Differing roles of nitric oxide in the pathogenesis of acute edematous versus necrotizing pancreatitis

Abstract

Background. Microcirculatory changes and leukocyte-endothelial interaction are both central to the pathogenesis of acute pancreatitis. We studied the effects of nitric oxide (NO) donors (intravenous or inhaled) and NO inhibitors, which affect each of these processes, on markers of experimental mild (edematous) and severe (necrotizing) pancreatitis in rats. Methods. Mild pancreatitis was induced with intravenous cerulein (n = 100) and severe pancreatitis with intravenous cerulein and intraductal glycodeoxycholic acid (n = 100). Each group was randomly divided into five equal treatment subgroups: control, NO-synthase substrate L-arginine, NO donor sodium nitroprusside, NO-synthase inhibitor N-nitro-L-arginine methyl ester ( l-NAME), and NO-inhalation. After 6 hours edema was measured by a wet/dry weight ratio, and pancreatic injury was quantified by tissue levels of trypsinogen activation peptides (TAPs) and by histologic analysis of inflammation and necrosis. Results. In mild pancreatitis (1) both NO donors reduced edema formation (p < 0.001) and also reduced intrapancreatic TAPs (p < 0.03); (2) l-NAME significantly increased tissue TAPs (p < 0.03); and (3) inhaled NO had no effect. In severe pancreatitis (1) both intravenous NO donors reduced edema formation (p < 0.005) and both markedly reduced intrapancreatic TAPs (p < 0.001); (2) l-NAME did not further increase the already high tissue TAPs; and (3) inhaled NO decreased tissue TAPs (p = 0.01). Evaluation of inflammation and necrosis by histologic scoring confirmed the reduction of pancreatic injury by NO donors and worsening with NO-synthase inhibitor. Conclusions. NO donors have a beneficial effect on edema formation in acute pancreatitis but confer more important protection against ectopic trypsinogen activation, which correlates with mortality, inflammation, and necrosis. Although direct microcirculatory action is likely, the salutary effect of inhaled NO in severe pancreatitis may suggest indirect action on circulating leukocytes, which are thought to potentiate tissue injury.