icatibant and Shock--Septic

The purpose of our work was to evaluate the role of bradykinin B2 receptors in the early phase (first 3 h) of bacterial lipopolysaccharide (LPS)-induced shock in anesthetized and mechanically ventilated rabbits and to determine if HOE 140, a specific, potent, and long-acting bradykinin B2-receptor antagonist, could improve survival in two murine models of septic shock. In rabbits, LPS injection induced rapid hypotension associated with metabolic acidosis. Three hours after the injection of LPS, we observed leukopenia, thrombocytopenia, and a moderate increase in arterial blood cyclic GMP. The injection-of HOE 140 [1.7-mumol/kg bolus intravenously (i.v.) 20 min before LPS] inhibited the decrease in blood pressure, but did not influence any of the other parameters studied. Mice were subjected to intraperitoneal (i.p.) injection of LPS, which induced almost 100% mortality in the 4 days after the injection. Pretreatment with HOE 140 (1 mg/kg i.p.) 30 min before the LPS injection and 4, 8, and 24 h afterward the injection did not improve survival at any given time during the 4 days of the study. Cecal ligation and puncture in mice induced a mortality rate > 90% in < or = 10 days. HOE 140 (1 mg/kg i.v.) given 30 min before cecal ligation did not significantly improve the survival rate. In contrast with previous reports, in the present study in a rabbit model of endotoxic shock (early phase) and in two murine models of septic shock, the involvement of bradykinin B2 receptors appeared to be minimal.

Topics: Adrenergic beta-Antagonists; Animals; Bradykinin; Cecum; Ligation; Lipopolysaccharides; Male; Mice; Punctures; Rabbits; Receptors, Bradykinin; Shock, Septic

The involvement of bradykinin and nitric oxide (NO) in the early (within 1 h) hemodynamic effects of bacterial lipopolysaccharide (LPS) were investigated in anaesthetised rats. Infusion of rats with LPS (14 mg/kg/h) produced a transient hypotension (nadir at 20 min) and reduced pressor responses to noradrenaline (NA,.1-1 microgram/kg, intravenously (i.v.)). Pretreatment of rats with NG-nitro-L-arginine methylester (L-NAME, 1 mg/kg, i.v.) produced a hypertension which counteracted but did not abolish the hypotension induced by LPS, although it entirely prevented LPS-induced hyporeactivity to NA. In control rats, the bradykinin B2 receptors antagonist HOE 140 (10 nmol/kg, i.v.) produced a transient hypotension, but it did not modify the reactivity to NA. In rats pretreated with HOE 140, subsequently infused with LPS, the drop in blood pressure and its time course after the onset of LPS infusion were not different from those elicited by HOE 140 or LPS separately. In addition, HOE 140 partially prevented the onset of hyporesponsiveness to NA induced by LPS. These results support the view that both bradykinin and NO are involved in the early hyporesponsiveness to NA. They suggest that other mechanisms than NO release are involved in the early hypotensive effects of LPS.

Topics: Animals; Arginine; Bradykinin; Bradykinin Receptor Antagonists; Hemodynamics; Hypotension; Lipopolysaccharides; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Norepinephrine; Rats; Rats, Wistar; Receptor, Bradykinin B2; Shock, Septic

Topics: Amino Acid Sequence; Animals; Bradykinin; Humans; Kinins; Molecular Sequence Data; Oligopeptides; Peptides; Shock, Septic