Bradykinin B2-receptor antagonism attenuates fatal cardiocirculatory breakdown induced by severe experimental pancreatitis

Objectives: To investigate the impact of the long-acting bradykinin B₂ receptor antagonist HOE 140 (Icatibant) on survival time in a model of severe porcine pancreatitis. Design: Randomized, controlled intervention trial. Subjects: Thirty domestic pigs of either gender anesthetized by intravenous application of piritramide, midazolam, and pancuronium and mechanically ventilated. Interventions: Pancreatitis was induced by an injection of sodium taurocholate (5%, 1 mL/kg body weight [BW]) and anterokinase (10 U/kg BW). Control animals (group 1, n = 10) underwent the spontaneous course of the disease. In two treatmeat groups, Icatibant was administered either in a low (100 nmol/kg BW; group 2, n = 10) or in a high dosage (5000 nmol/kg BW; group 3, n = 18). Measurements and Main Results: Mean survival time was significantly prolonged by Icatibant (controls, 6.6 hrs; group 2, 9.8 hrs; p = .022; group 3, 19.9 hrs; p = .007). Six hours postinduction, the decline of total peripheral resistance (52% of baseline) and cardiac index (92% of baseline) in controls was significantly improved by Icatibant, both in the low (16% and 44%; p < .05) and high (6% and 45%; p < .05) dosage. The concentrations of free, nonreceptor-bound kinin in plasma 6 hrs pestinduction were significantly lower in controls than in groups 2 and 3 animals (111 ± 50 vs. 208 ± 40 and 237 ± 52 fmol/mL, respectively). Six hours postinduction, the pretreatment with Icatibant was associated with significantly higher plasma concentrations of phospholipase A₂ (controls, +1194%; group 2, +2000%; group 3, +2285% of baseline values) and interleukin- 1 receptor antagonist (controls, 1900 ± 800; group 2, 3100 ± 800; group 3, 3800 ± 800 pg/mL). In contrast, the increase of urinary trypsinogen activation peptides indicating local pancreatic damage (589 ± 114 nmol/L in controls) was substantially attenuated by pretreatment with Icatibant (group 2, 467 ± 102, NS; 352 ± 91 nmol/L in group 3; p = .022 vs. controls). Systemic inflammatory reactions, however, as quantified by C-reactive protein and the extracellularly discharged neutrophil cytosolic inhibitor leukocyte neutral proteinase inhibitor were not influenced by the bradykinin B₂- receptor antagonist. Conclusions: Pretreatment with the bradykinin B₂ receptor antagonist Icatibant resulted in prolonged survival time and in delayed impairment of major macrocirculatory and pulmonary variables. Icatibant resulted in elevated concentrations of free, circulating kinin. This was associated with increased concentrations of phospholipase A₂ and interleukin-1 receptor antagonist, suggesting that circulating kinins strengthen the activation of some mediator cascades, the association of which with the kinin metabolism requires further experimental clarification. Other variables indicating a systemic inflammatory response (C-reactive protein, leukocyte neutral proteinase inhibitor) remained unaffected by Icatibant. Bradykinin antagonism distinctly ameliorated the local pancreatic damage, indicated by increased urinary concentrations of trypsinogen activation peptides. It is concluded that the kinin metabolism plays an important role in the pathophysiology of systemic complications after severe experimental pancreatitis.