Extracellular signaling molecules regulate intracellular events by way of complex transduction assemblies composed of several proteins: receptor, G protein, effector, inactivating enzyme. Much is known about the structure and function of these transducer proteins. A signaling molecule initiates transduction by binding to the receptor which then prompts the G protein to undergo a reaction cycle. This cycle involves guanine nucleotide binding and hydrolysis, G protein subunit dissociation, and interactions with an effector (e.g. adenylyl cyclase, phospholipase C), as well as with inactivating molecules. The result is altered generation of intracellular second messengers, protein transcription, or another profound cellular response. This signal transduction system also contains multiple mechanisms for turning off the signal such as phosphorylating, internalizing, or downregulating receptors, uncoupling the receptor-G protein complex, or cell-surface peptidases, and precipitating conformational changes in transducer elements. These aspects of signal transduction are examined in two well studied systems, namely the β2-adrenergic and the substance P transducers. Both complexes are important physiological neuroregulators in the gut and elsewhere. Pathophysiological mechanisms involving aberrent signal transduction have been implicated in various diseases including major common illnesses such as heart failure and gastrointestinal disorders such as cholera, other infectious diarrheas, and colitis.

Extracellular signaling molecules regulate intracellular events by way of complex transduction assemblies composed of several proteins: receptor, G protein, effector, inactivating enzyme. Much is known about the structure and function of these transducer proteins. A signaling molecule initiates transduction by binding to the receptor which then prompts the G protein to undergo a reaction cycle. This cycle involves guanine nucleotide binding and hydrolysis, G protein subunit dissociation, and interactions with an effector (e.g. adenylyl cyclase, phospholipase C), as well as with inactivating molecules. The result is altered generation of intracellular second messengers, protein transcription, or another profound cellular response. This signal transduction system also contains multiple mechanisms for turning off the signal such as phosphorylating, internalizing, or downregulating receptors, uncoupling the receptor-G protein complex, or cell-surface peptidases, and precipitating conformational changes in transducer elements. These aspects of signal transduction are examined in two well studied systems, namely the beta(2)-adrenergic and the substance P transducers. Both complexes are important physiological neuroregulators in the gut and elsewhere. Pathophysiological mechanisms involving aberrent signal transduction have been implicated in various diseases including major common illnesses such as heart failure and gastrointestinal disorders such as cholera, other infectious diarrheas, and colitis.

The physiology of the mesenteric circulation is described emphasizing important aspects of microcirculatory function and the factors which regulate blood flow to the bowel. Next, the pathophysiology of intestinal ischemia is considered with special focus on the disturbed mechanisms involved in ischemic disorders, such as active oxidant formation and inhibition of intrinsic protective systems. The histopathology of small intestinal and colonic ischemia and infarction is described. Finally, clinical issues are addressed including the diagnostic challenge and the management of these life-threatening disorders.

It has long been recognized that intestinal blood flow increases at mealtimes. Mesenteric hyperaemia is also evoked by activation of sensory peptidergic nerves. Our studies explored the possible role of endogenous nitric oxide (NO) in the rat intestinal vasodilator response to luminal instillation of an oleic acid plus bile mixture before and after acute intrajejunal instillation of capsaicin and after chronic pretreatment with capsaicin. In anaesthetized rats we measured jejunal blood flow (BF) with an ultrasonic Doppler flowmeter and systemic arterial pressure (AP) with a pressure transducer. Intestinal perfusion with 80 mM oleic acid in bile increased BF by 98±12%. Instillation of 4 mg of capsaicin into the jejunal lumen initially increased BF by 42±9% but was followed by vasoconstriction. Inhibition of NO synthase with 25 mg/kg i.v. N-nitro-L-arginine (L-NNA) decreased BF by 27±5% and increased AP by 37±11%. After treatment with L-NNA and after acute and chronic administration of capsaicin, the bile-oleate-induced maximal increases in BF above control levels were 42±7%, 65±12%, and 58±8%, respectively. The observed inhibitory effect of L-NNA on the intestinal hyperaemic response to the bile-oleate mixture was reversed by pretreatment with L-arginine (100 mg/kg i.V.). In capsaicin pretreated rats the subsequent bile-oleate-induced hyperaemia was reduced in magnitude but the inhibitory effects of L-NNA were proportionately the same as in animals not receiving capsaicin. These findings support the hypothesis that NO is involved with bile-oleate-induced mesenteric hyperaemia.

