Susceptibility to cerulein-induced pancreatitis in inducible nitric oxide synthase-deficient mice

Production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) h as been proposed as a pathogenic factor in acute pancreatitis, but its role has still not been fully examined. The present study explored the role of iNOS in cerulein-induced acute pancreatitis using iNOS-deficient mice. Twel ve- to 14-weck-old male mice (C57B1/6 and iNOS-deficient) were administered cerulein by intraperitoneal (i.p.) injection at hourly intervals for 7 hou rs and killed 24 hours later after the first dose. Pancreatic wet weight, p ancreatic myeloperoxidase (MPO) activity, and levels of plasma nitrite and serum amylase were measured. In another experiment isosorbide: dinitrate ta n NO donor) was given by oral gavage every 6 hours for 24 hours beginning s imultaneously with cerulein injections in iNOS-deficient mice. Cerulein adm inistration dose-dependently increased pancreatic wet weight, myeloperoxida se activity, and levels of nitrite and amylase in C57B1/6 mice. These param eters (except nitrite levels) were significantly intensified in iNOS-defici ent mice. At the dose employed, cerulein failed to increase nitrite levels in iNOS-deficient mice. The susceptibility to cerulein toxicity in iNOS-def icient mice was abolished by NO donor treatment. NO release from an iNOS so urce appears to play a protective role in cerulein-induced pancreatitis. At least in part, NO may prevent neutrophil accumulation after cerulein admin istration.