Effect of Selective iNOS Inhibition During Human Endotoxemia
Status:
Completed
Trial end date:
2005-09-01
Target enrollment:
Participant gender:
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.