Pasricha
- Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jiande D Z Chen
- Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland.,Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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16
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Hwang M, Kim JN, Kim BJ. Hesperidin depolarizes the pacemaker potentials through 5-HT 4 receptor in murine small intestinal interstitial cells of Cajal. Anim Cells Syst (Seoul) 2020; 24:84-90. [PMID: 32489687 PMCID: PMC7241530 DOI: 10.1080/19768354.2020.1746398] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 03/04/2020] [Accepted: 03/19/2020] [Indexed: 12/14/2022] Open
Abstract
Hesperidin, a citrus flavonoid, can exert numerous beneficial effects on human health. Interstitial cells of Cajal (ICC) are pacemaker cells in the gastrointestinal (GI) tract. In the present study, we investigated potential effects of hesperidin on pacemaker potential of ICC in murine small intestine and GI motility. A whole-cell patch-clamp configuration was used to record pacemaker potential in ICC, and GI motility was investigated in vivo by recording gastric emptying (GE) and intestinal transit rate (ITR). Hesperidin depolarized pacemaker potentials of ICC in a dose-dependent manner. Pre-treatment with methoctramine or 4-DAMP did not inhibit hesperidin-induced pacemaker potential depolarization. Neither a 5-HT3 receptor antagonist (Y25130) nor a 5-HT7 receptor antagonist (SB269970) reduced the effect of hesperidin on ICC pacemaker potential, whereas the 5-HT4 receptor antagonist RS39604 was found to inhibit this effect. In the presence of GDP-β-S, hesperidin-induced pacemaker potential depolarization was inhibited. Moreover, in the presence of U73122 and calphostin C, hesperidin did not depolarize pacemaker potentials. Furthermore, hesperidin accelerated GE and ITR in vivo. These results imply that hesperidin depolarized ICC pacemaker potential via 5-HT4 receptors, G protein, and PLC/PKC dependent pathways and that it increased GI motility. Therefore, hesperidin may be a promising novel drug to regulate GI motility.
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Affiliation(s)
- Minwoo Hwang
- Department of Sasang Constitutional Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Jeong Nam Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Republic of Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Republic of Korea
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17
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Huizinga JD. Recent advances in intestinal smooth muscle research: from muscle strips and single cells, via ICC networks to whole organ physiology and assessment of human gut motor dysfunction. J Smooth Muscle Res 2019; 55:68-80. [PMID: 31956167 PMCID: PMC6962316 DOI: 10.1540/jsmr.55.68] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 11/01/2019] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal smooth muscle research has evolved from studies on muscle strips to spatiotemporal mapping of whole organ motor and electrical activities. Decades of research on single muscle cells and small sections of isolated musculature from animal models has given us the groundwork for interpretation of human in vivo studies. Human gut motility studies have dramatically improved by high-resolution manometry and high-resolution electrophysiology. The details that emerge from spatiotemporal mapping of high-resolution data are now of such quality that hypotheses can be generated as to the physiology (in healthy subjects) and pathophysiology (in patients) of gastrointestinal (dys) motility. Such interpretation demands understanding of the musculature as a super-network of excitable cells (neurons, smooth muscle cells, other accessory cells) and oscillatory cells (the pacemaker interstitial cells of Cajal), for which mathematical modeling becomes essential. The developing deeper understanding of gastrointestinal motility will bring us soon to a level of precision in diagnosis of dysfunction that is far beyond what is currently available.
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Affiliation(s)
- Jan D. Huizinga
- Department of Medicine-Gastroenterology, McMaster University,
Hamilton, Ontario, Canada
- Farncombe Family Digestive Health Research Institute,
Hamilton, Ontario, Canada
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18
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Sanders KM. Spontaneous Electrical Activity and Rhythmicity in Gastrointestinal Smooth Muscles. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1124:3-46. [PMID: 31183821 PMCID: PMC7035145 DOI: 10.1007/978-981-13-5895-1_1] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The gastrointestinal (GI) tract has multifold tasks of ingesting, processing, and assimilating nutrients and disposing of wastes at appropriate times. These tasks are facilitated by several stereotypical motor patterns that build upon the intrinsic rhythmicity of the smooth muscles that generate phasic contractions in many regions of the gut. Phasic contractions result from a cyclical depolarization/repolarization cycle, known as electrical slow waves, which result from intrinsic pacemaker activity. Interstitial cells of Cajal (ICC) are electrically coupled to smooth muscle cells (SMCs) and generate and propagate pacemaker activity and slow waves. The mechanism of slow waves is dependent upon specialized conductances expressed by pacemaker ICC. The primary conductances responsible for slow waves in mice are Ano1, Ca2+-activated Cl- channels (CaCCs), and CaV3.2, T-type, voltage-dependent Ca2+ channels. Release of Ca2+ from intracellular stores in ICC appears to be the initiator of pacemaker depolarizations, activation of T-type current provides voltage-dependent Ca2+ entry into ICC, as slow waves propagate through ICC networks, and Ca2+-induced Ca2+ release and activation of Ano1 in ICC amplifies slow wave depolarizations. Slow waves conduct to coupled SMCs, and depolarization elicited by these events enhances the open-probability of L-type voltage-dependent Ca2+ channels, promotes Ca2+ entry, and initiates contraction. Phasic contractions timed by the occurrence of slow waves provide the basis for motility patterns such as gastric peristalsis and segmentation. This chapter discusses the properties of ICC and proposed mechanism of electrical rhythmicity in GI muscles.
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Affiliation(s)
- Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, NV, USA.
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19
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Vather R, O'Grady G, Lin AY, Du P, Wells CI, Rowbotham D, Arkwright J, Cheng LK, Dinning PG, Bissett IP. Hyperactive cyclic motor activity in the distal colon after colonic surgery as defined by high-resolution colonic manometry. Br J Surg 2018; 105:907-917. [PMID: 29656582 PMCID: PMC7938810 DOI: 10.1002/bjs.10808] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 10/18/2017] [Accepted: 11/21/2017] [Indexed: 01/10/2023]
Abstract
BACKGROUND Recovery after colonic surgery is invariably delayed by disturbed gut motility. It is commonly assumed that colonic motility becomes quiescent after surgery, but this hypothesis has not been evaluated rigorously. This study quantified colonic motility through the early postoperative period using high-resolution colonic manometry. METHODS Fibre-optic colonic manometry was performed continuously before, during and after surgery in the left colon and rectum of patients undergoing right hemicolectomy, and in healthy controls. Motor events were characterized by pattern, frequency, direction, velocity, amplitude and distance propagated. RESULTS Eight patients undergoing hemicolectomy and nine healthy controls were included in the study. Colonic motility became markedly hyperactive in all operated patients, consistently dominated by cyclic motor patterns. Onset of cyclic motor patterns began to a minor extent before operation, occurring with increasing intensity nearer the time of surgery; the mean(s.d.) active duration was 12(7) per cent over 3 h before operation and 43(17) per cent within 1 h before surgery (P = 0.024); in fasted controls it was 2(4) per cent (P < 0·001). After surgery, cyclic motor patterns increased markedly in extent and intensity, becoming nearly continuous (active duration 94(13) per cent; P < 0·001), with peak frequency 2-4 cycles per min in the sigmoid colon. This postoperative cyclic pattern was substantially more prominent than in non-operative controls, including in the fed state (active duration 27(20) per cent; P < 0·001), and also showed higher antegrade velocity (P < 0·001). CONCLUSION Distal gut motility becomes markedly hyperactive with colonic surgery, dominated by cyclic motor patterns. This hyperactivity likely represents a novel pathophysiological aspect of the surgical stress response. Hyperactive motility may contribute to gut dysfunction after surgery, potentially offering a new therapeutic target to enhance recovery.
