Kallikrein inhibitors limit B2 antagonist-induced progression of oedematous to haemorrhagic pancreatitis in rats

Thomas Griesbacher1, Irmgard Rainer1, Beate Tiran1, D. Michael Evans2, Bernhard A. Peskar1
1Medical University of Graz, 8010 Graz, Austria, 2Vantia Limited, Southampton SO16 7NP, UK

Exocrine hyperstimulation with caerulein is an established model for oedematous acute pancreatitis. Prevention by kinin B2 receptor antagonists of oedema formation induces a progression to a haemorrhagic course in this model. We have investigated whether increased kallikrein activity in the pancreas is responsible for vascular damage and whether this could be prevented by selective kallikrein inhibitors. Caerulein was infused i.v. in anaesthetized Sprague-Dawley rats (200-250 g) and vascular damage was assessed by histological evaluation and determination of haemoglobin accumulation in the tissue. In addition, oedema formation, tissue and plasma kallikrein activities and the endogenous kallikrein inhibitors α1-antitrypsin and α2-macroglobulin were measured. Haemorrhagic lesions induced by icatibant were associated with a pronounced reduction of α1-antitrypsin (P<0.01) and α2-macroglobulin (P<0.05) in the pancreas and a concomitant augmentation of tissue kallikrein activity (P<0.01). The tissue kallikrein inhibitor VA999024, or its combination with the plasma kallikrein inhibitor VA999026, inhibited oedema formation to the same extent (P<0.01) but did not induce vascular damage. Furthermore, VA999024 inhibited (P<0.05), rather than augmented tissue kallikrein activity. When icatibant was combined with VA999024 and VA999026, progression from oedematous to haemorrhagic pancreatitis was prevented completely. In conclusion, reduced oedema formation by B2 antagonists prevents influx of endogenous kallikrein inhibitors and thus causes an excessive activity of kallikrein in the pancreas leading to vascular damage. This can be prevented by a combined inhibition of both tissue-type and plasma-type kallikrein