Role of Inducible Nitric Oxide Synthase and Cyclooxygenase-2 in Endotoxin-Induced Cerebral Hyperemia

Abstract

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. (Stroke. 1998;29:1209-1218.)

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

“…The NO produced in endothelial cells activates COX to produce more eicosanoids (129,130). In many models of inflammation, there is a concommitant induction of both NOS-2 and COX-2, such as after intracerebroventricular injections of lipopolysaccharide (131) or cerebral ischemia (132), and the NO produced influences the COX-2 activity. NO also facilitates the induction of COX-2 by IL-1 (133).…”

Intracisternal Application of Endotoxin Enhances the Susceptibility to Subsequent Hypoxic-Ischemic Brain Damage in Neonatal Rats

“…In the present study, we did not measure body temperature in the rat pups, because this is extremely difficult to do in such small animals. However, in experiments on adult animals, fever has not been reported after intracerebroventricular administration of LPS (19,20). The experimental protocols were approved by the appropriate institutional review committee and met the guidelines of the governmental agency responsible.…”

Lipopolysaccharide-Induced Increase of Prostaglandin E2 Is Mediated by Inducible Nitric Oxide Synthase Activation of the Constitutive Cyclooxygenase and Induction of Membrane-Associated Prostaglandin E Synthase

“…Interestingly, PGE 2 was shown to synergize with NO in mediating LPS-induced cerebral hyperemia (14), whereas the vasoconstrictor thromboxane antagonizes NO-mediated vasodilation (15). Several in vitro reports have suggested that NO activates COX activity, but these observations are still controversial, and in vivo data are scarce (for a recent review, see Ref.…”