Despite aggressive medical and surgical therapy, septic shock continues to be the most common cause of morbidity and mortality in the intensive care unit. One common sequelae of septic shock is the development of systemic inflammation and resultant multiple organ dysfunction. Abundant evidence supports a prominent role for bradykinins in this inflammatory response. The kallikrein-kininogen- kinin system is activated by the administration of lipopolysaccharide (LPS). In addition, the administration of exogenous bradykinin reproduces the hemodynamic abnormalities of sepsis. These observations suggest that bradykinin inhibition may represent a novel strategy for the treatment of septic shock. A number of bradykinin antagonists of varying selectivities have been developed. Administration of these antagonists in rodent models have been demonstrated to mitigate the hypotension, leukopenia, and increases in circulating tumor necrosis factor levels induced by LPS administration. In addition, the bradykinin antagonist NPC 15669, in conjunction with antibiotics, has been demonstrated to improve outcome in a rodent fecal peritonitis model. We have developed a canine peritonitis model of septic shock which simulates the cardiovascular and hemodynamic abnormalities encountered in humans. This has become a useful model for evaluating novel therapies in sepsis. Scios Nova Inc. (Mountain View, CA) has a selective bradykinin antagonist. We will apply this agent in our canine model in order to assess its effect on the hemodynamic, cardiovascular, and biochemical derangements of sepsis. This will provide critical information as to whether this therapy should go on to be studied in humans with septic shock.
