PANCREATIC CHANGES ELICITED BY CHRONIC ADMINISTRATION OF EXCESS L-ARGININE

Male rats were injected daily ip (350 mg/100 g body weight) with L-arg inine from 1 to 4 weeks. Weekly changes were assessed by glucose toler ance, pancreatic insulin, histology, immunohistochemistry, ultrastruct ure, and quantification of insulin mRNA by in situ hybridization. Foll owing Week 1, light microscopy revealed areas of focal acinar cell deg eneration and incipient disaggregation of exocrine cytoarchitecture. U ltrastructural changes revealed initial attenuation in endoplasmic ret iculum and condensation and clumping of nuclear chromatin. Some mitoch ondria appeared swollen and the plasma membrane showed areas of focal disintegration. Islets appeared normal, although pancreatic insulin le vers were lower than controls as was the quantified signal for insulin mRNA. At the end of Week 2, acinar necrosis was evident throughout mo st pancreatic lobules. Increasing numbers of acinar cells underwent pr ogressive degeneration with further loss of plasma membrane integrity, the appearance of autophagic vacuoles, increased cytoplasmic debris, and mitochondrial disruption. At Week 4, only isolated single acinar c ells remained within a fibrous connective tissue matrix contiguous wit h ducts, blood vessels, intrapancreatic nerves, and islets. Immunohist ochemistry of islets and nerves revealed normal endocrine and neural c omponents. Although nonfasted, arginine-treated rats were normoglycemi c and no further significant changes in pancreatic insulin and mRNA we re found between Weeks 2 and 4, some impairment of glucose tolerance w as present throughout the 4-week period. Data support the hypothesis t hat excess arginine selectively destroys acinar cells. It is suggested that necrosis arises from attenuation in nucleoprotein synthesis whic h may result from amino acid imbalance and/or toxicity. Excess arginin e-treated animals may serve as a model for the study of acute and chro nic pancreatitis. (C) 1994 Academic Press, Inc.