Excessive nitric oxide (NO) production has been closely associated with the hemodynamic instability and death occurring during sepsis and septic shock. Despite this, agents designed to inhibit the inducible form of NO synthase (NOS), while increasing blood pressure, worsened outcome in patients with sepsis. Alternative methods for inhibiting the potentially harmful effects of NO are therefore now under study. One such agent is diethyltriaminepentacetate (DTPA) Iron III. This agent is a low molecular weight scavenger of free NO which does directly alter NOS function. Administration of DTPA Iron III in baboons challenged with a highly lethal dose of intravenous E. coli reduced intravascular nitrate levels and improved survival but did not have observable effects on hemodynamics. We studied whether this same agent would have similar beneficial effects in an animal model employing an extravascular site of infection. Rats were challenged with doses of E. coli via either intrabronchial or intravascular routes designed to produce high lethality rates. They were then treated with DTPA Iron III over a range of doses or placebo. Blood pressure, heart rate and circulating cellular mediators were measured continuously for 24 h and survival was observed for 168 h. As would be expected based on its scavenging of NO, increasing doses of DTPA Iron III resulted in dose ordered increases in blood pressure. However, no dose of DTPA Iron III, with either intrabronchial or intravascular E. coli improved survival rates, and in most cases survival rates were reduced. Thus in this rat model of sepsis, DTPA Iron III had very similar effects to those observed with NOS inhibitors in patients with sepsis. These results emphasize the important protective roles NO may play either in host defense or other functions during infection and sepsis.