DEXTRAN SULFATE ACTIVATES CONTACT SYSTEM AND MEDIATES ARTERIAL-HYPOTENSION VIA B-2 KININ RECEPTORS

To define some of the mechanisms underlying dextran sulfate (DXS)-indu ced hypotension, we investigated the effects of either the plasma kall ikrein inhibitor des-Pro(2)-[Arg(15)] aprotinin (BAY x 4620) or the sp ecific bradykinin B-2-receptor antagonist Hoe-140 on the hypotensive r esponse to DXS. In the first study, anesthetized miniature pigs were g iven DXS alone, DXS plus BAY x 4620 in various doses, or saline. As ex pected, DXS alone produced a profound but transient systemic arterial hypotension with a concomitant reduction in kininogen. Circulating kin in levels, complement fragment des-Arg-C3a, and fibrin monomer were al l increased. Treatment with BAY x 4620 produced a dose-dependent atten uation of these effects with complete blockade of the hypotension as w ell as the observed biochemical changes at the highest dose (360 mg). In a second study, two groups of pigs were given either DXS alone or D XS plus Hoe-140. DXS-induced hypotension was completely blocked by Hoe -140 pretreatment; however, kininogen was again depleted. We conclude, therefore, that DXS-induced hypotension is produced by activation of plasma kallikrein that results in the production of bradykinin and tha t liberation of bradykinin and its action on B-2 receptors in the vasc ulature are both necessary and sufficient to produce the observed effe cts on circulatory pressure.