Role of inducible nitric oxide synthase and cyclooxygenase-2 in endotoxin-induced cerebral hyperemia.
OBJECTIVE
Bacterial lipopolysaccharide (LPS), an endotoxin, has been reported to induce the expression of inducible isoforms of both nitric oxide synthase (iNOS) and cyclooxygenase (COX-2) in various cell types. LPS is also known to dilate systemic vasculature, including cerebral vessels. This study aimed to determine to what extent LPS induces iNOS and COX-2 expression in the brain and whether NO and/or cyclooxygenase metabolites derived from iNOS and/or COX-2 contribute to the LPS-induced cerebral hyperemia.


METHODS
Regional cerebral blood flow (rCBF) was measured by laser-Doppler flowmetry in halothane-anesthetized, artificially ventilated rats for 4 hours after intracerebroventricular administration of LPS.


RESULTS
LPS at doses of 0.01 mg/kg to 1 mg/kg caused dose-dependent, progressive increases in rCBF at 1 to 4 hours after administration. The increase in rCBF was attenuated by systemic administration of the selective iNOS inhibitor aminoguanidine (100 mg/kg IP) or the selective COX-2 inhibitor NS-398 (5 mg/kg IP), and it was abolished by preventing induction of these isoforms with dexamethasone (4 mg/kg IP). LPS significantly increased iNOS and COX-2 mRNA, iNOS protein, and iNOS and cyclooxygenase enzyme activity. The increases in iNOS and cyclooxygenase enzyme activity were eliminated by aminoguanidine and NS-398, respectively. Dexamethasone also prevented the increase in iNOS and cyclooxygenase activity.


CONCLUSIONS
These results indicate that induction of iNOS and COX-2 expression and the increased production of NO and vasodilator prostanoids in the brain contribute to the elevation in CBF after intracerebroventricular administration of LPS.
Okamoto
H
H
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Ito
O
O
Roman
R J
RJ
Hudetz
A G
AG
D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000201:enzymology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006339:Heart Rate; D006940:Hyperemia / Q000201:enzymology*; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017078:Laser-Doppler Flowmetry; D008070:Lipopolysaccharides; D008297:Male; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley
D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases