BACKGROUND: Microcirculatory dysfunction due to excessive nitric oxide production by the inducible nitric oxide synthase (iNOS) is often seen as a motor of sepsis-related organ dysfunction. Thus, blocking iNOS may improve organ function. Here, we investigated neuronal functional integrity in iNOS knock out (/) or l-NIL-treated wild-type (wt) ... animals in an endotoxic shock model. METHODS: Four groups of each 10 male mice (28 to 32g) were studied: wt, wt+lipopolysaccharide (LPS) (5mg/kg body weight i.v.), iNOS(/)+LPS, wt+LPS+l-NIL (5mg/kg body weight i.p. 30min before LPS). Electric forepaw stimulation was performed before LPS/vehicle and then at fixed time points repeatedly up to 4.5h. N1-P1 potential amplitudes as well as P1 latencies were calculated from EEG recordings. Additionally, cerebral blood flow was registered using laser Doppler. Blood gas parameters, mean arterial blood pressure, and glucose and lactate levels were obtained at the beginning and the end of experiments. Moreover, plasma IL-6, IL-10, CXCL-5, ICAM-1, neuron-specific enolase (NSE), and nitrate/nitrite levels were determined. RESULTS: Decline in blood pressure, occurrence of cerebral hyperemia, acidosis, and increase in lactate levels were prevented in both iNOS-blocked groups. SEP amplitudes and NSE levels remained in the range of controls. Effects were related to a blocked nitrate/nitrite level increase whereas IL-6, ICAM-1, and IL-10 were similarly induced in all sepsis groups. Only CXCL-5 induction was lower in both iNOS-blocked groups. CONCLUSIONS: Despite similar hyper-inflammatory responses, iNOS inhibition strategies appeared neurofunctionally protective possibly by stabilizing macro- as well as microcirculation. Overall, our data support modern sepsis guidelines recommending early prevention of microcirculatory failure.