Editors' ChoicePhysiology

Ido for Lowering Blood Pressure

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Science Signaling  16 Mar 2010:
Vol. 3, Issue 113, pp. ec78
DOI: 10.1126/scisignal.3113ec78

Systemic inflammation during sepsis, which is associated with increased circulating proinflammatory cytokines, can lead to a fatal drop in blood pressure. Production of nitric oxide (NO) increases during sepsis, and inhibiting its synthesis can temporarily increase mean arterial blood pressure; this manipulation fails, however, to improve long-term survival, suggesting the possible involvement of additional pathways in the decrease in blood pressure (see Hofmann). Like inducible nitric oxide synthase, production of the enzyme indoleamine-2,3-dioxygenase (Ido), which converts the amino acid tryptophan to N-formyl-kynurenine, is induced in vascular endothelium by proinflammatory cytokines, leading Wang et al. to investigate Ido function in blood vessels during systemic inflammation. Infection of mice with the ANKA strain of Plasmodium berghei led to the appearance of Ido in arterioles, a decrease in plasma tryptophan, an increase in plasma kynurenine (a product of N-formyl-kynurenine breakdown), and a drop in systolic blood pressure (SBP). Pharmacological inhibition of Ido with 1 methyl-D-tryptophan (1-Me-Trp) restored SBP in infected mice but had no effect on SBP in control mice or in infected mice that lacked either Ido or interferon-γ (IFN-γ), which is required for endothelial induction of Ido. Similar analyses implicated Ido in regulation of blood pressure during infection with another strain of malaria and in mice with lipopolysaccharide (LPS)–induced endotoxemia. IFN-γ induced Ido mRNA and protein in porcine aortic endothelial cells and promoted endothelial cell conversion of tryptophan to kynurenine. Tryptophan relaxed preconstricted porcine coronary arteries, an effect that was inhibited by 1-Me-Trp and depended on previous exposure to IFN-γ. Kynurenine also relaxed blood vessels, and, unlike tryptophan, its intravenous infusion elicited a transient decrease in the blood pressure of spontaneously hypertensive rats. Kynurenine stimulated both soluble guanylate cyclase (sGC) and adenylate cyclase and increased coronary artery cGMP (guanosine 3′,5′-monophosphate) and cAMP (adenosine 3′,5′-monophosphate) content. Intriguingly, whereas NO specifically stimulates heme-containing sGC, kynurenine stimulated oxidized heme-free sGC. The authors thus conclude that tryptophan metabolism to kynurenine represents a previously unknown pathway for regulation of blood pressure that may provide new therapeutic approaches to manipulating vascular tone.

Y. Wang, H. Liu, G. McKenzie, P. K. Witting, J.-P. Stasch, M. Hahn, D. Changsirivathanathamrong, B. J. Wu, H. J. Ball, S. R. Thomas, V. Kapoor, D. S. Celermajer, A. L. Mellor, J. F. Keaney Jr., N. H. Hunt, R. Stocker, Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat. Med. 16, 279–285 (2010). [PubMed]

F. Hofmann, Ido brings down the pressure in systemic inflammation. Nat. Med. 16, 265–267 (2010). [PubMed]

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