is reported to be associated with the development of hypotension associated with endotoxemia and sepsis. Electrochemical studies show that FeIII-(DTPA)2- binds NO stoichiometrically upon reduction to iron(II) at biologically relevant potentials to form a stable NO adduct. In contrast, FeI"I(HDFB)+ is a stable and efficient electrocatalyst for the reduction of NO to N20 at biologically relevant potentials. These results suggest that the mechanism of protection against death by septic shock involves NO scavenging and that particularly effective drugs that operate a low dosages may be designed based on the principle of redox catalysis. These complexes constitute a new family of drugs that rely on the special ability of transition metals to activate small molecules. Iron complexes could act as general NO scavengers and provide protection against septic shock. Iron complexes are capable of forming relatively stable NO adducts. Metal complexes, and in particular iron chelators, could act as "molecular sponges," mopping up the excess NO produced during septic shock. Iron chelators can sequester and (as for 2) catalyze conversion of NO to benign products. Demonstration of mechanistic aspects of septic shock protection in vivo, including interaction with other free radicals, may be hampered by the detection limits of current analytical techniques. To detect the NO Fe-DETC complexformation in livers of LPS-treated mice by the electron paramagnetic resonance, After screening a library of metal chelators and chelates [Fe(III)(H2DTPA)] and [Fe(III)(HDFB)]+ offered the highest mortality decrease in an experimental model of septic shock. The Fe(II) form of both complexes can bind NO, which appears to be related to their biological function. Survival was greatly enhanced by the administration of 4 or 2 either 2 h before and at the time of or 30 min after LPS. In contrast, the Fe3+-free ligands of these compounds, 3 and 1, were less protective when administered before and at the time of LPS and virtually ineffective when administered after LPS. The clear advantage of 4 over 2 when administered after LPS was observed over a large number of experiments [76% survival with 4 (n = 102 mice) and 38% survival with 2 (n =64 mice)]. The hydroxamic acid siderophore ferrioxamine B [Fe"'(HDFB)+] and the iron complex of diethylene- triamine-pentaacetic acid [FeI"(DTPA)2i] protected mice against death by septic shock induced by Corynebacterium parvum + lipopolysaccharide. Although Fem(DTPA)2- was somewhat more effective than FeI"(HDFB)+, the iron-free ligand H4DFB+ was significantly more effective than DTPA. The hydroxamic acid chelator has a much higher iron affinity than the amine carboxylate, allowing for more efficient formation of the FeI"(HDFB)+ complex upon administration of the iron-free ligand.

## Efficacy of Treatment With the Iron (III) Complex of Diethylenetriamine Pentaacetic Acid

Bacteremia and septic shock also are associated with overproduction of free radicals such as hydroxyl, superoxide, and carbon- and oxygen-centered radicals. In addition, nitric oxide (NO) overproduction is at least partly responsible for the vasodilation that causes a reduction in mean systemic arterial pressure (MSAP) and organ perfusion pressure during septic shock. This overproduction of NO likely results from early activation of the endothelial constitutive form of NO synthase followed by induction of the inducible form of NO synthase via TNF and IL-1.