ON THE PROTECTIVE MECHANISMS OF NITRIC-OXIDE IN ACUTE-PANCREATITIS

Background - Ectopic protease activation, microcirculatory changes, an d leucocyte activation are the main events in the pathogenesis of acut e pancreatitis. Nitric oxide (NO) is known to be a key mediator in the normal and inflamed pancreas. Aims - To investigate the targets on wh ich NO exerts its effect in caerulein induced pancreatitis. Methods - Acute pancreatitis was induced in rats which additionally received eit her the NO synthase substrate, L-arginine; the NO donor, sodium nitrop russide; or the NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). At six hours, pancreatic injury (oedema, leucocyte content, ectopic trypsinogen activation) was analysed and pancreatic oxygenati on and perfusion were determined. A direct influence of NO on amylase secretion and trypsinogen activation was evaluated separately in vitro . Results - Both NO donors reduced the grade of inflammation. L-NAME i ncreased the severity of inflammation, while decreasing pancreatic tis sue oxygenation. Although neither amylase secretion nor intracellular trypsinogen activation in caerulein stimulated pancreatic acini was in fluenced by either NO donors or inhibitors, both NO donors decreased i ntrapancreatic trypsinogen activation peptide (TAP) and pancreatic oed ema in vivo, and L-NAME increased TAP. Conclusions - NO protects again st injury caused by pancreatitis in the intact animal but has no disce rnible effect on isolated acini. It is likely that in pancreatitis NO acts indirectly via microcirculatory changes, including inhibition of leucocyte activation and preservation of capillary perfusion.