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Affiliation(s)
- R Vather
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - G O'Grady
- Department of Surgery, University of Auckland, Auckland, New Zealand
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - A Y Lin
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - P Du
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - C I Wells
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - D Rowbotham
- Department of Gastroenterology, Auckland District Health Board, Auckland, New Zealand
| | - J Arkwright
- Department of Computer Science, Engineering and Mathematics, Flinders University, Adelaide, South Australia, Australia
| | - L K Cheng
- Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealand
| | - P G Dinning
- Human Physiology, Flinders University, Adelaide, South Australia, Australia
- Department of Gastroenterology and Surgery, Flinders Medical Centre, Adelaide, South Australia, Australia
| | - I P Bissett
- Department of Surgery, University of Auckland, Auckland, New Zealand
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20
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Heyer GL, Boles LH, Harvey RA, Cismowski MJ. Gastric myoelectrical and neurohormonal changes associated with nausea during tilt-induced syncope. Neurogastroenterol Motil 2018; 30. [PMID: 28960795 DOI: 10.1111/nmo.13220] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2017] [Accepted: 09/07/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Nausea is a common prodromal symptom of neurally mediated syncope, but the biological factors linking nausea with syncope have not been studied. We aimed to characterize nausea during tilt-induced syncope by exploring related changes in gastric myoelectrical activity and plasma epinephrine, norepinephrine, and vasopressin concentrations across study phases of recumbency, tilt, syncope, and recovery. METHODS Electrogastrographic and plasma hormone changes were compared between patients with tilt-induced syncope and nausea (n = 18) and control subjects (n = 6) without symptoms or hemodynamic changes during tilt-table testing. KEY RESULTS Over a 4-minute period preceding syncope, sequential electrogastrography epochs demonstrated an increase over time in bradygastria (P = .003) and tachygastria (P = .014) power ratios, while the dominant frequency (P < .001) and the percent normogastria (P = .004) decreased. Syncope led to significant differences between cases and controls in electrogastrographic power ratios in each frequency range: bradygastria (P = .001), tachygastria (P = .005), and normogastria (P = .03). Nausea always followed electrogastrographic changes, and nausea resolution always preceded electrogastrographic normalization. Plasma vasopressin (676.5 ± 122.8 vs 91.2 ± 15.3 pg/mL, P = .012) and epinephrine (434 ± 91.3 vs 48.7 ± 2.5 pg/mL, P = .03), but not norepinephrine (P > .05), also differed with syncope between cases and controls. CONCLUSIONS AND INFERENCES The nausea related to tilt-induced syncope is temporally associated with changes in gastric myoelectrical activity and increases in plasma vasopressin and epinephrine. The biological mechanisms that induce syncope are physiologically distinct from other experimental models of nausea such as illusory self-motion, yet nausea with syncope appears to have similarly associated electrogastrographic and hormone changes. Thus, tilt-induced syncope could serve as an informative experimental model for nausea research.
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Affiliation(s)
- G L Heyer
- Division of Pediatric Neurology, Nationwide Children's Hospital, Columbus, OH, USA.,Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA
| | - L H Boles
- Department of Medicine, The Ohio State University, Columbus, OH, USA
| | - R A Harvey
- Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA
| | - M J Cismowski
- Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.,Center for Cardiovascular Research, Nationwide Children's Hospital, Columbus, OH, USA
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21
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Strege PR, Gibbons SJ, Mazzone A, Bernard CE, Beyder A, Farrugia G. EAVK segment "c" sequence confers Ca 2+-dependent changes to the kinetics of full-length human Ano1. Am J Physiol Gastrointest Liver Physiol 2017; 312:G572-G579. [PMID: 28336549 PMCID: PMC5495914 DOI: 10.1152/ajpgi.00429.2016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Revised: 03/07/2017] [Accepted: 03/15/2017] [Indexed: 01/31/2023]
Abstract
Anoctamin1 (Ano1 and TMEM16A) is a calcium-activated chloride channel specifically expressed in the interstitial cells of Cajal (ICC) of the gastrointestinal tract muscularis propria. Ano1 is necessary for normal electrical slow waves and ICC proliferation. The full-length human Ano1 sequence includes an additional exon, exon "0," at the NH2 terminus. Ano1 with exon 0 [Ano1(0)] had a lower EC50 for intracellular calcium ([Ca2+]i) and faster chloride current (ICl) kinetics. The Ano1 alternative splice variant with segment "c" encoding exon 13 expresses on the first intracellular loop four additional amino acid residues, EAVK, which alter ICl at low [Ca2+]i Exon 13 is expressed in 75-100% of Ano1 transcripts in most human tissues but only 25% in the human stomach. Our aim was to determine the effect of EAVK deletion on Ano1(0)ICl parameters. By voltage-clamp electrophysiology, we examined ICl in HEK293 cells transiently expressing Ano1(0) with or without the EAVK sequence [Ano1(0)ΔEAVK]. The EC50 values of activating and deactivating ICl for [Ca2+]i were 438 ± 7 and 493 ± 9 nM for Ano1(0) but higher for Ano1(0)ΔEAVK at 746 ± 47 and 761 ± 26 nM, respectively. Meanwhile, the EC50 values for the ratio of instantaneous to steady-state ICl were not different between variants. Congruently, the time constant of activation was slower for Ano1(0)ΔEAVK than Ano1(0) currents at intermediate [Ca2+]i These results suggest that EAVK decreases the calcium sensitivity of Ano1(0) current activation and deactivation by slowing activation kinetics. Differential expression of EAVK in the human stomach may function as a switch to increase sensitivity to [Ca2+]i via faster gating of Ano1.NEW & NOTEWORTHY Calcium-activated chloride channel anoctamin1 (Ano1) is necessary for normal slow waves in the gastrointestinal interstitial cells of Cajal. Exon 0 encodes the NH2 terminus of full-length human Ano1 [Ano1(0)], while exon 13 encodes residues EAVK on its first intracellular loop. Splice variants lack EAVK more often in the stomach than other tissues. Ano1(0) without EAVK [Ano1(0)ΔEAVK] has reduced sensitivity for intracellular calcium, attributable to slower kinetics. Differential expression of EAVK may function as a calcium-sensitive switch in the human stomach.
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22
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Chen JH, Zhang Q, Liu X, Li Z, Zhang C, Li K, Paul J, Ouyang J, Yu Y, Yu B, Huizinga JD, Chen JD, Luo H. Noninvasive measurements to evaluate the effects of military training on the human autonomic nervous system. ASIAN BIOMED 2017. [DOI: 10.5372/1905-7415.0804.314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Abstract
Background: Chinese university freshmen receive 4-weeks military training that involved moderate to intense physical exercise. Studies have demonstrated heterogeneous effects of exercise on the autonomic nervous system.
Objective: To evaluate the effects of training on the autonomic nervous system noninvasively using electrogastrograms, heart rate variability (HRV), pulse rate, and the sympathetic skin response (SSR).
Methods: Twenty freshmen received all assessments in the fasting state and after a standard meal: (1) one week before the training, (2) at the end of the second week of the training, and (3) one week after the training.
Results: (1) The training had a significant effect on meal-induced gastric pacemaker activity. Before the training, a standard meal did not increase the dominant frequency of gastric slow waves, but the frequency increased during and after the training; (2) The preprandial high frequency (HF), low frequency (LF), and very low frequency (VLF) components of heart rate variability decreased significantly after the training. The ratio of the LF and HF (LF/HF) of the heart rate variability (HRV) did not significantly change after a meal or training condition. The basal pulse rate did not change. The latencies of the sympathetic skin response (SSR), as measured in the arm muscle, increased in response to the training.
Conclusion: Military training affects meal-induced changes in gastric pacemaker activity, causes a marked reduction of the vagal tone to the heart with maintenance of the vagal-sympathetic balance, and its effects on SSR may reflect a reduction in sympathetic tone.
