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


METHODS
Randomized, controlled intervention trial.


METHODS
Thirty domestic pigs of either gender anesthetized by intravenous application of piritramide, midazolam, and pancuronium and mechanically ventilated.


METHODS
Pancreatitis was induced by an injection of sodium taurocholate (5%, 1 mL/kg body weight [BW]) and enterokinase (10 U/kg BW). Control animals (group 1, n = 10) underwent the spontaneous course of the disease. In two treatment 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 = 10).


RESULTS
Mean survival time was significantly prolonged 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 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 postinduction 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, 3600+/-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.
Yekebas
E
E
Department of Surgery, University Hospital Eppendorf, Hamburg, Germany.
Treede
H
H
Jochum
M
M
Gippner-Steppert
C
C
Bloechle
C
C
Knoefel
W T
WT
Scholz
J
J
Fink
E
E
Izbicki
J R
JR
D000208:Acute Disease; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D065168:Bradykinin Receptor Antagonists; D002097:C-Reactive Protein / Q000032:analysis / Q000187:drug effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006439:Hemodynamics / Q000187:drug effects; D007705:Kinins / Q000097:blood / Q000187:drug effects; D010195:Pancreatitis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D010455:Peptides / Q000187:drug effects / Q000652:urine; D010741:Phospholipases A / Q000097:blood / Q000187:drug effects; D054467:Phospholipases A2; D011897:Random Allocation; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000187:drug effects; D013552:Swine; D018746:Systemic Inflammatory Response Syndrome / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D065168:Bradykinin Receptor Antagonists; D007705:Kinins; D010455:Peptides; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; C065679:icatibant; D002097:C-Reactive Protein; D010741:Phospholipases A; D054467:Phospholipases A2; D001920:Bradykinin