Abstract 2366: Kynurenine is a Novel Contributor to Hypotension in Human Sepsis
Background: The enzyme indoleamine 2,3-dioxygenase (IDO) converts the essential amino acid tryptophan to kynurenine. IDO shares many functional similarities with inducible nitric oxide synthase and is also induced in sepsis. We investigated whether IDO plays a role in hypotension in human septic shock.
Methods: Patients (n=16) with septic shock had IDO activity assessed (expressed as the ratio of kynurenine to tryptophan) and the severity of their hypotension determined (expressed as their inotrope requirement) during the course of illness. Healthy and hypotension-matched non-septic controls were also studied. As a model of sepsis, endotoxemia was induced in wild type and IDO−/− mice and the effect of 1-methyl-D-tryptophan (1MT, a competitive inhibitor of IDO) was determined. In vitro vessel functional studies were performed to determine the direct vascular effect of tryptophan and kynurenine.
Results: Inotrope requirements correlated strongly with IDO activity (p<0.001). IDO activity increased greatly with sepsis (up to nine-fold) and was significantly higher than in the two control groups (p<0.005). Furthermore in mice, sepsis led to hypotension which was attenuated in both wild type treated with 1MT (p<0.05) and IDO−/− mice (p<0.005). Tryptophan only dilated arteries from septic mice while kynurenine dose-dependently dilated aortic rings from healthy mice.
Conclusion: This study shows a significant correlation between IDO activity and hypotension in human septic shock. Vessel function studies demonstrate that kynurenine, the product of tryptophan metabolism by IDO, is a novel and important vasodilator contributing to hypotension in sepsis. Inhibiting IDO in humans may provide a novel therapeutic target for the treatment of septic shock.