Kallikrein inhibitors limit kinin B 2 antagonist‐induced progression of oedematous to haemorrhagic pancreatitis in rats

• Published in: British journal of pharmacology Vol. 155; no. 6; pp. 865 - 874
• Main Authors: Griesbacher, T, Rainer, I, Tiran, B, Peskar, B A
• Format: Journal Article
• Language: English
• Published: 29.01.2009
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.321

Background and purpose: Exocrine hyperstimulation with caerulein is an established model for oedematous acute pancreatitis. Prevention of oedema formation by bradykinin B 2 receptor antagonists 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. Experimental approach: Caerulein was infused i.v. and vascular damage was assessed by histological evaluation and determination of haemoglobin accumulation in the tissue. In addition, oedema formation, tissue and plasma kallikrein (PK) activities and the endogenous kallikrein inhibitors α 1 ‐antitrypsin (α 1 ‐AT) and α 2 ‐macroglobulin (α 2 ‐M) were measured. Key results: Haemorrhagic lesions induced by icatibant in caerulein‐induced pancreatitis were associated with a reduction in α 1 ‐AT and α 2 ‐M in the pancreas and a concomitant augmentation of tissue kallikrein (TK) activity. The TK inhibitor VA999024 (previously FE999024), or its combination with the PK inhibitor VA999026 (previously FE999026), inhibited oedema formation to the same extent but did not induce vascular damage. Furthermore, VA999024 inhibited TK activity. When icatibant was combined with VA999024 and VA999026, progression from oedematous to haemorrhagic pancreatitis was abolished. Conclusions and implications: Reduced oedema formation by B 2 antagonists prevented influx of endogenous kallikrein inhibitors and led to 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. Kallikrein inhibitors thus should be further evaluated for their therapeutic potential in preventing haemorrhagic lesions in acute pancreatitis. British Journal of Pharmacology (2008) 155 , 865–874; doi: 10.1038/bjp.2008.321 ; published online 11 August 2008