The increased production of pro-inflammatory cytokines and nitric oxide have been postulated to contribute to the deleterious sequella of LPS administration. To date, clinical strategies to control these responses using individual specific inhibitors have been disappointing. The aim of the present study was to determine whether a tetravalent guanylhydrazone compound (CNI-1493) attenuates LPS-induced stress responses by suppressing multiple inflammatory mediators. Rats were injected intravenously with either CNI-1493 (10 mg/kg) or vehicle (1 mL NaCI) 60 min prior to the injection of LPS (100 μg/100 g body weight). LPS produced a 20% decrease in mean arterial blood pressure and a significant increase in circulating TNF-α levels as well as in tissue content of TNF-α, IL-1β, and IL-6. This was associated with a marked increase in lung and gut apoptosis and myeloperoxidase (MPO) activities as well as with an increase in lung and spleen nitric oxide end products (NOx). Pretreatment with CNI-1493 attenuated the LPS-induced drop in mean arterial blood pressure (MABP) and blunted (40%) the rise in circulating TNF-α levels. CNI-1493 attenuated the LPS-induced increase in tissue cytokine (TNF-α, IL-1β, and IL-6) content in lung and spleen but did not alter that of liver or gut. CNI-1493 pretreatment protected both lung and gut from LPS-induced apoptosis and in addition attenuated the rise in MPO activity in the gut. These results suggest diverse effects of CNI-1493 that are tissue specific and that confer protection against the hemodynamic and inflammatory responses to LPS.