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Affiliation(s)
- Ji-Hong Chen
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Qian Zhang
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Xin Liu
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Zhixin Li
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Cuizhen Zhang
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Kongling Li
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jonathan Paul
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jingming Ouyang
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Yuanjie Yu
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Baoping Yu
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jan D. Huizinga
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China, Canada
- Wuhan University from McMaster University, Hamilton, Ontario L8N3Z5, Canada
| | - Jiande D.Z. Chen
- Department of Gastroenterology and Hepatology, University of Texas Medical Branch, TX, 77550, United States of America
| | - Hesheng Luo
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan 430060, China
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23
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Brijs J, Hennig GW, Kellermann AM, Axelsson M, Olsson C. The presence and role of interstitial cells of Cajal in the proximal intestine of shorthorn sculpin (Myoxocephalus scorpius). ACTA ACUST UNITED AC 2016; 220:347-357. [PMID: 27875260 DOI: 10.1242/jeb.141523] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 11/03/2016] [Indexed: 12/27/2022]
Abstract
Rhythmic contractions of the mammalian gastrointestinal tract can occur in the absence of neuronal or hormonal stimulation owing to the generation of spontaneous electrical activity by interstitial cells of Cajal (ICC) that are electrically coupled to smooth muscle cells. The myogenically driven component of gastrointestinal motility patterns in fish probably also involves ICC; however, little is known of their presence, distribution and function in any fish species. In the present study, we combined immunohistochemistry and in vivo recordings of intestinal motility to investigate the involvement of ICC in the motility of the proximal intestine in adult shorthorn sculpin (Myoxocephalus scorpius). Antibodies against anoctamin 1 (Ano1, a Ca2+-activated Cl- channel), revealed a dense network of multipolar, repeatedly branching cells in the myenteric region of the proximal intestine, similar in many regards to the mammalian ICC-MY network. The addition of benzbromarone, a potent blocker of Ano1, altered the motility patterns seen in vivo after neural blockade with TTX. The results indicate that ICC are integral for the generation and propagation of the majority of rhythmic contractile patterns in fish, although their frequency and amplitude can be modulated via neural activity.
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Affiliation(s)
- Jeroen Brijs
- Department of Biological and Environmental Sciences, University of Gothenburg, SE-405 30 Göteborg, Sweden
| | - Grant W Hennig
- Department of Physiology and Cell Biology, University of Reno, Nevada, NV 89557, USA
| | - Anna-Maria Kellermann
- Department of Nature and Engineering, Bremen University of Applied Sciences, Bremen 28199, Germany
| | - Michael Axelsson
- Department of Biological and Environmental Sciences, University of Gothenburg, SE-405 30 Göteborg, Sweden
| | - Catharina Olsson
- Department of Biological and Environmental Sciences, University of Gothenburg, SE-405 30 Göteborg, Sweden
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24
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Li H, Chen JH, Yang Z, Huang M, Yu Y, Tan S, Luo H, Huizinga JD. Neurotensin Changes Propulsive Activity into a Segmental Motor Pattern in the Rat Colon. J Neurogastroenterol Motil 2016; 22:517-28. [PMID: 26882114 PMCID: PMC4930308 DOI: 10.5056/jnm15181] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Revised: 12/31/2015] [Accepted: 01/10/2016] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND/AIMS Neurotensin is a gut-brain peptide with both inhibitory and excitatory actions on the colonic musculature; our objective was to understand the implications of this for motor patterns occurring in the intact colon of the rat. METHODS The effects of neurotensin with concentrations ranging from 0.1-100 nM were studied in the intact rat colon in vitro, by investigating spatio-temporal maps created from video recordings of colonic motility before and after neurotensin. RESULTS Low concentration of neurotensin (0.1-1 nM) inhibited propagating long distance contractions and rhythmic propagating motor complexes; in its place a slow propagating rhythmic segmental motor pattern developed. The neurotensin receptor 1 antagonist SR-48692 prevented the development of the segmental motor pattern. Higher concentrations of neurotensin (10 nM and 100 nM) were capable of restoring long distance contraction activity and inhibiting the segmental activity. The slow propagating segmental contraction showed a rhythmic contraction-- relaxation cycle at the slow wave frequency originating from the interstitial cells of Cajal associated with the myenteric plexus pacemaker. High concentrations given without prior additions of low concentrations did not evoke the segmental motor pattern. These actions occurred when neurotensin was given in the bath solution or intraluminally. The segmental motor pattern evoked by neurotensin was inhibited by the neural conduction blocker lidocaine. CONCLUSIONS Neurotensin (0.1-1 nM) inhibits the dominant propulsive motor patterns of the colon and a distinct motor pattern of rhythmic slow propagating segmental contractions develops. This motor pattern has the hallmarks of haustral boundary contractions.
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Affiliation(s)
- Hongfei Li
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China
| | - Ji-Hong Chen
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China.,Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Zixian Yang
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China
| | - Min Huang
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China
| | - Yuanjie Yu
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China
| | - Shiyun Tan
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China
| | - Hesheng Luo
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China
| | - Jan D Huizinga
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China.,Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, ON, Canada
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Chen JH, Yang Z, Yu Y, Huizinga JD. Haustral boundary contractions in the proximal 3-taeniated rabbit colon. Am J Physiol Gastrointest Liver Physiol 2016; 310:G181-92. [PMID: 26635318 DOI: 10.1152/ajpgi.00171.2015] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023]
Abstract
The rabbit proximal colon is similar in structure to the human colon. Our objective was to study interactions of different rhythmic motor patterns focusing on haustral boundary contractions, which create the haustra, using spatiotemporal mapping of video recordings. Haustral boundary contractions were seen as highly rhythmic circumferential ring contractions that propagated slowly across the proximal colon, preferentially but not exclusively in the anal direction, at ∼0.5 cycles per minute; they were abolished by nerve conduction blockers. When multiple haustral boundary contractions propagated in the opposite direction, they annihilated each other upon encounter. Ripples, myogenic propagating ring contractions at ∼9 cycles per min, induced folding and unfolding of haustral muscle folds, creating an anarchic appearance of contractile activity, with different patterns in the three intertaenial regions. Two features of ripple activity were prominent: frequent changes in propagation direction and the occurrence of dislocations showing a frequency gradient with the highest intrinsic frequency in the distal colon. The haustral boundary contractions showed an on/off/on/off pattern at the ripple frequency, and the contraction amplitude at any point of the colon showed waxing and waning. The haustral boundary contractions are therefore shaped by interaction of two pacemaker activities hypothesized to occur through phase-amplitude coupling of pacemaker activities from interstitial cells of Cajal of the myenteric plexus and of the submuscular plexus. Video evidence shows the unique role haustral folds play in shaping contractile activity within the haustra. Muscarinic agents not only enhance the force of contraction, they can eliminate one and at the same time induce another neurally dependent motor pattern.
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Affiliation(s)
- Ji-Hong Chen
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China; and Farncombe Family Digestive Health Research Institute, McMaster University Department of Medicine, Hamilton, Ontario, Canada
| | - Zixian Yang
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China; and
| | - Yuanjie Yu
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China; and
| | - Jan D Huizinga
- Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Key Laboratory of Hubei Province for Digestive System Diseases, Wuhan, Hubei Province, China; and Farncombe Family Digestive Health Research Institute, McMaster University Department of Medicine, Hamilton, Ontario, Canada
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Strege PR, Bernard CE, Mazzone A, Linden DR, Beyder A, Gibbons SJ, Farrugia G. A novel exon in the human Ca2+-activated Cl- channel Ano1 imparts greater sensitivity to intracellular Ca2. Am J Physiol Gastrointest Liver Physiol 2015; 309:G743-9. [PMID: 26359375 PMCID: PMC4628966 DOI: 10.1152/ajpgi.00074.2015] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 09/06/2015] [Indexed: 01/31/2023]
Abstract
Anoctamin 1 (Ano1; TMEM16A) is a Ca(2+)-activated Cl(-) channel (CACC) expressed in interstitial cells of Cajal. The mechanisms by which Ca(2+) regulates Ano1 are incompletely understood. In the gastrointestinal tract, Ano1 is required for normal slow wave activity and is involved in regulating cell proliferation. Splice variants of Ano1 have varying electrophysiological properties and altered expression in disease states. Recently, we identified a transcript for human Ano1 containing a novel exon-"exon 0" upstream of and in frame with exon 1. The electrophysiological properties of this longer Ano1 isoform are unknown. Our aim was to determine the functional contribution of the newly identified exon to the Ca(2+) sensitivity and electrophysiological properties of Ano1. Constructs with [Ano1(+0)] or without [Ano1(-0)] the newly identified exon were transfected into human embryonic kidney-293 cells. Voltage-clamp electrophysiology was used to determine voltage- and time-dependent parameters of whole cell Cl(-) currents between isoforms with varying concentrations of intracellular Ca(2+), extracellular anions, or Cl(-) channel inhibitors. We found that exon 0 did not change voltage sensitivity and had no impact on the relative permeability of Ano1 to most anions. Ano1(+0) exhibited greater changes in current density but lesser changes in kinetics than Ano1(-0) in response to varying intracellular Ca(2+). The CACC inhibitor niflumic acid inhibited current with greater efficacy and higher potency against Ano1(+0) compared with Ano1(-0). Likewise, the Ano1 inhibitor T16Ainh-A01 reduced Ano1(+0) more than Ano1(-0). In conclusion, human Ano1 containing exon 0 imparts its Cl(-) current with greater sensitivity to intracellular Ca(2+) and CACC inhibitors.
