Selective inhibition of the activity of inducible nitric oxide synthase prevents the circulatory failure, but not the organ injury/dysfunction, caused by endotoxin.
Inhibitors of nitric oxide synthase (NOS) attenuate the circulatory failure caused by endotoxin, but the role of NO in the development of multiple organ dysfunction and the relative contribution of NO produced by endothelial NOS and inducible NOS (iNOS) to organ injury remains unclear. Here we report for the first time that 1400W, a novel and highly selective inhibitor of iNOS activity, attenuates the delayed hypotension as well as the rise in the plasma levels of nitrite/nitrate caused by endotoxin in the rat. Inhibition of iNOS activity with 1400W administered either before or 2 h after endotoxin injection did not, however, attenuate the hepatocellular injury, renal dysfunction, or pancreatic injury in this model. Similarly, administration of another selective inhibitor of iNOS activity, L-NIL, 2 h after endotoxin injection abolished the rise in nitrite/nitrate and attenuated the delayed hypotension caused by endotoxin, but failed to ameliorate organ injury. Thus, selective inhibition of iNOS activity with 1400W attenuates the circulatory failure induced by endotoxin in the rat, but fails to influence the degree of organ injury/dysfunction.
Wray
G M
GM
The William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, United Kingdom.
Millar
C G
CG
Hinds
C J
CJ
Thiemermann
C
C
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D007668:Kidney / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000293:injuries / Q000503:physiopathology; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009102:Multiple Organ Failure / Q000517:prevention & control*; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D051381:Rats; D012772:Shock, Septic / Q000188:drug therapy / Q000503:physiopathology*
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C090663:N(6)-(1-iminoethyl)lysine; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D009566:Nitrates; D009573:Nitrites; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008239:Lysine