title: The role of bradykinin and the effect of the bradykinin receptor antagonist icatibant in porcine sepsis.
abstract: Bradykinin (BK) is regarded as an important mediator of edema, shock, and inflammation during sepsis. In this study, we evaluated the contribution of BK in porcine sepsis by blocking BK and by measuring the stable BK metabolite, BK1-5, using anesthetized pigs. The effect of BK alone, the efficacy of icatibant to block this effect, and the recovery of BK measured as plasma BK1-5 were first investigated. Purified BK injected intravenously induced an abrupt fall in blood pressure, which was completely prevented by pretreatment with icatibant. BK1-5 was detected in plasma corresponding to the doses given. The effect of icatibant was then investigated in an established model of porcine gram-negative sepsis. Neisseria meningitidis was infused intravenously without any pretreatment (n = 8) or pretreated with icatibant (n = 8). Negative controls received saline only. Icatibant-treated pigs developed the same degree of severe sepsis as did the controls. Both groups had massive capillary leakage, leukopenia, and excessive cytokine release. The plasma level of BK1-5 was low or nondetectable in all pigs. The latter observation was confirmed in supplementary studies with pigs undergoing Escherichia coli or polymicrobial sepsis induced by cecal ligation and puncture. In conclusion, icatibant completely blocked the hemodynamic effects of BK but had no beneficial effects on N. meningitidis-induced edema, shock, and inflammation. This and the fact that plasma BK1-5 in all the septic pigs was virtually nondetectable question the role of BK as an important mediator of porcine sepsis. Thus, the data challenge the current view of the role of BK also in human sepsis.
authors.affiliation: Institute of Immunology, Rikshospitalet University Hospital, University of Oslo, Norway.
authors.forename: Andreas
authors.initials: A
authors.lastname: Barratt-Due
authors.forename: Harald Thidemann
authors.initials: HT
authors.lastname: Johansen
authors.forename: Andrey
authors.initials: A
authors.lastname: Sokolov
authors.forename: Ebbe Billmann
authors.initials: EB
authors.lastname: Thorgersen
authors.forename: Bernt Christian
authors.initials: BC
authors.lastname: Hellerud
authors.forename: Jan Leo
authors.initials: JL
authors.lastname: Reubsaet
authors.forename: Knut Fredrik
authors.initials: KF
authors.lastname: Seip
authors.forename: Tor Inge
authors.initials: TI
authors.lastname: Tønnessen
authors.forename: Julie Katrine
authors.initials: JK
authors.lastname: Lindstad
authors.forename: Anne
authors.initials: A
authors.lastname: Pharo
authors.forename: Albert
authors.initials: A
authors.lastname: Castellheim
authors.forename: Tom Eirik
authors.initials: TE
authors.lastname: Mollnes
authors.forename: Erik Waage
authors.initials: EW
authors.lastname: Nielsen
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D065168:Bradykinin Receptor Antagonists; D004487:Edema / Q000188:drug therapy / Q000382:microbiology; D007249:Inflammation / Q000188:drug therapy / Q000382:microbiology; D009345:Neisseria meningitidis / Q000472:pathogenicity; D018805:Sepsis / Q000188:drug therapy / Q000378:metabolism*; D012769:Shock / Q000188:drug therapy / Q000382:microbiology; D013552:Swine
chemical_list: D065168:Bradykinin Receptor Antagonists; C065679:icatibant; D001920:Bradykinin