In the present work, the relation of cytoprotection of neurotensin to nitric oxide (NO), cGMP and cAMP was investigated in primary cultured mouse hepatocytes. The results are as follows: After administration of acetaminophen (20 mmol/L) to the medium, the leakage of GOT and GPT increased significantly. Pretreatment with neurotensin (10(-7) mol/L) before acetaminophen reduced the leakage of GOT and GPT. No synthase inhibitor, L-NAME, completely blocked the cytoprotective effect of neurotensin. Neurotensin could enhance the intracellular cGMP content, but had no effect on cAMP content. These results indicate that the protective effect of neurotensin on hepatocytes is mediated by NO probably by enhancing intracellular cGMP content.