Bradykinin B2 receptor involvement in rabbit and murine models of septic shock.

Abstract

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.