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This Article Full Text Full Text (PDF) All Versions of this Article: 289/2/H823    most recent 00605.2004v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Spöhr, F. Articles by Weimann, J. Search for Related Content PubMed PubMed Citation Articles by Spöhr, F. Articles by Weimann, J.

Role of endogenous nitric oxide in endotoxin-induced alteration of hypoxic pulmonary vasoconstriction in mice

¹Department of Anaesthesiology, Ruprecht-Karls-University, Heidelberg; ²Institute of Physiology, Charité-Berlin Medical School, Campus Benjamin Franklin, Berlin; ³Institute of Experimental Surgery, Ruprecht-Karls-University, Heidelberg; and ⁴Department of Anaesthesiology and Intensive Care Medicine, Charité-Berlin Medical School, Campus Benjamin Franklin, Berlin, Germany

Submitted 17 June 2004 ; accepted in final form 17 March 2005

Pulmonary vasoconstriction in response to alveolar hypoxia (HPV) is frequently impaired in patients with sepsis or acute respiratory distress syndrome or in animal models of endotoxemia. Pulmonary vasodilation due to overproduction of nitric oxide (NO) by NO synthase 2 (NOS2) may be responsible for this impaired HPV after administration of endotoxin (LPS). We investigated the effects of acute nonspecific (N^G-nitro-L-arginine methyl ester, L-NAME) and NOS2-specific [L-N⁶-(1-iminoethyl)lysine, L-NIL] NOS inhibition and congenital deficiency of NOS2 on impaired HPV during endotoxemia. The pulmonary vasoconstrictor response and pulmonary vascular pressure-flow (P-Q) relationship during normoxia and hypoxia were studied in isolated, perfused, and ventilated lungs from LPS-pretreated and untreated wild-type and NOS2-deficient mice with and without L-NAME or L-NIL added to the perfusate. Compared with lungs from untreated mice, lungs from LPS-challenged wild-type mice constricted less in response to hypoxia (69 ± 17 vs. 3 ± 7%, respectively, P < 0.001). Perfusion with L-NAME or L-NIL restored this blunted HPV response only in part. In contrast, LPS administration did not impair the vasoconstrictor response to hypoxia in NOS2-deficient mice. Analysis of the pulmonary vascular P-Q relationship suggested that the HPV response may consist of different components that are specifically NOS isoform modulated in untreated and LPS-treated mice. These results demonstrate in a murine model of endotoxemia that NOS2-derived NO production is critical for LPS-mediated development of impaired HPV. Furthermore, impaired HPV during endotoxemia may be at least in part mediated by mechanisms other than simply pulmonary vasodilation by NOS2-derived NO overproduction.

gene deletion; lipopolysaccharide; pulmonary circulation; pulmonary vascular pressure-flow relationship; distensible vessel model

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