Selective inducible nitric oxide inhibition can restore hemodynamics, but does not improve neurological dysfunction in experimentally-induced septic shock in rats.
In this study, we evaluated the time course of changes in inducible nitric oxide synthase (iNOS) in the brain by using the rat model of sepsis induced by cecal ligation and puncture (CLP) and examined whether selective iNOS inhibition can prevent the hemodynamic and neurological changes induced by sepsis. Male Wistar rats were randomly divided into four groups: control, sham, CLP, and CLP + the selective iNOS inhibitor L-N6-(1-iminoethyl)-lysine (L-NIL). Septic shock was induced in the rats by CLP under pentobarbital anesthesia, and then we measured hemodynamic variables, neurological indicators, blood gases, plasma levels of nitrate/nitrite (an indicator of the biosynthesis of NO), and brain iNOS activity and nitrotyrosine levels after 1, 6, 12, and 24 h. Plasma nitrite was increased at 12 and 24 h in the CLP group. The activity of iNOS in the brain was increased at 12 and 24 h after CLP (at 12 h: control, 0.3 +/- 0.05; sham, 0.3 +/- 0.1; CLP, 1.3 +/- 0.08*; CLP + L-NIL, 0.33 +/- 0.1 fmol x mg(-1) x min(-1); at 24 h: control, 0.27 +/- 0.08; sham, 0.31 +/- 0.1; CLP, 1.0 +/- 0.3*; CLP + L-NIL, 0.34 +/- 0.1 fmol x mg(-1) x min(-1); mean +/- SD; *P < 0.05). Brain nitrotyrosine was increased at 24 h after CLP (at 24 h: control, 6.7 +/- 0.4; sham, 6.7 +/- 0.5; CLP, 11.2 +/- 2.8*; CLP + L-NIL, 7.52 +/- 0.5 densitometric units; means +/- SD; *P < 0.01). In contrast, in both the CLP and CLP + L-NIL groups, the consciousness reflex was significantly decreased at 24 h after CLP. Selective iNOS inhibition restored the hemodynamic changes induced by sepsis but could not improve neurological dysfunction.
Kadoi
Yuji
Y
*Department of Intensive Care, Gunma University, School of Medicine, Gunma, Japan; and †Department of Anesthesiology, Gunma University, Graduate School of Medicine, Gunma, Japan.
Goto
Fumio
F
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002118:Calcium / Q000502:physiology; D002432:Cecum / Q000293:injuries / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007375:Interleukin-1 / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D008297:Male; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000209:etiology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000150:complications* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
D004791:Enzyme Inhibitors; D007375:Interleukin-1; C090663:N(6)-(1-iminoethyl)lysine; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008239:Lysine; D002118:Calcium