title: Mechanisms of circulatory and intestinal barrier dysfunction during whole body hyperthermia.
abstract: This work tested the hypotheses that splanchnic oxidant generation is important in determining heat tolerance and that inappropriate.NO production may be involved in circulatory dysfunction with heat stroke. We monitored colonic temperature (T(c)), heart rate, mean arterial pressure, and splanchnic blood flow (SBF) in anesthetized rats exposed to 40 degrees C ambient temperature. Heating rate, heating time, and thermal load determined heat tolerance. Portal blood was regularly collected for determination of radical and endotoxin content. Elevating T(c) from 37 to 41.5 degrees C reduced SBF by 40% and stimulated production of the radicals ceruloplasmin, semiquinone, and penta-coordinate iron(II) nitrosyl-heme (heme-.NO). Portal endotoxin concentration rose from 28 to 59 pg/ml (P < 0.05). Compared with heat stress alone, heat plus treatment with the nitric oxide synthase (NOS) antagonist N(omega)-nitro-L-arginine methyl ester (L-NAME) dose dependently depressed heme-.NO production and increased ceruloplasmin and semiquinone levels. L-NAME also significantly reduced lowered SBF, increased portal endotoxin concentration, and reduced heat tolerance (P < 0.05). The NOS II and diamine oxidase antagonist aminoguanidine, the superoxide anion scavenger superoxide dismutase, and the xanthine oxidase antagonist allopurinol slowed the rates of heme-.NO production, decreased ceruloplasmin and semiquinone levels, and preserved SBF. However, only aminoguanidine and allopurinol improved heat tolerance, and only allpourinol eliminated the rise in portal endotoxin content. We conclude that hyperthermia stimulates xanthine oxidase production of reactive oxygen species that activate metals and limit heat tolerance by promoting circulatory and intestinal barrier dysfunction. In addition, intact NOS activity is required for normal stress tolerance, whereas overproduction of.NO may contribute to the nonprogrammed splanchnic dilation that precedes vascular collapse with heat stroke.
authors.affiliation: Department of Exercise Science, University of Iowa, Iowa City, Iowa 52242, USA. dmhall@kirkwood.cc.ia.us
authors.forename: D M
authors.initials: DM
authors.lastname: Hall
authors.forename: G R
authors.initials: GR
authors.lastname: Buettner
authors.forename: L W
authors.initials: LW
authors.lastname: Oberley
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.forename: R D
authors.initials: RD
authors.lastname: Matthes
authors.forename: C V
authors.initials: CV
authors.lastname: Gisolfi
mesh_terms: D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004578:Electron Spin Resonance Spectroscopy; D019446:Endotoxemia / Q000378:metabolism / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005334:Fever / Q000378:metabolism* / Q000503:physiopathology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D018882:Heat Stress Disorders / Q000378:metabolism / Q000503:physiopathology; D007408:Intestinal Absorption / Q000502:physiology*; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011092:Polyethylene Glycols / Q000494:pharmacology; D011169:Portal Vein; D051381:Rats; D017207:Rats, Sprague-Dawley; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology*; D013379:Substrate Specificity; D013482:Superoxide Dismutase / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D005609:Free Radicals; D006146:Guanidines; D011092:Polyethylene Glycols; D000493:Allopurinol; D001120:Arginine; D019001:Nitric Oxide Synthase; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester