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Effects of a selective iNOS inhibitor versus norepinephrine in the treatment of septic shock.

Abstract
Inhibition of NOS is not beneficial in septic shock; selective inhibition of the inducible form (iNOS) may represent a better option. We compared the effects of the selective iNOS inhibitor BYK191023 with those of norepinephrine (NE) in a sheep model of septic shock. Twenty-four anesthetized, mechanically ventilated ewes received 1.5 g/kg body weight of feces into the abdominal cavity to induce sepsis. Animals were randomized into three groups (each n = 8): NE-only, BYK-only, and NE + BYK. The sublingual microcirculation was evaluated with sidestream dark-field videomicroscopy. MAP was higher in the NE + BYK group than in the other groups, but there were no significant differences in cardiac index or systemic vascular resistance. Mean pulmonary arterial pressure was lower in BYK-treated animals than in the NE-only group. PaO2/FiO2 was higher and lactate concentration lower in the BYK groups than in the NE-only group. Mesenteric blood flow was higher in BYK groups than in the NE-only group. Renal blood flow was higher in the NE + BYK group than in the other groups. Functional capillary density and proportion of perfused vessels were higher in the BYK groups than in the NE-only group 18 h after induction of peritonitis. Survival times were similar in the three groups. In this model of peritonitis, selective iNOS inhibition had more beneficial effects than NE on pulmonary artery pressures, gas exchange, mesenteric blood flow, microcirculation, and lactate concentration. Combination of this selective iNOS inhibitor with NE allowed a higher arterial pressure and renal blood flow to be maintained.
AuthorsFuhong Su, Hongchuan Huang, Kazuki Akieda, Giovanna Occhipinti, Katia Donadello, Michael Piagnerelli, Daniel De Backer, Jean-Louis Vincent
JournalShock (Augusta, Ga.) (Shock) Vol. 34 Issue 3 Pg. 243-9 (Sep 2010) ISSN: 1540-0514 [Electronic] United States
PMID20160666 (Publication Type: Comparative Study, Journal Article)
Chemical References
  • 2-(2-(4-methoxypyridin-2-yl)ethyl)-3H-imidazo(4,5-b)pyridine
  • Imidazoles
  • Lactates
  • Pyridines
  • Nitric Oxide Synthase Type II
  • Norepinephrine
Topics
  • Animals
  • Drug Evaluation, Preclinical
  • Female
  • Imidazoles (therapeutic use)
  • Lactates (blood)
  • Microcirculation (drug effects)
  • Models, Animal
  • Mouth Floor (blood supply)
  • Nitric Oxide Synthase Type II (antagonists & inhibitors)
  • Norepinephrine (therapeutic use)
  • Peritonitis (complications)
  • Pulmonary Gas Exchange (drug effects)
  • Pulmonary Wedge Pressure (drug effects)
  • Pyridines (therapeutic use)
  • Random Allocation
  • Renal Circulation (drug effects)
  • Sheep
  • Shock, Septic (drug therapy, enzymology, etiology, physiopathology)
  • Splanchnic Circulation (drug effects)

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