Effect of Selective iNOS Inhibition During Human Endotoxemia

Overview

Sepsis or endotoxemia is manifested by hypotension, resistance to vasopressors, myocardial depression,and altered organ blood flow distribution. The mechanisms underlying the cardiovascular dysfunction during sepsis are complex; however, they are partially mediated by an uncontrolled production of NO by inducible NO synthase (iNOS).Control subjects received 2 ng/kg E. coli endotoxin, whereas the active intervention group received endotoxin in the presence of selective iNOS-inhibitor aminoguanidine. Hemodynamics, vascular responses to norepinephrine, acetylcholine and sodium nitroprusside, as well as circulating cytokines and other mediators of inflammation were measured. We tested the hypothesis that inhibition of NO-synthesis prevented the LPS-mediated insensitivity to noradrenalin and endothelial-dependent vasorelaxation. Furthermore, we tested whether NO participates in occurrence of the endotoxin tolerance in humans by using the iNOS inhibitor aminoguanidine on healthy volunteers with endotoxemia. At 0; 2 and 4 hours after the LPS challenge whole blood was stimulated with five TLR agonists in vitro and pro- and anti-inflammatory cytokines were measured.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Prevention
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 2005

Interventions

  • Drug: Aminoguanidine
  • Drug: endotoxin

Clinical Trial Outcome Measures

Primary Measures

  • Hemodynamics
    • Time Frame: 24 hrs after LPS administration
  • Markers of Inflammation
    • Time Frame: 24 hrs after LPS administration
  • Cytokines
    • Time Frame: 24 hrs after LPS administration
  • Markers of Renal Injury
    • Time Frame: 24 hrs after LPS administration
  • Inducible NO synthase expression
    • Time Frame: 24 hrs after LPS administration
  • NO-metabolites
    • Time Frame: 24 hrs after LPS administration
  • Mediators of Vascular reactivity
    • Time Frame: 24 hrs after LPS administration
  • Sensitivity to norepinephrine
    • Time Frame: 24 hrs after LPS administration
  • Endothelial-dependent vasorelaxation
    • Time Frame: 24 hrs after LPS administration

Participating in This Clinical Trial

Inclusion Criteria

  • Healthy volunteers Exclusion Criteria:

  • tendency towards fainting – alcohol abuse – nicotine abuse – drugs abuse

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 35 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Radboud University Medical Center
  • Overall Official(s)
    • Peter Pickkers, PhD, Principal Investigator, Radboud University Medical Center

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