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Protection against lipopolysaccharide‐induced endothelial dysfunction in resistance and conduit vasculature of iNOS knockout mice
Author(s) -
Chauhan Sharmila D.,
Seggara Gloria,
Vo Phuong A.,
Macallister Raymond J.,
Hobbs Adrian J.,
Ahluwalia Amrita
Publication year - 2003
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/fj.02-0668fje
Subject(s) - endothelial dysfunction , mesenteric arteries , aorta , lipopolysaccharide , nitric oxide synthase , medicine , nitric oxide , endocrinology , enos , inflammation , endothelium , chemistry , artery
Endothelial dysfunction is a characteristic of, and may be pathogenic in, inflammatory cardiovascular diseases, including sepsis. The mechanism underlying inflammation‐induced endothelial dysfunction may be related to the expression and activity of inducible nitric oxide synthase (iNOS). This possibility was investigated in isolated resistance (mesenteric) and conduit (aorta) arteries taken from lipopolysaccharide (LPS)‐treated (12.5 mg/kg i.v.) or saline‐treated iNOS knockout (KO) and wild‐type (WT) mice. LPS pretreatment (for 15 h, but not 4 h) profoundly suppressed responses to acetylcholine (ACh) and significantly reduced sensitivity to the NO donor spermine‐NONOate (SPER‐NO) in aorta and mesenteric arteries of WT mice. This effect was temporally associated with iNOS protein expression in both conduit and resistance arteries and with a 10‐fold increase in plasma NO x levels. In contrast, no elevation of plasma NO x was observed in LPS‐treated iNOS KO animals, and arteries dissected from these animals did not express iNOS or display hyporeactivity to ACh or SPER‐NO. The mechanism underlying this phenomenon may be suppression of eNOS expression, as observed in arteries of WT animals, that was absent in arteries of iNOS KO animals. These results clearly demonstrate that iNOS induction plays an integral role in mediation of the endothelial dysfunction associated with sepsis in both resistance and conduit arteries.