ENDOGENOUS B-1 RECEPTOR-MEDIATED HYPOTENSION PRODUCED BY CONTACT SYSTEM ACTIVATION IN THE PRESENCE OF ENDOTOXEMIA

Previous studies have shown that an intravenous infusion of dextran su lfate (DXS) causes arterial hypotension via release of bradykinin (BK) and stimulation of bradykinin B-2 receptors in pigs. The bradykinin B -1 receptor is not physiologically present but its expression can be i nduced by bacterial lipopolysaccharide (LPS). This study was designed to assess the relative roles of bradykinin B-2 and B-1 receptors in th e hypotensive response produced by DXS in LPS-treated pigs. In LPS-tre ated 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 rec eiving the selective B-2 receptor antagonist Hoe-140 a significant att enuation of the peak fall in blood pressure to DXS was observed. In pi gs treated with Hoe-140 and the selective B-1 receptor antagonist CP-0 298 (Lys(0)-Leu(8)-des-Arg(9)-bradykinin) DXS infusion had no effect o n blood pressure. This is the first demonstration in vivo that followi ng activation of the contact system both B-2 and B-1 receptors are inv olved in the resulting hypotensive response. This would be consistent with the production of BK (which stimulates B-2 receptors) that is sub sequently converted to the biologically active metabolite des-Arg(9)-B K in sufficient concentrations to activate B1 receptors. The significa nce of these observations to pathophysiology remains to be determined. (C) 1998 Elsevier Science B.V. All rights reserved.