Role of inducible nitric oxide synthase and cyclooxygenase-2 in endotoxin-induced cerebral hyperemia
H Okamoto, O Ito, RJ Roman, AG Hudetz - Stroke, 1998 - Am Heart Assoc
H Okamoto, O Ito, RJ Roman, AG Hudetz
Stroke, 1998•Am Heart AssocBackground and Purpose—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 …
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 …
Background and Purpose—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.
Am Heart Assoc