Abstract 3679: Kynurenine is a Novel Vasodilator in Human Septic Shock
Kynurenine is produced when the enzyme indoleamine 2,3-dioxygenase (IDO) metabolises the essential amino acid tryptophan. IDO expression is induced in endothelial cells of resistance vessels when mice are infected with malaria (a model of systemic inflammation). These mice become hypotensive and treatment with 1-methyl-tryptophan, an IDO inhibitor, restores normal blood pressure. In vitro vessel function studies have shown that kynurenine acts as an endothelium-independent relaxant. Kynurenine contributes to the hypotension in human septic shock. Patients admitted to ICU with a diagnosis of septic shock (sepsis with hypotension not responsive to fluids) had serum levels of kynurenine and tryptophan measured throughout the course of their illness. Systemic IDO activity was inferred from the kynurenine/tryptophan ratio and was correlated with the degree of hypotension assessed as each patient’s inotrope requirements. The kynurenine/tryptophan ratio changed in parallel with the inotrope requirements in our cohort of 12 patients. Each patient’s maximal kynurenine/tryptophan ratio increased significantly, up to 10-fold, during the ICU stay. The mean kynurenine/tryptophan ratio of our septic cohort was 5-fold higher than those of the general population (p<0.01). We also studied the role of kynurenine and IDO in mice during endotoxemia-induced hypotension. In wild-type mice, the degree of hypotension correlated closely with the serum kynurenine/ tryptophan ratio, and treatment with the IDO inhibitor 1-methyl-tryptophan restored normal blood pressure. In IDO knockout mice, endotoxemia-induced hypotension was significantly attenuated (drop in systolic BP 22 mmHg versus 35 mmHg, p=<0.05), and the IDO inhibitor no longer affected blood pressure. This study provides correlation data between IDO activity and hypotension in humans with septic shock and in a mouse model of systemic inflammation. Thus kynurenine, the product of IDO metabolism of tryptophan, is a novel vasodilator contributing to the hypotension observed in septic shock.