We evaluated the effects of potential factors in autoregulatory escape from norepinephrine-induced vasoconstriction in rat anterior mesenteric artery. We determined mesenteric artery blood flow velocity with a pulsed Doppler, sonic flowmeter, and systemic arterial blood pressure with a transducer. A 4-min norepinephrine infusion (0.125−1.0 × 10−8 M/min) intravenously evoked a dose-dependent, initial vasoconstriction that was followed by rapid escape of blood flow toward or above the control value during sustained norepinephrine administration. Neonatal capsaicin treatment enhanced vasoconstrictor responses to norepinephrine but failed to affect escape parameters. Propranolol decreased norepinephrine-induced escape dose dependently. Adenosine deaminase attenuated escape, and the combination of this enzyme plus propranolol nearly abolished escape from norepinephrine-induced vasoconstriction. Methylene blue also diminished autoregulatory escape. These findings suggest that norepinephrine-induced autoregulatory escape involves simultaneous β-adrenoceptor, purinergic, and endothelial mediation. Norepinephrine-evoked mesenteric vasoconstriction appears to involve predominantly α2-adrenoceptors and is modulated by peptidergic sensory nerves and adenosine.

The sections in this article are: 1 Pathophysiology of Ischemic Injury 1.1 Nonocclusive Intestinal Ischemia 1.1.1 Mechanisms 1.1.2 Therapeutic Implications 1.2 Occlusive Disease 2 Shock and Intestinal Circulation 3 Portal Hypertension 4 Inflammatory Bowel Disease 5 Ulcers 6 Other Diseases 6.1 Hypertension 6.2 Diabetes Mellitus 6.3 Arteriovenous Malformations 6.4 Dumping Syndrome and Secretory Disorders 6.5 Miscellaneous Disorders

Review Articles| November 04 2008 Ischemic Colitis Subject Area: Gastroenterology Raul Huet; Raul Huet University of Kansas School of Medicine, Kansas City, Kans., USA Search for other works by this author on: This Site PubMed Google Scholar Eugene D. Jacobson Eugene D. Jacobson University of Kansas School of Medicine, Kansas City, Kans., USA Search for other works by this author on: This Site PubMed Google Scholar Dig Dis (1987) 5 (4): 222–236. https://doi.org/10.1159/000171176 Article history Published Online: November 04 2008 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Raul Huet, Eugene D. Jacobson; Ischemic Colitis. Dig Dis 1 April 1987; 5 (4): 222–236. https://doi.org/10.1159/000171176 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsDigestive Diseases Search Advanced Search Article PDF first page preview Close Modal 1987Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. You do not currently have access to this content.

Cytoprotection confers increased cellular resistance to various damaging challenges. For example, the administration of certain prostaglandins (PG) prevents injury or facilitates recovery from injury in tissues exposed to noxious substances, such as ethanol, aspirin, and indomethacin. In addition, naturally occurring PG (E and I types) may play a physiological role in protecting the gastroduodenal mucosa against corrosion by gastric juice. Within a responsive tissue, not all cells may be protected by PG against severe damage. Thus, while PG will not prevent necrosis of the gastric epithelial monolayer during exposure to 100% ethanol, it does protect the deeper gastric cells of the mucosa from destruction. Cytoprotection of the gastroduodenal mucosa is independent of the antisecretory activity of PG. The ED100 cytoprotective dose of a prostaglandin may be less than 1% of the ED50 antisecretory dose of the same agent, and some cytoprotective prostaglandins are not antisecretory in some animal models. The best of the proposed mechanisms to account for cytoprotection include stimulation of mucus or HCO3 secretion, and mucosal vasodilation. However, there are no definitive data to substantiate these hypotheses and, in fact, evidence does exist to disprove each theory. Gastric mucosal exposure to mildly damaging concentrations of an agent will increase mucosal resistance to subsequent exposure to a much greater and more damaging concentration of the same agent. This "adaptive cytoprotection" can be abolished by indomethacin, an inhibitor of endogenous prostaglandin synthesis.

The basic mechanisms underlying cytoprotection of gastrointestinal mucosae against damage are not understood. One hypothesis is that the initial and primary system affected by a cytoprotective agent is the local circulation of the tissue that is being protected. According to this circulatory hypothesis, a cytoprotective prostaglandin would increase gastric mucosal blood flow, thereby ameliorating the effect of topical damaging agents, such as ethanol, aspirin or bile salts. Four questions need to be considered in order to evaluate the circulatory hypothesis: (i) What degree of ischemia is necessary to break the gastric mucosal barrier? (ii) Is peptic ulcer disease due to local ischemia of the mucosa? (iii) Do mucosal damaging agents invariably reduce gastric blood flow? (iv) Do cytoprotective agents invariably increase gastric blood flow? A survey of available literature concerning blood flow and damage to the gastric mucosa suggests that: (i) severe degrees of gastric ischemia are necessary to impair vital functions of the epithelial cells of the stomach; (ii) peptic ulcer disease is not a manifestation of isolated gastric ischemia; (iii) mucosal damaging agents do not invariably reduce gastric blood flow; and (iv) cytoprotective drugs do not invariably increase gastric mucosal blood flow. The weight of available evidence does not support the circulatory hypothesis about the mechanism of cytoprotection.