OBJECTIVE: Heme oxygenase(HO)/carbon monoxide(CO) system and nitric oxide synthase(NOS)/nitric oxide(NO) system are up-regulated after recurrent febrile seizures(FS).The relationship between HO/CO and NOS/NO systems is unknown. This study examined the effect of the HO inhibitor zinc protoporphyrin Ⅸ (ZnPP-Ⅸ) on the expression of neuronal NOS (nNOS) mRNA and protein and also the plasma NO content in rats with recurrent FS. The goal was to study the effect of CO on the NOS/NO system. METHODS: Forty-eight developing rats were randomly assigned into three groups: Control group, FS group, and ZnPP-Ⅸ-treated FS group (n=16 each). FS were induced in rats by exposure to warm water bath, once every 2 days, 10 times in all. Plasma levels of NO and CO were detected by spectrophotometry. The expression of nNOS mRNA was detected in hippocampal neurons by in situ hybridization. nNOS protein expression in hippocampal neurons was examined by Western blot analysis. RESULTS: Recurrent FS induced an increased expression of nNOS mRNA and protein in hippocampal neurons. ZnPP-Ⅸ treatment decreased the concentrations of CO in plasma and increased the expression of nNOS mRNA and protein in hippocampal neurons and the NO content in plasma. CONCLUSIONS: Exogenously administering the HO inhibitor ZnPP-Ⅸ may increase the nNOS gene expression and NO production in recurrent FS, suggesting that CO might down-regulate the activity of NOS/NO system.