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Sung SK, Kim SJ, Ahn TS, Hong NR, Park HS, Kwon YK, Kim BJ. Effects of Dangkwisoo‑san, a traditional herbal medicine for treating pain and blood stagnation, on the pacemaker activities of cultured interstitial cells of Cajal. Mol Med Rep 2015; 12:6370-6376. [PMID: 26260469 DOI: 10.3892/mmr.2015.4203] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 07/17/2015] [Indexed: 11/06/2022] Open
Abstract
The interstitial cells of Cajal (ICCs) are the pacemaker cells in the gastrointestinal (GI) tract. In the present study, the effects of Dangkwisoo‑san (DS) on pacemaker potentials in cultured ICCs from the small intestine of the mouse were investigated. The whole‑cell patch‑clamp configuration was used to record pacemaker potentials from cultured ICCs and the increase in intracellular Ca2+ concentration ([Ca2+i) was analyzed in cultured ICCs using fura‑2‑acetoxymethyl ester. The generation of pacemaker potentials in the ICCs was observed. DS produced pacemaker depolarizations in a concentration dependent manner in current clamp mode. The 4‑diphenylacetoxy‑N‑methyl‑piperidine methiodide muscarinic M3 receptor antagonist inhibited DS‑induced pacemaker depolarizations, whereas methoctramine, a muscarinic M2 receptor antagonist, did not. When guanosine 5'‑[β‑thio] diphosphate (GDP‑β‑S; 1 mM) was in the pipette solution, DS marginally induced pacemaker depolarizations, whereas low Na+ solution externally eliminated the generation of pacemaker potentials and inhibited the DS‑induced pacemaker depolarizations. Additionally, the nonselective cation channel blocker, flufenamic acid, inhibited the DS‑induced pacemaker depolarizations. Pretreatment with Ca2+‑free solution and thapsigargin, a Ca2+‑ATPase inhibitor in the endoplasmic reticulum, also eliminated the generation of pacemaker currents and suppressed the DS‑induced pacemaker depolarizations. In addition, [Ca2+]i analysis revealed that DS increased [Ca2+]i. These results suggested that DS modulates pacemaker potentials through muscarinic M3 receptor activation in ICCs by G protein‑dependent external and internal Ca2+ regulation and external Na+. Therefore, DS were observed to affect intestinal motility through ICCs.
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Affiliation(s)
- Soon-Ki Sung
- Department of Neurosurgery, Pusan National University, Yangsan Hospital, Yangsan, Gyeongsangnam-do 626‑870, Republic of Korea
| | - Sung Jin Kim
- Department of Neurosurgery, Pusan National University, Yangsan Hospital, Yangsan, Gyeongsangnam-do 626‑870, Republic of Korea
| | - Tae Seok Ahn
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626‑870, Republic of Korea
| | - Noo Ri Hong
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626‑870, Republic of Korea
| | - Hyun Soo Park
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626‑870, Republic of Korea
| | - Young Kyu Kwon
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626‑870, Republic of Korea
| | - Byung Joo Kim
- Division of Longevity and Biofunctional Medicine, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 626‑870, Republic of Korea
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Mazet B. Gastrointestinal motility and its enteric actors in mechanosensitivity: past and present. Pflugers Arch 2014; 467:191-200. [PMID: 25366494 DOI: 10.1007/s00424-014-1635-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Revised: 10/14/2014] [Accepted: 10/19/2014] [Indexed: 12/14/2022]
Abstract
Coordinated contractions of the smooth muscle layers of the gastrointestinal (GI) tract are required to produce motor patterns that ensure normal GI motility. The crucial role of the enteric nervous system (ENS), the intrinsic ganglionated network located within the GI wall, has long been recognized in the generation of the main motor patterns. However, devising an appropriate motility requires the integration of informations emanating from the lumen of the GI tract. As already found more than half a century ago, the ability of the GI tract to respond to mechanical forces such as stretch is not restricted to neuronal mechanisms. Instead, mechanosensitivity is now recognized as a property of several non-neuronal cell types, the excitability of which is probably involved in shaping the motor patterns. This brief review gives an overview on how mechanosensitivity of different cell types in the GI tract has been established and, whenever available, on what ionic conductances are involved in mechanotransduction and their potential impact on normal GI motility.
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Affiliation(s)
- Bruno Mazet
- Aix Marseille Université, CNRS, CRN2M UMR 7286, CS80011 Bd Pierre Dramard, 13344, Marseille Cedex 15, France,
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Blair PJ, Rhee PL, Sanders KM, Ward SM. The significance of interstitial cells in neurogastroenterology. J Neurogastroenterol Motil 2014; 20:294-317. [PMID: 24948131 PMCID: PMC4102150 DOI: 10.5056/jnm14060] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 06/06/2014] [Accepted: 06/07/2014] [Indexed: 12/21/2022] Open
Abstract
Smooth muscle layers of the gastrointestinal tract consist of a heterogeneous population of cells that include enteric neurons, several classes of interstitial cells of mesenchymal origin, a variety of immune cells and smooth muscle cells (SMCs). Over the last number of years the complexity of the interactions between these cell types has begun to emerge. For example, interstitial cells, consisting of both interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor alpha-positive (PDGFRα(+)) cells generate pacemaker activity throughout the gastrointestinal (GI) tract and also transduce enteric motor nerve signals and mechanosensitivity to adjacent SMCs. ICC and PDGFRα(+) cells are electrically coupled to SMCs possibly via gap junctions forming a multicellular functional syncytium termed the SIP syncytium. Cells that make up the SIP syncytium are highly specialized containing unique receptors, ion channels and intracellular signaling pathways that regulate the excitability of GI muscles. The unique role of these cells in coordinating GI motility is evident by the altered motility patterns in animal models where interstitial cell networks are disrupted. Although considerable advances have been made in recent years on our understanding of the roles of these cells within the SIP syncytium, the full physiological functions of these cells and the consequences of their disruption in GI muscles have not been clearly defined. This review gives a synopsis of the history of interstitial cell discovery and highlights recent advances in structural, molecular expression and functional roles of these cells in the GI tract.
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Affiliation(s)
- Peter J Blair
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA; and
| | - Poong-Lyul Rhee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA; and
| | - Sean M Ward
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA; and
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Blair PJ, Rhee PL, Sanders KM, Ward SM. The significance of interstitial cells in neurogastroenterology. J Neurogastroenterol Motil 2014. [PMID: 24948131 DOI: 10.5056/jnm140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Smooth muscle layers of the gastrointestinal tract consist of a heterogeneous population of cells that include enteric neurons, several classes of interstitial cells of mesenchymal origin, a variety of immune cells and smooth muscle cells (SMCs). Over the last number of years the complexity of the interactions between these cell types has begun to emerge. For example, interstitial cells, consisting of both interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor alpha-positive (PDGFRα(+)) cells generate pacemaker activity throughout the gastrointestinal (GI) tract and also transduce enteric motor nerve signals and mechanosensitivity to adjacent SMCs. ICC and PDGFRα(+) cells are electrically coupled to SMCs possibly via gap junctions forming a multicellular functional syncytium termed the SIP syncytium. Cells that make up the SIP syncytium are highly specialized containing unique receptors, ion channels and intracellular signaling pathways that regulate the excitability of GI muscles. The unique role of these cells in coordinating GI motility is evident by the altered motility patterns in animal models where interstitial cell networks are disrupted. Although considerable advances have been made in recent years on our understanding of the roles of these cells within the SIP syncytium, the full physiological functions of these cells and the consequences of their disruption in GI muscles have not been clearly defined. This review gives a synopsis of the history of interstitial cell discovery and highlights recent advances in structural, molecular expression and functional roles of these cells in the GI tract.
