HEMODYNAMIC-EFFECTS OF BRADYKININ ANTAGONISM IN PORCINE GRAM-NEGATIVESEPSIS

Activation of the kallikrein-kinin system in sepsis has long been reco gnized, but its role, beneficial or pathologic, has not been defined. Recently, however, specific bradykinin (BK) antagonists have become av ailable and this study investigated the effects of a BK antagonist, NP C17731 (Scios-Nova) on systemic and pulmonary hemodynamics in a model of gram-negative sepsis. Anesthetized swine were studied for 5 h recei ving a 1-h infusion of saline (controls, group 1, N = 8) or live Pseud omonas aeruginosa (septic, group 2, N = 8). Group 3 (treatment, N = 6) received NPC17731 (5 mg/kg initial bolus followed by 1 mg/kg hourly) just prior To the onset of sepsis. Group 2 animals showed a rapid decr ease in systemic arterial pressure (SAP) from 30 min onward, and susta ined significant hypotension from 2 h onward In group 3, SAP fell simi larly until 2 h then progressively rose, returning To baseline levels by 5 h. In contrast, cardiac index fell progressively, from 3 h onward in groups 2 and 3. Systemic vascular resistance index (SVRI) fell sig nificantly by 2 h in group 2 animals, recovering to baseline by 5 h. G roup 3 showed a similar initial fall followed by a rebound increase in SVRI, which, at 5 h was significantly raised above the other groups. Group 2 developed significant, persistent pulmonary artery hypertensio n which was nor reduced by NPC17731. The data imply a significant role for bradykinin in the pathogenesis of hypotension in septic shock in this model. Septic shock was reversed by a BK antagonist which increas ed peripheral resistance without affecting cardiac output. However, NP C17731 exerted no effect on the pulmonary circulation. BK antagonists may play a beneficial role in the armamentarium against septic shock.