actions of NO, including smooth muscle relaxation, platelet aggregation and adherence, as well as neutrophil chemotaxis. However, *NO can adversely affect cellular metabolism through its disruption of iron-sulfur clusters in essential energy-generating enzymes involved in mitochondrial electron transport, glycolysis, and the Krebs cycle. Further, high concentrations of induced macrophage produced NO can directly interfere with DNA in target cells, resulting in fragmentation. Another critical reaction that 'NO undergoes during inflammation is with the superoxide anion radical (02j, yielding peroxynitrite (OONO-). OONO- is a potent oxidant that can decay under acidic conditions to produce a powerful hydoxyl-like free radical. This reaction between *NO and 02 can have a protective or damaging consequence, depending on the individual sites and rates of production of the free radicals, and the redox status of both the generating cells as well as the target cells. OONO- formation can initiate adverse effects such as lipid peroxidation of membranes, and modification of structural proteins through nitration of tyrosine residues (14). Indeed, increased levels of 3-nitrotyrosine have been detected in the lungs of patients with sepsis and animals with acute lung injury. However, OONO- can also S-nitrosylate glutathione and other thiol-containing substances to form S-nitrosothiols, which have marked cardioprotective and cytoprotective effects. The damaging effect of NOS inhibition may be, in part, mediated by oxygen radicals and platelet deposition, suggesting a cytoprotective role of NO in preventing microvascular thrombosis and as a free radical scavenger. In addition, 'NO has a protective role in hepatic microcirculatory dysfunction during sepsis through its effect on leukocyte adherence to sinusoidal walls. 'NO may also protect against circulatory vasoconstrictors during inflammation, as enhanced 'NO synthesis counteracted phenylephrine-induced increases in intrahepatic resistance in endotoxin-treated rats. Finally, we have recently demonstrated that different types of NOS inhibitors resulted in detectable apoptosis in the liver following LPS injection. This increase in apoptosis was present even with L-N-iminoethyl-lysine (L-NIL), a rather specific inhibitor of iNOS, revealing another important protective role of NO as an antiapoptotic agent in sepsis. Even though overproduction of *NO in the vasculature contributes to the vasodilatation seen in septic shock, iNOS expression during inflammation also represents a beneficial, adaptive response in some organ systems. Moreover, different tissues can react dissimilarly to the effects of 'NO cytotoxicity. In this setting, global nonselective inhibition of NOS, including the potentially undesirable consequences of eNOS inhibition, would be harmful. If confirmed, this would suggest that use of isoform-specific inhibitors of NOS within the vascular bed would be more appropriate. Pulmonary Hypertension and Reduced Cardiac Output Pulmonary hypertension and reduced cardiac output can be major side effects of continuous NO synthase inhibition. Pulmonary vasoconstriction is undesirable because it may compromise pulmonary gas exchange and because it increases the workload on the right ventricle. In cases where strain already exists on the right ventricle (e.g. sepsis or PEEP ventilation) or in cases where right sided cardiac reserve is minimal, such increase in workload may lead to right ventricular failure, reduced cardiac output and compromised tissue perfusion.