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Affiliation(s)
- Peter J Blair
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
| | - Poong-Lyul Rhee
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kenton M Sanders
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
| | - Sean M Ward
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
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Huizinga JD, Chen JH. The myogenic and neurogenic components of the rhythmic segmentation motor patterns of the intestine. Front Neurosci 2014; 8:78. [PMID: 24782705 PMCID: PMC3989585 DOI: 10.3389/fnins.2014.00078] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 03/28/2014] [Indexed: 12/19/2022] Open
Affiliation(s)
- Jan D Huizinga
- Department of Medicine, Farncombe Family Digestive Health Research Institute, McMaster University Hamilton, ON, Canada
| | - Ji-Hong Chen
- Key Laboratory of Hubei Province for Digestive System Diseases, Department of Gastroenterology and Hepatology, Renmin Hospital of Wuhan University, Wuhan University Institute of Digestive and Liver Diseases Wuhan, China
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Wright GWJ, Parsons SP, Loera-Valencia R, Wang XY, Barajas-López C, Huizinga JD. Cholinergic signalling-regulated KV7.5 currents are expressed in colonic ICC-IM but not ICC-MP. Pflugers Arch 2013; 466:1805-18. [PMID: 24375291 DOI: 10.1007/s00424-013-1425-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 12/02/2013] [Accepted: 12/10/2013] [Indexed: 12/17/2022]
Abstract
Interstitial cells of Cajal (ICC) and the enteric nervous system orchestrate the various rhythmic motor patterns of the colon. Excitation of ICC may evoke stimulus-dependent pacemaker activity and will therefore have a profound effect on colonic motility. The objective of the present study was to evaluate the potential role of K(+) channels in the regulation of ICC excitability. We employed the cell-attached patch clamp technique to assess single channel activity from mouse colon ICC, immunohistochemistry to determine ICC K(+) channel expression and single cell RT-PCR to identify K(+) channel RNA. Single channel activity revealed voltage-sensitive K(+) channels, which were blocked by the KV7 blocker XE991 (n = 8), which also evoked inward maxi channel activity. Muscarinic acetylcholine receptor stimulation with carbachol inhibited K(+) channel activity (n = 8). The single channel conductance was 3.4 ± 0.1 pS (n = 8), but with high extracellular K(+), it was 18.1 ± 0.6 pS (n = 22). Single cell RT-PCR revealed Ano1-positive ICC that were positive for KV7.5. Double immunohistochemical staining of colons for c-Kit and KV7.5 in situ revealed that intramuscular ICC (ICC-IM), but not ICC associated with the myenteric plexus (ICC-MP), were positive for KV7.5. It also revealed dense cholinergic innervation of ICC-IM. ICC-IM and ICC-MP networks were found to be connected. We propose that the pacemaker network in the colon consists of both ICC-MP and ICC-IM and that one way of exciting this network is via cholinergic KV7.5 channel inhibition in ICC-IM.
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Affiliation(s)
- George W J Wright
- Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, HSC-3N8, 1200 Main Street West, Hamilton, ON, L8N 3Z5, Canada,
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Song J, Yin J, Sallam HS, Bai T, Chen Y, Chen JDZ. Electroacupuncture improves burn-induced impairment in gastric motility mediated via the vagal mechanism in rats. Neurogastroenterol Motil 2013; 25:807-e635. [PMID: 23848593 DOI: 10.1111/nmo.12183] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 06/16/2013] [Indexed: 12/16/2022]
Abstract
BACKGROUND Delayed gastric emptying (GE) is common in patients with severe burns. This study was designed to investigate effects and mechanisms of electroacupuncture (EA) on gastric motility in rats with burns. METHODS Male rats (intact and vagotomized) were implanted with gastric electrodes, chest and abdominal wall electrodes for investigating the effects of EA at ST-36 (stomach-36 or Zusanli) on GE, gastric slow waves, autonomic functions, and plasma interleukin 6 (IL-6) 6 and 24 h post severe burns. KEY RESULTS (i) Burn delayed GE (P < 0.001). Electroacupuncture improved GE 6 and 24 h post burn (P < 0.001). Vagotomy blocked the EA effect on GE. (ii) Electroacupuncture improved burn-induced gastric dysrhythmia. The percentage of normal slow waves was increased with EA 6 and 24 h post burn (P = 0.02). (iii) Electroacupuncture increased vagal activity assessed by the spectral analysis of heart rate variability (HRV). The high-frequency component reflecting vagal component was increased with EA 6 (P = 0.004) and 24 h post burn (P = 0.03, vs sham-EA). (iv) Electroacupuncture attenuated burn-induced increase in plasma IL-6 at both 6 (P = 0.03) and 24 h post burn (P = 0.003). CONCLUSIONS & INFERENCES Electroacupuncture at ST-36 improves gastric dysrhythmia and accelerates GE in rats with burns. The improvement seems to be mediated via the vagal pathway involving the inflammatory cytokine IL-6.
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Affiliation(s)
- J Song
- Division of Gastroenterology, University of Texas Medical Branch, Galveston, TX, USA; Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Lees-Green R, Du P, O'Grady G, Beyder A, Farrugia G, Pullan AJ. Biophysically based modeling of the interstitial cells of cajal: current status and future perspectives. Front Physiol 2011; 2:29. [PMID: 21772822 PMCID: PMC3131535 DOI: 10.3389/fphys.2011.00029] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2011] [Accepted: 06/13/2011] [Indexed: 12/29/2022] Open
Abstract
Gastrointestinal motility research is progressing rapidly, leading to significant advances in the last 15 years in understanding the cellular mechanisms underlying motility, following the discovery of the central role played by the interstitial cells of Cajal (ICC). As experimental knowledge of ICC physiology has expanded, biophysically based modeling has become a valuable tool for integrating experimental data, for testing hypotheses on ICC pacemaker mechanisms, and for applications in in silico studies including in multiscale models. This review is focused on the cellular electrophysiology of ICC. Recent evidence from both experimental and modeling domains have called aspects of the existing pacemaker theories into question. Therefore, current experimental knowledge of ICC pacemaker mechanisms is examined in depth, and current theories of ICC pacemaking are evaluated and further developed. Existing biophysically based ICC models and their physiological foundations are then critiqued in light of the recent advances in experimental knowledge, and opportunities to improve these models are identified. The review concludes by examining several potential clinical applications of biophysically based ICC modeling from the subcellular through to the organ level, including ion channelopathies and ICC network degradation.
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Affiliation(s)
- Rachel Lees-Green
- Auckland Bioengineering Institute, The University of Auckland Auckland, New Zealand
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Sakakibara Y, Asahina M, Suzuki A, Hattori T. Gastric myoelectrical differences between Parkinson's disease and multiple system atrophy. Mov Disord 2010; 24:1579-86. [PMID: 19514051 DOI: 10.1002/mds.22265] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The electrogastrogram (EGG) was recorded for 24 hours in 17 Parkinson's disease (PD) patients, 17 multiple system atrophy (MSA) patients, and 8 healthy control subjects to elucidate the differences in the EGG findings between the two diseases. Eight EGG segments (3 preprandial, 3 postprandial, and 2 sleep segments) were selected from the total recording for spectral analysis, from which we obtained the dominant frequency (DF), instability coefficient of DF (ICDF), and low (LFR%), normal (NFR%), and high (HFR%) range power percentages of the total power. PD patients showed irregular slow waves, high HFR%, and high ICDF, whereas MSA patients showed regular slow waves and low ICDF. Although DF and NFR% increased after meal in controls, postprandial increases in DF and NFR% were less significant in both patient groups compared to the controls. The PD patients presented gastric dysrhythmias indicating gastric pacemaker disturbances. The MSA patients showed regular slow waves with low variability of the slow wave rhythm (low ICDF), which might have resulted from the involvement of gastric autonomic nerve function.
