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Cardiovasc Res. 1999 Mar;41(3):754-64.

Cytokine-induced venodilatation in humans in vivo: eNOS masquerading as iNOS.

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  • 1Centre for Clinical Pharmacology & Therapeutics, Wolfson Institute for Biomedical Research, University College London, UK.

Abstract

OBJECTIVE:

Venodilatation is a feature of endotoxaemia and sepsis. We have tested directly the hypothesis that three cytokines (IL-1 beta, TNF alpha 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-1 beta 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-1 beta 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-1 beta induces expression of GTP cyclohydrolase-1 which leads to increased generation of BH4 and activation of eNOS. This study identifies IL-1 beta 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.

PMID:
10435048
[PubMed - indexed for MEDLINE]
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