ATTENUATION BY SELECTIVE KALLIKREIN INHIBITORS OF HEMORRHAGIC LESIONS INDUCED BY BRADYKININ B2 ANTAGONISTS IN CERULEIN-INDUCED PANCREATITIS

Abstract

Listen

Translate article

Introduction: Kinin B2 receptor antagonists effectively prevent edema formation in cerulein-induced acute pancreatitis. However, this is complicated by hemorrhagic lesions in the pancreas at later time points. We have investigated whether this is due to a reduced influx of endogenous protease inhibitors into the pancreas and a concomitant excessive augmentation of tissue kallikrein activity. Methods: Pancreatitis was induced in anaesthetized rats by i.v. infusion of cerulein. The animals were pretreated with the B2 receptor antagonist icatibant and/or selective inhibitors of tissue kallikrein (tKI) and plasma kallikrein (pKI) (Evans et al., Immunopharmacology, 1996; 32: 115-116 and 117-118 ). Six hours later, tissue samples were excised, assessed histologically, and analyzed for hemoglobin in the pancreatic tissue. Results: Cerulein alone did not induce signs of vascular damage. Tissue hemoglobin levels were similar to those of controls without pancreatitis. Pretreatment with icatibant produced an about 10-fold elevation (p < 0.01) in tissue hemoglobin concentrations. Although tKI inhibited the edema to an extent similar to icatibant, signs of vascular damage were absent. The hemorrhage induced by icatibant was largely attenuated by a concomitant treatment with tKI and pKI (p < 0.05). Influx of endogenous inhibitors of kallikreins (α1-antitrypsin, α2-macroglobulin) was significantly (p < 0.05) reduced by icatibant and tKI. However, tissue kallikrein activity was increased 10-100 fold by icatibant (p < 0.01), whereas it was strongly inhibited (p < 0.05) by tKI. Conclusions: Our results suggest that increased levels of kallikrein activity in the pancreas in the absence of edema formation are involved in the induction of hemorrhagic lesions induced by icatibant in this model. Inhibition of tissue and plasma kallikrein thus seems to be a highly interesting strategy for the prevention of this kind of tissue damage in acute pancreatitis.