Bradykinin B-2-receptor antagonism attenuates fatal cardiocirculatory breakdown induced by severe experimental pancreatitis

Objectives: To investigate the impact of the long-acting bradykinin B-2 rec eptor 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 ve ntilated. Interventions: Pancreatitis was induced by an injection of sodium taurochol ate (5%, 1 mL/kg body weight [BW]) and enterokinase (10 U/kg BW). Control a nimals (group 1, n = 10) underwent the spontaneous course of the disease. I n two treatment groups, Icatibant was administered either in a low (100 nmo l/kg BW; group 2, n = 10) or in a high dosage (5000 nmol/kg BW; group 3, n = 10), Measurements and Main Results: Mean survival time was significantly prolong ed by Icatibant (controls, 6.6 hrs; group 2, 9.8 hrs; p = .022; group 3, 10 .9 hrs; p = .007). Six hours postinduction, the decline of total peripheral resistance (52% of baseline) and cardiac index (92% of baseline) in contro ls 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 postinduction were significantly lo wer in controls than in groups 2 and 3 animals (111 +/- 50 vs. 208 +/- 40 a nd 237 +/- 52 fmol/ml respectively). Six hours postinduction, the pretreatm ent with Icatibant was associated with significantly higher plasma concentr ations of phospholipase A(2) (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, 3600 +/- 800 pg/mL). In contr ast, the increase of urinary trypsinogen activation peptides indicating loc al pancreatic damage (589 +/- 114 nmol/L in controls) was substantially att enuated by pretreatment with Icatibant (group 2, 467 +/- 102, NS; 352 +/- 9 1 nmol/L in group 3; p = .022 vs. controls). Systemic inflammatory reaction s, however, as quantified by C-reactive protein and the extracellularly dis charged neutrophil cytosolic inhibitor leukocyte neutral proteinase inhibit or were not influenced by the bradykinin B-2-receptor antagonist. Conclusions: Pretreatment with the bradykinin B-2-receptor antagonist Icati bant resulted in prolonged survival time and in delayed impairment of major macrocirculatory and pulmonary variables. Icatibant resulted in elevated c oncentrations of free, circulating kinin. This was associated with increase d concentrations of phospholipase A(2) and interleukin-1 receptor antagonis t, suggesting that circulating kinins strengthen the activation of some med iator 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 inh ibitor) remained unaffected by Icatibant. Bradykinin antagonism distinctly ameliorated the local pancreatic damage, indicated by increased urinary con centrations of trypsinogen activation peptides. It is concluded that the ki nin metabolism plays an important role in the pathophysiology of systemic c omplications after severe experimental pancreatitis.