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(Circulation Research. 2000;87:e18.)
© 2000 American Heart Association, Inc.

UltraRapid Communication

iNOS Gene Expression Modulates Microvascular Responsiveness in Endotoxin-Challenged Mice

Presented in abstract form at the 32nd annual meeting of the Association for Academic Surgery, Seattle, Wash, November 19–22, 1998.

Walter A. Boyle, III, Lakshmi S. Parvathaneni, Virginie Bourlier, Craig Sauter, Victor E. Laubach, J. Perren Cobb

From the Departments of Anesthesiology (Anesthesiology Research Unit) (W.A.B., L.S.P., V.B., C.S.), Surgery (Cellular Injury and Adaptation Laboratory) (L.S.P., J.P.C.), and Molecular Biology and Pharmacology (W.A.B.), Washington University School of Medicine, St. Louis, Mo; and the Department of Surgery (V.E.L.), University of Virginia Health Sciences Center, Charlottesville, Va.

Correspondence to Dr Walter A. Boyle, Washington University School of Medicine, Box 8054, 660 S Euclid Ave, St. Louis, MO 63110. E-mail boylew{at}notes.wustl.edu

Abstract—Septic shock is characterized by vasodilation and decreased responsiveness to vasoconstrictors. Recent studies suggest this results from nitric oxide (NO) overproduction after expression of the calcium-independent isoform of NO synthase (iNOS) in smooth muscle cells. However, direct evidence linking iNOS (NOS2) expression and decreased microvascular responsiveness after septic stimuli is lacking. In the present study, we determined the effect of bacterial lipopolysaccharide (LPS, 20 mg/kg, IP) on smooth muscle contraction and endothelial relaxation in mesenteric resistance arteries from wild-type and iNOS knockout mice. Four hours after challenge with LPS or saline in vivo, concentration-dependent responses to norepinephrine (NE) and acetylcholine (NE+ACh) were measured in cannulated, pressurized vessels ex vivo. In vessels from wild-type mice, NE-induced contraction was markedly impaired after LPS, and pretreatment with the iNOS inhibitor aminoguanidine (AG) partly restored the NE contraction. In contrast, NE contraction in microvessels from iNOS knockout mice was unaffected by LPS. ACh-induced relaxation was unaffected by LPS in vessels from either genotype. These data provide direct evidence that iNOS gene expression mediates the LPS-induced decrease in microvascular responsiveness to vasoconstrictors. Moreover, the observation that AG did not fully restore NE contraction after LPS, whereas iNOS gene deficiency did, suggests that iNOS expression plays a central role in the development of the NO-independent effect of LPS on microvascular responsiveness. Finally, our data indicate that LPS or iNOS expression has little effect on endothelium-dependent relaxation, and eNOS activity does not appear to play a role in the decreased smooth muscle responsiveness after LPS in this model. The full text of this article is available at http://www.circresaha.org.

Key Words: transgenic mice • inducible nitric oxide synthase • microvascular • lipopolysaccharide • sepsis