title: Role of endogenous nitric oxide in endotoxin-induced alteration of hypoxic pulmonary vasoconstriction in mice.
abstract: 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.
authors.affiliation: Department of Anaesthesiology, Ruprecht-Karls-University, Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Spöhr
authors.forename: Annemiek J M
authors.initials: AJ
authors.lastname: Cornelissen
authors.forename: Cornelius
authors.initials: C
authors.lastname: Busch
authors.forename: Martha M
authors.initials: MM
authors.lastname: Gebhard
authors.forename: Johann
authors.initials: J
authors.lastname: Motsch
authors.forename: Eike O
authors.initials: EO
authors.lastname: Martin
authors.forename: Jörg
authors.initials: J
authors.lastname: Weimann
mesh_terms: D000818:Animals; D004731:Endotoxins / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000037:antagonists & inhibitors; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000172:deficiency; D052247:Nitric Oxide Synthase Type II; D011652:Pulmonary Circulation / Q000187:drug effects*; D012119:Respiration / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D004731:Endotoxins; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C090663:N(6)-(1-iminoethyl)lysine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D008239:Lysine; D019331:NG-Nitroarginine Methyl Ester