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Protective Effects of NOS and/or sGC Inhibitors Combined with Antioxidant in LPS‐Induced Organ Dysfunction
Author(s) -
Doursout MarieFrancoise,
Liang Yang Yan,
Sharina Iraida,
Sharin Vladislav G.,
Murad Ferid
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.912.23
Subject(s) - nitrotyrosine , nitric oxide , antioxidant , pharmacology , peroxynitrite , reactive oxygen species , chemistry , proinflammatory cytokine , septic shock , lipopolysaccharide , reactive nitrogen species , shock (circulatory) , nitric oxide synthase , acetylcysteine , pathophysiology , sepsis , biochemistry , medicine , inflammation , superoxide , enzyme , organic chemistry
Overproduction of nitric oxide (NO) has been described in the pathophysiology of septic shock. Among LPS‐induced proinflammatory metabolites, reactive oxygen species (ROS) are considered to play a crucial pathogenetic role in the tissue injury that can lead to organ failure. Our study was designed to counteract the effects of LPS‐induced hypotension using N‐methyl‐L‐arginine (L‐NMA), an inhibitor of NO production and/or ODQ, a specific inhibitor of sGC activity in the presence and absence of N‐acetylcysteine (NAC) in LPS‐treated rats. Group 1 (n=6) received LPS alone (20 mg/kg IV), whereas Group 2 (n=12) received LPS+L‐NMA (20 mg/kg IV), Group 3 (n=12) received LPS+ODQ, and Group 4 (n=12) received LPS + L‐NMA/ODQ in the presence and absence of NAC. Cardiovascular parameters, NO production, cellular antioxidant capacity and nitrotyrosine formation, as a molecular marker of ROS/RNS were recorded for 24 hrs. Our preliminary data show that LPS induces a cardiac depression associated with iNOS expression leading to increases in nitrate production and nitrotyrosine formation. Combined treatment of L‐NMA/ODQ abolished LPS‐induced hypotension, whereas NAC significantly decreased nitrotyrosine formation. These results indicate that LPS‐detrimental cardiovascular effects can be attenuated by early treatment, e.g. combined NOS and sGC inhibition in the presence of antioxidant.