Nitric oxide has been implicated in the hypotension of septic shock. Approximately 50 percent of patients dying of septic shock succumb to refractory hypotension. In this investigation, we are studying the therapeutic value of nitric oxide synthase (NOS) inhibition of septic shock in an awake canine model. Initial experiments in endotoxin-challenged canines with two different NOS inhibitors, Nv-amino-L-arginine (J Exp Med, 1992) and Nv-methyl-L-arginine (Am J Physiol, 1995), have revealed unexpected toxicities and some limitations to this approach. Clinical development of Nv-amino-L-arginine was stopped due to these findings. In our next investigation in this series, we used lower doses of Nv-methyl-L-arginine with and without a conventional vasopressor (epinephrine) to better simulate the clinical conditions under which these agents are likely to be used clinically (Crit Care Med, 1998). This study employed an E. coli peritonitis model of septic shock to examine the effects of these agents in an actual infection. Nv-methyl-L-arginine produced mainly additive effects with epinephrine. Nv-methyl-L-arginine could not be shown to improve survival or alter sepsis-induced myocardial depression. However, at the doses studied, the combination of Nv-methyl-L-arginine and epinephrine was not harmful, and the NOS inhibitor preserved cardiac function better than epinephrine. Nv-methyl-L-arginine remains in Phase II clinical trials. A Phase III trial of high dose Nv-methyl-L-arginine, in combination with conventional vasopressors, was recently halted because of excess mortality in the treatment arm of the study. Although the therapeutic role of NOS inhibition in septic shock remains to be defined, these agents have unique characteristics that warrant further study. NOS inhibitors that are highly selective for the induced isoform of this enzyme (the isoform implicated in septic shock) are being sought for future studies. An investigation examining the cardiovascular effects and impact on survival of further upregulating the nitric oxide pathway in septic shock, in the presence and absence of antioxidant therapy, is ongoing. In these experiments, animals will receive one of four treatments: 1.) L-arginine, the substrate for NOS; 2.) N-acetylcysteine, an antioxidant and NO carrier; 3.) both of these agents; or 4.) neither agent. Preliminary analysis of this study suggests that L-arginine increases mortality in a dose-dependent manner. Harmful doses may be similar to the L-arginine infusion rates used for total parenteral nutrition.
