title: Bradykinin-induced pulmonary vasoconstriction is time and inducible nitric oxide synthase dependent in a peritonitis sepsis model.
abstract: In an isolated perfused lung model, bradykinin induced pulmonary vasoconstriction in rats made septic by the injection of lipopolysaccharide (LPS). To mimic the pathophysiology of sepsis in humans more closely, we investigated pulmonary endothelial injury in a peritonitis model (cecal ligation and perforation; CLP). Male Sprague-Dawley rats were randomly divided into nine groups (n = 6-8). LPS and CLP rats were compared after 6 h with and without treatment with a selective inhibitor of inducible nitric oxide synthase (iNOS), L-N(6)-(1-iminoethyl)-lysine. Time dependency was investigated in CLP-treated rats at 24 h. The pulmonary circulation was isolated and perfused with a constant flow after the rats' tracheas were intubated and ventilated. Bradykinin (1, 3, and 6 microg) was injected, and changes in perfusion pressure were measured. Lungs were harvested for Western blot analysis to determine the role of iNOS in pulmonary endothelial dysfunction. In contrast to CLP 24 h rats, dose-dependent bradykinin-induced pulmonary vasoconstriction was observed in LPS and CLP 6 h rats. Concomitant administration of L-N(6)-(1-iminoethyl)-lysine significantly attenuated this vasoconstriction in both groups. The iNOS protein was expressed in lung homogenates from LPS 6 h and CLP 6 h but not from CLP 24 h rats. Both sepsis models caused bradykinin-induced pulmonary vasoconstriction, with the CLP groups demonstrating a time dependency of this effect. In conjunction with the time-dependent decrease in iNOS protein, the attenuated bradykinin-induced vasoconstriction due to selective iNOS inhibition suggests an important role for iNOS in pulmonary endothelial injury for both sepsis models.
authors.affiliation: Department of Anesthesiology and Intensive Care, University of Münster, Münster, Germany.
authors.forename: Lars G
authors.initials: LG
authors.lastname: Fischer
authors.forename: Jan H
authors.initials: JH
authors.lastname: Hilpert
authors.forename: Hendrik
authors.initials: H
authors.lastname: Freise
authors.forename: Doreen
authors.initials: D
authors.lastname: Wendholt
authors.forename: Hugo
authors.initials: H
authors.lastname: Van Aken
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Sielenkämper
mesh_terms: D000818:Animals; D001794:Blood Pressure; D001920:Bradykinin / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D008168:Lung / Q000098:blood supply*; D008239:Lysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D010538:Peritonitis / Q000503:physiopathology*; D011652:Pulmonary Circulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000503:physiopathology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: C090663:N(6)-(1-iminoethyl)lysine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008239:Lysine; D001920:Bradykinin