Role of the kinin-mediated edema for the accumulation of kinins in the pancreas in experimental pancreatitis

Abstract

Endogenous kinins have been found earlier to be the major mediators responsible for the development of the pancreatic edema during ceruleininduced acute pancreatitis in the rat. We have now tried to determine the time course of the release of kinins in the pancreas and to establish the consequence of a prevention of the edema formation by a specific bradykinin (BK) B z receptor antagonist, icatibant (Hoe-140; DArg-Hyp3-ThiS-DTic7-OicS-BK). Pancreatitis was induced by i.e. infusion of cerulein (67 pmol/kg/min) for periods of up to 2 h. Samples of the pancreatic tissue were excised immediately at the end of the infusions or following a recovery period of 24 h. For determination of immunoreactive kinins, antibodies to BK were raised in rabbits after carbodiimide coupling of BK to bovine serum albumin. Crossreactivity of the antibodies with kinin-related peptides were: BK 100%, Ile-Ser-BK 100%, Lys-BK 67%, Met-Lys-BK 59%, des-Argg-BK 1%, icatibant < 0.01%. The detection limit for BK was 50 pg using [3H]-BK as tracer. Significant increases in tissue kinin levels were determined as early as 10 min after the start of the cerulein infusion, i.e. prior to any signs of edema formation. Peak kinin levels coincided with the peak of the edema formation at 45 rain and amounted to 521-+74 pg/g dry wt (p<0.01 compared to 108 -+ 33 pg/g dry wt in controls). Surprisingly, no increases in kinin levels were found throughout the duration of the 2 h infusion of caerulein in animals pretreated with icatibant (100 nmol/kg, s.c.); kinin levels (80--120 pg/g) were indistinguishable from those of controls. On the day after pancreatitis, the edema and the associated hemoconcentration were completely resolved. Nevertheless, pancreatic kinin levels still were twice as high (189 -+ 44 pg/g, p < 0.05) as those of control rats (92-+ 14 pg/g). This increase was not attenuated (242 -+ 34 pg/g) in animals treated with icatibant (100 nmol/kg + 3x50 nmol/kg at intervals of 2 h) before and after cerulein. The results show that prevention of the kinin-mediated edema also leads to an attenuation of the accumulation of kinins in the pancreatic tissue. The most likely explanations for this observation are a reduced inflow of kinin precursor peptides from the blood into the pancreas and/or an improved outflow of kiningenerating enzymes from the tissue similar to what has been demonstrated previously for amylase and lipase. The fact that increased kinin levels are detectable even in the recovery phase suggests that kinin-mediated phenomena other than edema formation such as pain could be a target for a therapeutic administration of BK antagonists in acute pancreatitis. Supported by the Pain Research Commission of the Austrian Academy of Sciences.