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Du P, O'Grady G, Davidson JB, Cheng LK, Pullan AJ. Multiscale modeling of gastrointestinal electrophysiology and experimental validation. Crit Rev Biomed Eng 2010; 38:225-54. [PMID: 21133835 PMCID: PMC3090448 DOI: 10.1615/critrevbiomedeng.v38.i3.10] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Normal gastrointestinal (GI) motility results from the coordinated interplay of multiple cooperating mechanisms, both intrinsic and extrinsic to the GI tract. A fundamental component of this activity is an omnipresent electrical activity termed slow waves, which is generated and propagated by the interstitial cells of Cajal (ICCs). The role of ICC loss and network degradation in GI motility disorders is a significant area of ongoing research. This review examines recent progress in the multiscale modeling framework for effectively integrating a vast range of experimental data in GI electrophysiology, and outlines the prospect of how modeling can provide new insights into GI function in health and disease. The review begins with an overview of the GI tract and its electrophysiology, and then focuses on recent work on modeling GI electrical activity, spanning from cell to body biophysical scales. Mathematical cell models of the ICCs and smooth muscle cell are presented. The continuum framework of monodomain and bidomain models for tissue and organ models are then considered, and the forward techniques used to model the resultant body surface potential and magnetic field are discussed. The review then outlines recent progress in experimental support and validation of modeling, and concludes with a discussion on potential future research directions in this field.
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Affiliation(s)
- Peng Du
- Auckland Bioengineering Institute, The University of Auckland, New Zealand.
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Cheng LK, O’Grady G, Du P, Egbuji JU, Windsor JA, Pullan AJ. Gastrointestinal system. WILEY INTERDISCIPLINARY REVIEWS. SYSTEMS BIOLOGY AND MEDICINE 2010; 2:65-79. [PMID: 20836011 PMCID: PMC4221587 DOI: 10.1002/wsbm.19] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The functions of the gastrointestinal (GI) tract include digestion, absorption, excretion, and protection. In this review, we focus on the electrical activity of the stomach and small intestine, which underlies the motility of these organs, and where the most detailed systems descriptions and computational models have been based to date. Much of this discussion is also applicable to the rest of the GI tract. This review covers four major spatial scales: cell, tissue, organ, and torso, and discusses the methods of investigation and the challenges associated with each. We begin by describing the origin of the electrical activity in the interstitial cells of Cajal, and its spread to smooth muscle cells. The spread of electrical activity through the stomach and small intestine is then described, followed by the resultant electrical and magnetic activity that may be recorded on the body surface. A number of common and highly symptomatic GI conditions involve abnormal electrical and/or motor activity, which are often termed functional disorders. In the last section of this review we address approaches being used to characterize and diagnose abnormalities in the electrical activity and how these might be applied in the clinical setting. The understanding of electrophysiology and motility of the GI system remains a challenging field, and the review discusses how biophysically based mathematical models can help to bridge gaps in our current knowledge, through integration of otherwise separate concepts.
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Affiliation(s)
- Leo K. Cheng
- Auckland Bioengineering Institute, The University of Auckland, Auckland 1142, New Zealand
| | - Gregory O’Grady
- Auckland Bioengineering Institute, The University of Auckland, Auckland 1142, New Zealand
- Department of Surgery, The University of Auckland, Auckland 1142, New Zealand
| | - Peng Du
- Auckland Bioengineering Institute, The University of Auckland, Auckland 1142, New Zealand
- Department of Surgery, The University of Auckland, Auckland 1142, New Zealand
| | - John U. Egbuji
- Auckland Bioengineering Institute, The University of Auckland, Auckland 1142, New Zealand
- Department of Surgery, The University of Auckland, Auckland 1142, New Zealand
| | - John A. Windsor
- Department of Surgery, The University of Auckland, Auckland 1142, New Zealand
| | - Andrew J. Pullan
- Auckland Bioengineering Institute, The University of Auckland, Auckland 1142, New Zealand
- Department of Engineering Science, The University of Auckland, Auckland 1142, New Zealand
- Department of Surgery, Vanderbilt University, Nashville, TN 37235–5225
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Garcia-Lopez P, Garcia-Marin V, Martínez-Murillo R, Freire M. Updating old ideas and recent advances regarding the Interstitial Cells of Cajal. ACTA ACUST UNITED AC 2009; 61:154-69. [PMID: 19520112 DOI: 10.1016/j.brainresrev.2009.06.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2009] [Revised: 05/30/2009] [Accepted: 06/01/2009] [Indexed: 12/11/2022]
Abstract
Since their discovery by Cajal in 1889, the Interstitial Cells of Cajal (ICC) have generated much controversy in the scientific community. Indeed, the nervous, muscle or fibroblastic nature of the ICC has remained under debate for more than a century, as has their possible physiological function. Cajal and his colleagues considered them to be neurons, while contemporary histologists like Kölliker and Dogiel categorized these cells as fibroblasts. More recently, the role of ICC in the origin of slow-wave peristaltism has been elucidated, and several studies have shown that they participate in neurotransmission (intercalation theory). The fact that ICC assemble in the circular muscular layer and that they originate from cells which emerge from the ventral neural tube (VENT cells), a source of neurons, glia and ICC precursors other than the neural crest, suggests a neural origin for this particular subset of ICC. The discovery that ICC express the Kit protein, a type III tyrosine kinase receptor encoded by the proto-oncogene c-kit, has helped better understand their physiological role and implication in pathological conditions. Gleevec, a novel molecule designed to inhibit the mutant activated version of c-Kit receptors, is the drug of choice to treat the so-called gastrointestinal stromal tumours (GIST), the most common non-epithelial neoplasm of the gastrointestinal tract. Here we review Cajal's original contributions with the aid of unique images taken from Cajal's histological slides (preserved at the Cajal Museum, Cajal Institute, CSIC). In addition, we present a historical review of the concepts associated with this particular cell type, emphasizing current data that has advanced our understanding of the role these intriguing cells fulfil.
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Affiliation(s)
- P Garcia-Lopez
- Cajal Institute, CSIC, Avda Doctor Arce 37, 28002 - Madrid, Spain
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So KY, Kim SH, Sohn HM, Choi SJ, Parajuli SP, Choi S, Yeum CH, Yoon PJ, Jun JY. Carbachol regulates pacemaker activities in cultured interstitial cells of Cajal from the mouse small intestine. Mol Cells 2009; 27:525-31. [PMID: 19466600 DOI: 10.1007/s10059-009-0076-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2008] [Revised: 03/17/2009] [Accepted: 03/24/2009] [Indexed: 11/25/2022] Open
Abstract
We studied the effect of carbachol on pacemaker currents in cultured interstitial cells of Cajal (ICC) from the mouse small intestine by muscarinic stimulation using a whole cell patch clamp technique and Ca2+-imaging. ICC generated periodic pacemaker potentials in the current-clamp mode and generated spontaneous inward pacemaker currents at a holding potential of-70 mV. Exposure to carbachol depolarized the membrane and produced tonic inward pacemaker currents with a decrease in the frequency and amplitude of the pacemaker currents. The effects of carbachol were blocked by 1-dimethyl-4-diphenylacetoxypiperidinium, a muscarinic M(3) receptor antagonist, but not by methotramine, a muscarinic M(2) receptor antagonist. Intracellular GDP-beta-S suppressed the carbachol-induced effects. Carbachol-induced effects were blocked by external Na+-free solution and by flufenamic acid, a non-selective cation channel blocker, and in the presence of thapsigargin, a Ca2+-ATPase inhibitor in the endoplasmic reticulum. However, carbachol still produced tonic inward pacemaker currents with the removal of external Ca2+. In recording of intracellular Ca2+ concentrations using fluo 3-AM dye, carbachol increased intracellular Ca2+ concentrations with increasing of Ca2+ oscillations. These results suggest that carbachol modulates the pacemaker activity of ICC through the activation of non-selective cation channels via muscarinic M(3) receptors by a G-protein dependent intracellular Ca2+ release mechanism.
