title: Cyclooxygenase inhibitors attenuate bradykinin-induced vasoconstriction in septic isolated rat lungs.
abstract: Cyclooxygenase (COX) products play an important role in modulating sepsis and subsequent endothelial injury. We hypothesized that COX inhibitors may attenuate endothelial dysfunction during sepsis, as measured by receptor-mediated bradykinin (BK)-induced vasoconstriction and/or receptor-independent hypoxic pulmonary vasoconstriction (HPV). Rats were administered intraperitoneally a nonselective COX inhibitor (indomethacin, 5 or 10 mg/kg) or a selective COX-2 inhibitor (NS-398, 4 or 8 mg/kg) 1 h before lipopolysaccharide (LPS, 15 mg/kg), or saline (control). Three hours later, the rats were anesthetized, the lungs were isolated, and pulmonary vasoreactivity was assessed with BK (0.3, 1.0, and 3.0 microg) and HPV (3% O(2)). Perfusion pressure was monitored as an index of vasoconstriction. To investigate what receptor-subtype is mediating BK responses, the BK(1)-receptor antagonist des-Arg(9)-[Leu(8)]-BK, the BK(2)-receptor antagonist HOE-140, or the thromboxane A(2)-receptor antagonist SQ 29548 (all at 1 microM) were added to the perfusate. BK-induced vasoconstriction was significantly increased in LPS lungs (1.4-5.2 mm Hg) compared with control (0.1-1.1 mm Hg). In LPS lungs, indomethacin 10 mg/kg significantly decreased BK vasoconstriction by 78% +/- 9%, whereas 5 mg/kg did not. NS-398, 4 mg/kg, significantly attenuated BK vasoconstriction at 0.3 microg (71% +/- 7%) and 1.0 microg (56% +/- 12%), whereas 8 mg/kg attenuated 0.3 microg BK (57% +/- 14%), compared with LPS lungs. HPV was increased in LPS lungs (21.5 +/- 2 mm Hg) compared with control lungs (9.8 +/- 0.6 mm Hg). Indomethacin 5 mg/kg increased HPV in LPS lungs; otherwise, HPV was not altered by COX inhibition. BK-induced vasoconstriction was prevented by BK(2), but not BK(1) or thromboxane A(2)-receptor antagonism. This study suggests that nonselective COX inhibition, and possibly inhibition of the inducible isoform COX-2, may attenuate sepsis-induced, receptor-mediated vasoconstriction in rats.
  
  
  CONCLUSIONS
  This study demonstrated that, in an isolated rat lung model, nonselective inhibition of the cyclooxygenase pathway, and possibly selective inhibition of the inducible cyclooxygenase-2 isoform, may attenuate sepsis-induced endothelial dysfunction.
authors.affiliation: Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Westfälische-Wilhelms-Universität Münster, Germany.
authors.forename: L G
authors.initials: LG
authors.lastname: Fischer
authors.forename: M W
authors.initials: MW
authors.lastname: Hollmann
authors.forename: D J
authors.initials: DJ
authors.lastname: Horstman
authors.forename: G F
authors.initials: GF
authors.lastname: Rich
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000502:physiology; D018805:Sepsis / Q000503:physiopathology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D008070:Lipopolysaccharides; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; D009569:Nitric Oxide; C065679:icatibant; C045749:SQ 29548; D001920:Bradykinin