Clinical Trial: Effect of Selective iNOS Inhibition During Human Endotoxemia

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Effect of Selective iNOS Inhibition During Human Endotoxemia

Brief Summary: 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.

Detailed Summary:
Sponsor: Radboud University

Current Primary Outcome:

  • 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 ]


Original Primary Outcome:

  • Hemodynamics
  • Markers of Inflammation
  • Cytokines
  • Markers of Renal Injury
  • Inducible NO synthase expression
  • NO-metabolites
  • Mediators of Vascular reactivity
  • Sensitivity to norepinephrine
  • Endothelial-dependent vasorelaxation


Current Secondary Outcome:

Original Secondary Outcome:

Information By: Radboud University

Dates:
Date Received: September 12, 2005
Date Started: January 2005
Date Completion:
Last Updated: April 14, 2008
Last Verified: April 2008