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Affiliation(s)
- Keum Young So
- Department of Anesthesiology, College of Medicine, Chosun University, Gwangju 501-759, Korea
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Sevcencu C. Gastric Stimulation for Dysmotility Disorders and Obesity. Neuromodulation 2009. [DOI: 10.1016/b978-0-12-374248-3.00075-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Davis MJ, Davis AM, Lane MM, Ku CW, Gashev AA. Rate-sensitive contractile responses of lymphatic vessels to circumferential stretch. J Physiol 2008; 587:165-82. [PMID: 19001046 DOI: 10.1113/jphysiol.2008.162438] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Phasic contractile activity in rat portal vein is more sensitive to the rate of change in length than to absolute length and this response is widely assumed to be a general characteristic of myogenic behaviour for vascular smooth muscle. Previously, we found that rat lymphatic vessels exhibit phasic contractile behaviour similar to that of portal vein. In the present study, we hypothesized that lymphatic muscle would exhibit rate-sensitive contractile responses to stretch. The hypothesis was tested on rat mesenteric lymphatics (90-220 microm, i.d.) using servo-controlled wire- and pressure-myograph systems to enable ramp increases in force or pressure at different rates. Under isometric conditions in wire-myograph preparations, both the amplitude and the frequency of phasic activity were enhanced at more optimal preloads, but superimposed upon this effect were bursts of contractions that occurred only during fast preload ramps. In such cases, the ratio of contraction frequency during the ramp to that at the subsequent plateau (at optimal preload) was > 1. Further, the frequency ratio increased as a function of the preload ramp speed, consistent with a rate-sensitive mechanism. In contrast, the amplitude ratio was < 1 and declined further with higher ramp speeds. Downward preload ramps produced corresponding rate-sensitive inhibition of contraction frequency but not amplitude. Similar findings were obtained in pressurized lymphatics in response to pressure ramps and steps. Our results suggest that lymphatics are sensitive to the rate of change in preload/pressure in a way that is different from portal vein, possibly because the pacemaker for generating electrical activity is rate sensitive but lymphatic muscle is not. The behaviour may be widely present in collecting lymphatic vessels and is probably an important mechanism for rapid adaptation of the lymphatic pump to local vascular occlusion.
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Affiliation(s)
- Michael J Davis
- Department of Medical Pharmacology and Physiology University of Missouri School of Medicine 1 Hospital Dr., Rm. M451 Columbia, MO 65212, USA.
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Aviv R, Sanmiguel CP, Kliger A, Policker S, Haddad W, Hagiike M, Soffer EE. The use of gastric electrical signals for algorithm for automatic eating detection in dogs. Neurogastroenterol Motil 2008; 20:369-76. [PMID: 18179613 DOI: 10.1111/j.1365-2982.2007.01044.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Food ingestion increases fundic impedance (FI) and reduces antral slow wave rate (SWR). Our aim was to determine if such changes can be integrated into an algorithm for automatic eating detection (AED). When incorporated in implantable medical devices, AED can time treatment to food intake without need for patient input. Four dogs were implanted with fundic and antral electrodes, connected to an implantable recording device. Changes in FI and SWR induced by fixed meals of different weights were determined, and were used to build an AED algorithm. Its performance was then tested on the same animals given an ad libitum access to food. The effects of gastric balloon distension and nitroglycerin on SWR and FI were also tested. Fixed meals reduced SWR in a weight-dependent manner, R(2) = 0.936, P < 0.05 baseline compared to 50, 100, 200 and 400 g. Meals increased FI above baseline in a weight-dependent manner; R(2) = 0.994, P < 0.05 baseline compared to 200 and 400 g. During ad libitum intake, the AED algorithm detected 86% of all meals > or =15 g. Gastric distension reduced SWR and increased FI. Nitroglycerin reduced SWR. AED, using changes in FI and gastric SWR is feasible. Changes in FI and SWR are induced primarily by the presence of food in the stomach.
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Affiliation(s)
- R Aviv
- MetaCure (USA) Inc., Orangeburg, NY, USA
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Abstract
The proposed functions of the interstitial cells of Cajal (ICC) are to 1) pace the slow waves and regulate their propagation, 2) mediate enteric neuronal signals to smooth muscle cells, and 3) act as mechanosensors. In addition, impairments of ICC have been implicated in diverse motility disorders. This review critically examines the available evidence for these roles and offers alternate explanations. This review suggests the following: 1) The ICC may not pace the slow waves or help in their propagation. Instead, they may help in maintaining the gradient of resting membrane potential (RMP) through the thickness of the circular muscle layer, which stabilizes the slow waves and enhances their propagation. The impairment of ICC destabilizes the slow waves, resulting in attenuation of their amplitude and impaired propagation. 2) The one-way communication between the enteric neuronal varicosities and the smooth muscle cells occurs by volume transmission, rather than by wired transmission via the ICC. 3) There are fundamental limitations for the ICC to act as mechanosensors. 4) The ICC impair in numerous motility disorders. However, a cause-and-effect relationship between ICC impairment and motility dysfunction is not established. The ICC impair readily and transform to other cell types in response to alterations in their microenvironment, which have limited effects on motility function. Concurrent investigations of the alterations in slow-wave characteristics, excitation-contraction and excitation-inhibition couplings in smooth muscle cells, neurotransmitter synthesis and release in enteric neurons, and the impairment of the ICC are required to understand the etiologies of clinical motility disorders.
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Affiliation(s)
- Sushil K Sarna
- Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, Department of Internal Medicine, Neuroscience, and Cell Biology, The University of Texas Medical Branch at Gavelston, Galveston, TX 77555-1064, USA.
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Takeda Y, Koh SD, Sanders KM, Ward SM. Differential expression of ionic conductances in interstitial cells of Cajal in the murine gastric antrum. J Physiol 2007; 586:859-73. [PMID: 18033817 DOI: 10.1113/jphysiol.2007.140293] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Two distinct populations of interstitial cells of Cajal (ICC) exist within the tunica muscularis of the gastric antrum, and these cells serve different physiological functions. One population of ICC generates and actively propagates electrical slow waves, and the other population of ICC is innervated by excitatory and inhibitory motor neurons and mediates enteric motor neurotransmission. In spite of the key role of ICC in gastric excitability, little is known about the ionic conductances that underlie the functional diversity of these cells. In the present study we isolated ICC from the murine gastric antrum and investigated the Ca(2+)-dependent ionic conductances expressed by these cells using the patch clamp technique. Conductances in ICC were compared with those expressed in smooth muscle cells. The cells studied were identified by RT-PCR using cell-specific primers that included Myh11 (smooth muscle cells), Kit (ICC) and Uchl1 (enteric neurons) following electrophysiolgical recordings. Distinct ionic conductances were observed in Kit-positive cells. One group of ICC expressed a basal non-selective cation conductance (NSCC) that was inhibited by an increase in [Ca(2+)](i) in a calmodulin (CaM)-dependent manner. A second population of ICC generated spontaneous transient inward currents (STICs) and expressed a basal noisy NSCC that was facilitated by an increase in [Ca(2+)](i) in a CaM-dependent manner. The [Ca(2+)](i)-facilitated NSCC in ICC was blocked by the Cl(-) channel antagonists 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), anthracene-9-carboxylate (9-AC) and niflumic acid. These data suggest that distinct NSCC are expressed in subpopulations of ICC and these conductances may underlie the functional differences of these cells within the gastric antrum.
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Affiliation(s)
- Yukari Takeda
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
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Brading AF, Heaton JPW, Hashitani H. A survey of commonalities relevant to function and dysfunction in pelvic and sexual organs. Int J Impot Res 2007; 20:1-16. [PMID: 17717525 DOI: 10.1038/sj.ijir.3901568] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Micturition, defecation and sexual function are all programmed through spinal reflexes that are under descending control from higher centres. Interaction between these reflexes can clearly be perceived, and evidence is accumulating the dysfunction in one reflex is often associated with dysfunction in another. In this article, we describe some of the basic properties and neural control of the smooth muscles mediating the reflexes, reviewing the common features that underlie these reflex functions, and what changes may be responsible for dysfunction. We propose that autonomic control within the pelvis predisposes pelvic and sexual organs to crosstalk, with the consequence that diseases and conditions of the pelvis are subject to convergence on a functional level. It should be expected that disturbance of the function of one system will inevitably impact adjacent systems.
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Affiliation(s)
- A F Brading
- Oxford Continence Group, University Department of Pharmacology, Oxford, UK.
