Dextran sulfate activates contact system and mediates arterial hypotension via B2 kinin receptors

To define some of the mechanisms underlying dextran sulfate
(DXS)-induced hypotension, we investigated the effects of either
the plasma kallikrein inhibitor des-Pro2-[Arg15] aprotinin (BAY x
4620) or the specific bradykinin B2-receptor antagonist Hoe-140 on
the hypotensive response to DXS. In the first study, anesthetized
miniature pigs were given DXS alone, DXS plus BAY x 4620 in various
doses, or saline. As expected, DXS alone produced a profound but
transient systemic arterial hypotension with a concomitant
reduction in kininogen. Circulating kinin levels, complement
fragment des-Arg-C3a, and fibrin monomer were all increased.
Treatment with BAY x 4620 produced a dose-dependent attenuation of
these effects with complete blockade of the hypotension as well 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 DXS
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 that liberation of bradykinin and its action on B2
receptors in the vasculature are both necessary and sufficient to
produce the observed effects on circulatory pressure.