From the Departments of Anesthesiology (H.O., A.G.H.) and Physiology
(O.I., R.J.R., A.G.H.), Medical College of Wisconsin, Milwaukee, Wis.
Correspondence to Dr Antal G. Hudetz, Department of Anesthesiology, MEB Room 462C, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226. E-mail ahudetz{at}mcw.edu
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.
Department
of Anesthesiology,
Baylor College of Medicine,
Houston, Texas
© 1998 American Heart Association, Inc.
Original Contributions
Role of Inducible Nitric Oxide Synthase and Cyclooxygenase-2 in Endotoxin-Induced Cerebral Hyperemia
Editorial Comment
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