icatibant and Endotoxemia

Previous studies have shown that an intravenous infusion of dextran sulfate (DXS) causes arterial hypotension via release of bradykinin (BK) and stimulation of bradykinin B2 receptors in pigs. The bradykinin B1 receptor is not physiologically present but its expression can be induced by bacterial lipopolysaccharide (LPS). This study was designed to assess the relative roles of bradykinin B2 and B1 receptors in the hypotensive response produced by DXS in LPS-treated pigs. In LPS-treated pigs a continuous infusion of DXS produced a progressive drop in blood pressure that peaked at approximately 30 min after onset of the infusion and returned to baseline after another 30 min. In animals receiving the selective B2 receptor antagonist Hoe-140 a significant attenuation of the peak fall in blood pressure to DXS was observed. In pigs treated with Hoe-140 and the selective B1 receptor antagonist CP-0298 (Lys(0)-Leu(8)-des-Arg(9)-bradykinin) DXS infusion had no effect on blood pressure. This is the first demonstration in vivo that following activation of the contact system both B2 and B1 receptors are involved in the resulting hypotensive response. This would be consistent with the production of BK (which stimulates B2 receptors) that is subsequently converted to the biologically active metabolite des-Arg(9)-BK in sufficient concentrations to activate B 1 receptors. The significance of these observations to pathophysiology remains to be determined.

Topics: Adrenergic beta-Antagonists; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Dextran Sulfate; Endotoxemia; Hypotension; Lipopolysaccharides; Receptor, Bradykinin B1; Receptor, Bradykinin B2; Receptors, Bradykinin; Swine; Up-Regulation