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Liu S, Xu J, Chen JD. Roles of putative neurotransmitters in the regulation of gastric and intestinal slow waves in conscious dogs. J Gastroenterol Hepatol 2007; 22:1044-50. [PMID: 17608850 DOI: 10.1111/j.1440-1746.2007.04916.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIMS Slow waves play an important role in controlling the frequency and propagation of gastrointestinal contractions. However, mechanisms involved in the modulation of slow wave activity in vivo are still unclear. In this study, the roles of different neurotransmitters in the regulation of gastrointestinal slow waves were investigated in conscious dogs. METHODS Female dogs implanted with electrodes in the stomach and the small bowel were used in a seven-session study. Gastrointestinal myoelectrical activity was recorded at baseline and after i.v. saline, atropine, atropine methyl nitrate, guanethidine, Nomega-nitro-L-arginine (L-NNA), ondansetron or naloxone. RESULTS Both atropine and atropine methyl nitrate induced tachygastria, bradygastria and arrhythmia. No difference was noted in the effects between atropine and atropine methyl nitrate. L-NNA increased the dominant frequency of small-intestinal slow waves but had no effect on gastric slow waves. Guanethidine, ondansetron and naloxone did not affect the dominant frequency, power or percentage of normal gastrointestinal slow waves. CONCLUSION Acetylcholine acting at muscarinic receptors seems to play an important role in the regulation of gastric slow waves. Nitric oxide may play a role in modulating intestinal slow waves but not gastric slow waves. Sympathetic pathways, 5-HT(3) receptors and opioid receptors (especially micro-opioid receptors) do not play a role in the regulation of gastric or intestinal slow waves under normal physiological conditions.
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Affiliation(s)
- Shi Liu
- Division of Gastroenterology, University of Texas Medical Branch, Galveston, Texas, USA
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Kito Y, Suzuki H. Role of K+ channels in the regulation of electrical spontaneous activity of the mouse small intestine. Pflugers Arch 2007; 455:505-14. [PMID: 17602242 DOI: 10.1007/s00424-007-0306-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2007] [Revised: 05/25/2007] [Accepted: 06/01/2007] [Indexed: 10/23/2022]
Abstract
The roles of K(+) channels in the regulation of slow waves and pacemaker potentials recorded from mouse small intestine were investigated using intracellular recording techniques in the presence of nifedipine. Iberiotoxin (0.1 microM) and charybdotoxin (0.1 microM) had no effect on the generation of slow waves recorded from circular smooth muscle cells. Apamin (0.3 microM) depolarized the membrane and decreased the amplitude of early, rapid repolarization of slow waves, without altering the amplitude, frequency, duration, or maximum rate of rise of the initial upstroke phase (dV/dt(max)). The early, rapid repolarization was enhanced by phenylephrine (15 microM). 4-Aminopyridine (4-AP, 5 mM) depolarized the membrane and increased the amplitude and dV/dt(max) of slow waves. Both apamin and 4-AP depolarized the membrane and decreased the amplitude and dV/dt(max) of pacemaker potentials recorded from interstitial cells of Cajal distributed in the myenteric region (ICC-MY). Membrane depolarization with a high-K(+) solution decreased the amplitude and dV/dt(max) of slow waves. These results suggest that apamin-sensitive K(+) conductance and 4-AP-sensitive K(+) conductance may contribute to the resting membrane potential of circular smooth muscle cells. The early, rapid repolarization of slow waves appears to result from the opening of apamin-sensitive K(+) conductance. 4-AP-sensitive K(+) conductance is likely to be activated in the initial upstroke component (primary component) of slow waves. In ICC-MY, membrane depolarization induced by apamin or 4-AP may result from electrotonic spread from smooth muscle cells.
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Affiliation(s)
- Yoshihiko Kito
- Department of Physiology, Nagoya City University Medical School, Nagoya, Japan.
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Wiesław T, Adam K, Artur B, Lech B, Krzysztof B. Nissen fundoplication improves gastric myoelectrical activity characteristics and symptoms in gastroesophageal reflux patients: evaluation in transcutaneous electrogastrography. Surg Endosc 2007; 22:134-40. [PMID: 17497194 DOI: 10.1007/s00464-007-9389-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2007] [Revised: 01/09/2007] [Accepted: 01/27/2007] [Indexed: 10/23/2022]
Abstract
BACKGROUND Gastric myoelectrical activity disorders play an essential role in the pathophysiology of gastroesophageal reflux disease (GERD), although little is known about gastric motility following surgical treatment of the disease. The aim of present study was to analyze the impact of Nissen fundoplication on both gastric myoelectrical activity, measured using the transcutaneous electrogastrography technique (EGG), and change in digestive symptoms. METHODS In 43 patients with GERD, EGG was recorded before and after the Nissen procedure and compared with the EGG obtained in eight healthy volunteers. Symptoms of epigastric pain, belching, regurgitation, heartburn, postprandial abdominal distension, and early satiety were recorded. At a three-week and a one-year postoperative follow-up, these tests were repeated. RESULTS In fasted patients before the operation, the slow-wave frequency distribution (normogastria, 53.7%; bradygastria, 44.2%; dysrhythmia, 47.1%) was significantly different compared with that of controls (89.2%, 7.0%, and 10.4%, respectively). No major changes in slow-wave frequency distribution were observed after a meal in examined patients, besides a significant rise in tachygastria (12.4%). Three weeks following the Nissen fundoplication, the fasting slow-wave frequency distribution did not change significantly compared with the preoperative period, being 58.1% for normogastria, 43.2% for bradygastria, and 12.0% for tachygastria. The abnormal distribution of slow waves (bradygastria + tachygastria) was not significantly affected by Nissen fundoplication, being 47.1% before and 44.9% after the operation, respectively. At the same time and still one year after operation there was a significant improvement in all clinical symptoms measured. CONCLUSION EGG showed that Nissen fundoplication influenced and might improve the slow-wave generation in gastric pacemaker. Dyspeptic symptoms were also improved up to one year postoperatively.
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Affiliation(s)
- Tarnowski Wiesław
- Department of General and Gastroenterological Surgery, Orlowski's Hospital, MCPE, 231 Czerniakowska Street, 00-416, Warsaw, Poland.
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Sevcencu C. Gastrointestinal Mechanisms Activated by Electrical Stimulation to Treat Motility Dysfunctions in the Digestive Tract: A Review. Neuromodulation 2007; 10:100-12. [DOI: 10.1111/j.1525-1403.2007.00098.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Daniel EE, Yazbi AE, Mannarino M, Galante G, Boddy G, Livergant J, Oskouei TE. Do gap junctions play a role in nerve transmissions as well as pacing in mouse intestine? Am J Physiol Gastrointest Liver Physiol 2007; 292:G734-45. [PMID: 17122366 DOI: 10.1152/ajpgi.00428.2006] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Varicosities of nitrergic and other nerves end on deep muscular plexus interstitial cells of Cajal or on CD34-positive, c-kit-negative fibroblast-like cells. Both cell types connect to outer circular muscle by gap junctions, which may transmit nerve messages to muscle. We tested the hypotheses that gap junctions transmit pacing messages from interstitial cells of Cajal of the myenteric plexus. Effects of inhibitors of gap junction conductance were studied on paced contractions and nerve transmissions in small segments of circular muscle of mouse intestine. Using electrical field stimulation parameters (50 V/cm, 5 pps, and 0.5 ms) which evoke near maximal responses to nitrergic, cholinergic, and apamin-sensitive nerve stimulation, we isolated inhibitory responses to nitrergic nerves, inhibitory responses to apamin-sensitive nerves and excitatory responses to cholinergic nerves. 18beta-Glycyrrhetinic acid (10, 30, and 100 microM), octanol (0.1, 0.3, and 1 mM) and gap peptides (300 microM of (40)Gap27, (43)Gap26, (37,43)Gap27) all failed to abolish neurotransmission. 18beta-Glycyrrhetinic acid inhibited frequencies of paced contractions, likely owing to inhibition of l-type Ca(2+) channels in smooth muscle, but octanol or gap peptides did not. 18beta-Glycyrrhetinic acid and octanol, but not gap peptides, reduced the amplitudes of spontaneous and nerve-induced contractions. These reductions paralleled reductions in contractions to exogenous carbachol. Additional experiments with gap peptides in both longitudinal and circular muscle segments after N(G)-nitro-l-arginine and TTX revealed no effects on pacing frequencies. We conclude that gap junction coupling may not be necessary for pacing or nerve transmission to the circular muscle of the mouse intestine.
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Affiliation(s)
- E E Daniel
- Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
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