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J Am Coll Cardiol, 2003; 42:1656-1662, doi:10.1016/j.jacc.2003.06.002
© 2003 by the American College of Cardiology Foundation
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BASIC SCIENCE

Inflammation-induced vasoconstrictorhyporeactivity is caused by oxidative stress

Johannes Pleiner, MD*, Friedrich Mittermayer, MD*, Georg Schaller, MD*, Claudia Marsik, MD*, Raymond J. MacAllister, MD, FRCP{dagger} and Michael Wolzt, MD*,*

* Department of Clinical Pharmacology, University of Vienna, Vienna, Austria
{dagger} Centre for Clinical Pharmacology and Therapeutics, Department of Medicine, University College London, London, United Kingdom

Manuscript received January 28, 2003; revised manuscript received May 15, 2003, accepted June 19, 2003.

* Reprint requests and correspondence: Dr. Michael Wolzt, Department of Clinical Pharmacology, Allgemeines Krankenhaus Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
michael.wolzt{at}univie.ac.at

OBJECTIVES: We sought to determine the role of oxidative stress in the development of vascular dysfunction in inflammation.

BACKGROUND: Hyporeactivity to catecholamines and other vasoconstrictors is present in acute inflammation. Because oxidative stress plays a significant role in inflammation, impaired responsiveness may be overcome by anti-oxidants.

METHODS: In randomized, double-blind, cross-over studies, forearm blood flow (FBF) responses to norepinephrine (NE), angiotensin II (ANG II), and vasopressin (VP) were assessed before and 4 h after induction of systemic inflammation by low doses of Escherichia coli endotoxin (lipopolysaccharide [LPS], 20 IU/kg intravenously) or after placebo in healthy volunteers. Furthermore, the effect of intra-arterial vitamin C (24 mg/min) or placebo on NE-induced or ANG II-induced vasoconstriction was studied after LPS.

RESULTS: Administration of LPS caused systemic and forearm vasodilation, increased white blood cell count, elevated body temperature, and reduced vitamin C plasma concentrations. Lipopolysaccharide decreased the responses of FBF to NE by 59%, to ANG II by 25%, and to VP by 51% (n = 9, p < 0.05, all effects). Co-administration of vitamin C completely restored the response to NE and to ANG II, which was comparable to that observed under baseline conditions (n = 8).

CONCLUSIONS: E. coli-endotoxemia reduces FBF responsiveness to vasoconstrictors. The hyporeactivity can be corrected by high doses of vitamin C, suggesting that oxidative stress may represent an important target for inflammation-induced impaired vascular function.

Abbreviations and Acronyms
  ANG II = angiotensin II
  ANOVA = analysis of variance
  BP = blood pressure
  FBF = forearm blood flow
  LPS = lipopolysaccharide (E. coli endotoxin)
  NE = norepinephrine
  NO = nitric oxide
  NOS = nitric oxide synthase
  NOx = nitrite
  O2. = superoxide radicals
  ROS = reactive oxygen species
  VP = vasopressin




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