We examined the ability of a highly potent synthetic protease inhibitor, nafamostat mesilate (FUT-175), to protect the rat pancrease against AP induced by a supramaximal dose of caerulein (CR). Rats received a 6-h, continuous intravenous (iv) infusion of either CR alone or CR + a 6-h infusion of either 2.5, 5.0, 10.0, 25.0, or 50.0 mg of FUT-175/kg/h. Pancreas weights and serum chymotrypsinogen concentrations were significantly elevated by approximately 85 and 75%, respectively, over values in saline infused rats. Pancreas weights in rats treated with CR + FUT-175 at doses from 2.5-25.0 mg/kg/h were significantly reduced by approximately 20% compared to rats given CR along, and histology showed a reduction in the extent and size of acinar cell vacuolization and reduced interstitial edema compared to rats treated with CR alone. Serum chymotrypsinogen concentrations in rats treated with CR and either 5.0 or 10.0 mg of FUT-175/kg/h were significantly lower than in rats given CR alone. Significant mortality occurred in rats infused with FUT-175 at doses of either 25.0 or 50.0 mg of FUT-175/kg/h. These data indicate that serine proteases appear to be involved in the pathogenesis of CR induced AP in rats and that FUT-175 administered in low doses (2.5-10.0 mg/kg/h) provides significant protection against this form of pancreatitis.