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The use of intravenous fluids is important for the therapy of acute pancreatitis. Normal saline (NS) and lactated ringers (LR) are commonly used. Lactate can have distinct physiological effects acting as a buffer, metabolic intermediate, and receptor ligand. A G-protein-coupled receptor (GPR81) activated by lactate has recently been described. We examined the hypothesis that lactate might have distinct effects in disease models of acute pancreatitis Methods: Using cerulein-hyperstimulation models, trypsinogen activation was assayed in vitro in isolated pancreatic cells and in vivo. Results: In acinar cells, lactate (1-20 mM) sensitized cells to cerulein-induced trypsinogen and chymotrypsinogen activation. The effects of lactate were concentration-dependent and saturable. Amylase secretion was not affected. GPR81 lactate receptor is expressed in rat pancreatic acinar cells, as determined by PCR. In vivo studies showed that pretreatment of rats with LR enhanced cerulein (50 πg/kg) induced trypsinogen activation compared to normal saline infusion. LR contains 2.7 mM calcium, lactate containing buffer without calcium caused similar sensitization as LR. Conclusion: These findings demonstrate that lactate sensitizes the rat pancreas to pancreatitis responses, possibly through a novel G-protein-coupled receptor. These studies suggest that the effect of LR should be studied in conditions with an increased risk of pancreatitis such as pancreatic trauma and ERCP.