title: Quinidine, but not eicosanoid antagonists or dexamethasone, protect the gut from platelet activating factor-induced vasoconstriction, edema and paralysis.
abstract: Intestinal circulatory disturbances, atony, edema and swelling are of great clinical relevance, but the related mechanisms and possible therapeutic options are poorly characterized, in part because of the difficulties to comprehensively analyze these conditions. To overcome these limitations we have developed a model of the isolated perfused rat small intestine where all of these symptoms can be studied simultaneously. Here we used this model to study the role of eicosanoids, steroids and quinidine in platelet-activating factor (PAF)-induced intestinal disorders. A vascular bolus of PAF (0.5 nmol) triggered release of thromboxane and peptidoleukotrienes into the vascular bed (peak concentration 35 nM and 0.8 nM) and reproduced all symptoms of intestinal failure: mesenteric vasoconstriction, translocation of fluid and macromolecules from the vasculature to the lumen and lymphatics, intestinal edema formation, loss of intestinal peristalsis and decreased galactose uptake. All effects of PAF were abolished by the PAF-receptor antagonist ABT491 (2.5 μM). The COX and LOX inhibitors ASA and AA861 (500 μM, 10 μM) did not exhibit barrier-protective effects and the eicosanoid antagonists SQ29548 and MK571 (10 μM, each) only moderately attenuated the loss of vascular fluid, the redistribution to the lumen and the transfer of FITC dextran to the lumen. The steroid dexamethasone (10 μM) showed no barrier-protective properties and failed to prevent edema formation. Quinidine (100 μM) inhibited the increase in arterial pressure, stabilized all the intestinal barriers, and reduced lymph production and the transfer of FITC dextran to the lymph. While quinidine by itself reduced peristalsis, it also obviated paralysis, preserved intestinal functions and prevented edema formation. We conclude that quinidine exerts multiple protective effects against vasoconstriction, edema formation and paralysis in the intestine. The therapeutic use of quinidine for intestinal ailments deserves further study.
authors: Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Division of Barrier Integrity, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
authors: Ingmar
authors: I
authors: Lautenschläger
authors: Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors: Inéz
authors: I
authors: Frerichs
authors: Division of Barrier Integrity, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
authors: Heike
authors: H
authors: Dombrowsky
authors: Division of Barrier Integrity, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany; Division of Mucosal Immunology and Diagnostic, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
authors: Jürgen
authors: J
authors: Sarau
authors: Division of Clinical and Experimental Pathology, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.
authors: Torsten
authors: T
authors: Goldmann
authors: Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors: Karina
authors: K
authors: Zitta
authors: Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors: Martin
authors: M
authors: Albrecht
authors: Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors: Norbert
authors: N
authors: Weiler
authors: Institute of Pharmacology and Toxicology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
authors: Stefan
authors: S
authors: Uhlig
mesh_terms: D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004195:Disease Models, Animal; D004487:Edema / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D015777:Eicosanoids / Q000494:pharmacology; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D010243:Paralysis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D010972:Platelet Activating Factor / Q000008:administration & dosage / Q000009:adverse effects*; D020011:Protective Agents / Q000494:pharmacology*; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D015777:Eicosanoids; D010972:Platelet Activating Factor; D020011:Protective Agents; D003907:Dexamethasone; D011802:Quinidine