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
This article has been cited by other articles:
 |
|
 |
|
  S. Y. S. Feng, D. J. Phillips, E. M. Stockx, V. Y. H. Yu, and A. M. Walker Endotoxin has acute and chronic effects on the cerebral circulation of fetal sheep Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2009; 296(3): R640 - R650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Wood and D. Giroux Expression of Nitric Oxide Synthase Isoforms in the Ovine Fetal Brain: Alteration by Hormonal and Hemodynamic Stimuli Reproductive Sciences, July 1, 2006; 13(5): 329 - 337. [Abstract] [PDF]
|
|
|
|
 |
|
 R. Hernanz, A. M. Briones, M. J. Alonso, E. Vila, and M. Salaices Hypertension alters role of iNOS, COX-2, and oxidative stress in bradykinin relaxation impairment after LPS in rat cerebral arteries Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H225 - H234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Ospina, H. N. Brevig, D. N. Krause, and S. P. Duckles Estrogen suppresses IL-1{beta}-mediated induction of COX-2 pathway in rat cerebral blood vessels Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H2010 - H2019. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Johnston, M. R. Van Scott, C. Kommineni, L. L. Millecchia, J. Dortch-Carnes, and J. S. Fedan Hyperosmolar Solution Effects in Guinea Pig Airways. IV. Lipopolysaccharide-Induced Alterations in Airway Reactivity and Epithelial Bioelectric Responses to Methacholine and Hyperosmolarity J. Pharmacol. Exp. Ther., January 1, 2004; 308(1): 37 - 46. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-P. Wang, C. Sato, K. Mizoguchi, Y. Yamashita, M. Oe, and H. Maeta Lipopolysaccharide triggers late preconditioning against myocardial infarction via inducible nitric oxide synthase Cardiovasc Res, October 1, 2002; 56(1): 33 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Devaux, C. Seguin, S. Grosjean, N. de Talance, V. Camaeti, A. Burlet, F. Zannad, C. Meistelman, P.-M. Mertes, and D. Longrois 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 J. Immunol., October 1, 2001; 167(7): 3962 - 3971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. A. Gunnett, D. D. Lund, Y. Chu, R. M. Brooks II, F. M. Faraci, and D. D. Heistad NO-Dependent Vasorelaxation Is Impaired After Gene Transfer of Inducible NO-Synthase Arterioscler Thromb Vasc Biol, August 1, 2001; 21(8): 1281 - 1287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Brian Jr., F. M. Faraci, and S. A. Moore COX-2-dependent delayed dilatation of cerebral arterioles in response to bradykinin Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2023 - H2029. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Okamoto, R. J. Roman, J. P. Kampine, and A. G. Hudetz Endotoxin Augments Cerebral Hyperemic Response to Halothane by Inducing Nitric Oxide Synthase and Cyclooxygenase Anesth. Analg., October 1, 2000; 91(4): 896 - 903. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. T. Murray, M. E. Wylam, and J. G. Umans Nitric Oxide and Septic Vascular Dysfunction Anesth. Analg., January 1, 2000; 90(1): 89 - 89. [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. GOODWIN, L. M. LANDINO, and L. J. MARNETT Effects of nitric oxide and nitric oxide-derived species on prostaglandin endoperoxide synthase and prostaglandin biosynthesis FASEB J, July 1, 1999; 13(10): 1121 - 1136. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. E. Brian Jr, S. A. Moore, F. M. Faraci, and H. A. Kontos Expression and Vascular Effects of Cyclooxygenase-2 in Brain • Editorial Comment Stroke, December 1, 1998; 29(12): 2600 - 2606. [Abstract] [Full Text] [PDF]
|
|