© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
Cytokine-induced venodilatation in humans in vivo: eNOS masquerading as iNOS
aCentre for Clinical Pharmacology & Therapeutics, Wolfson Institute for Biomedical Research, University College London, 5 University St, London WC1E 6JJ, UK
bMolecular Biology Laboratory, Wolfson Institute for Biomedical Research, University College London, 5 University St, London WC1E 6JJ, UK
* Corresponding author. Tel.: +44-171-209-6351; Fax: +44-171-813-2846; E-mail: patrick.vallance@ucl.ac.uk
Objective: Venodilatation is a feature of endotoxaemia and sepsis. We have tested directly the hypothesis that three cytokines (IL-1β, TNF
and IL-6) generated during endotoxaemia affect venous tone in humans in vivo by increasing NO generation and explored whether the NO comes from the iNOS or eNOS isoform. Design and intervention: Cytokines were given into a superficial vein in very low doses sufficient only to produce changes in the study vessel. The effects of cytokines on the response to noradrenaline were examined. Results: IL-1β increased basal NO-induced dilatation in the study vein, and this was sufficient to attenuate the constrictor response to exogenous noradrenaline or sympathetic stimulation. The effects were maximal at 6 h and both NG-monomethyl-L-arginine and aminoguanidine caused significant reversal of the IL-1β effects. However, no induction of iNOS mRNA was detected in the tissue samples. Instead, mRNA encoding eNOS and GTP cyclohydrolase-1 was detected in all vessels. Conclusion: The simplest explanation of these results is that IL-1β induces expression of GTP cyclohydrolase-1 which leads to increased generation of BH4 and activation of eNOS. This study identifies IL-1β as a key cytokine causing physiologically significant venodilatation in humans by increasing NO generation and suggests that this can occur even in the absence of iNOS expression.
KEYWORDS Nitric oxide; Veins; Septic shock; GTP cyclohydrolase 1; Human; Cytokines; Tetrahydrobiopterin; Inducible nitric oxide synthase
1 These authors contributed equally to this work and should be considered as joint first authors.
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