Pharmacologic modulation of increased release of gluconeogenic precursors from extra-splanchnic organs in sepsis

The effect of sterile inflammation and sepsis on the release of lactate and amino acids by peripheral tissues was investigated by removing the splanchnic organs (liver and small intestines) from the circulation and monitoring changes in plasma substrates for 30 min. Functional hepatectomy was performed in rats 5-7 days following the intraperitoneal introduction of a fecal-agar pellet (1.5 ml) [sterile vs. Bacteriodes fragilis (10(8) CFU) + E. coli (10(3) CFU)]. Following functional hepatectomy, dichloroacetate, an activator of the pyruvate dehydrogenase complex, significantly inhibited both lactate and alanine release. L-cycloserine, an inhibitor of alanine aminotransferase, significantly (P less than .05) reduced alanine following hepatectomy. Methionine sulfoximine, an inhibitor of glutamine synthetase, significantly (P less than .005) decreased glutamine accumulation following functional hepatectomy in each of the conditions examined. Treatment with each of these drugs abolished the differences between control and sepsis following hepatectomy. These results demonstrate that alterations in the amino acid profiles during sepsis may be modulated in peripheral organs pharmacologically by utilizing known inhibitors of critical regulatory enzymes.