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

Objective: Venodilatation is a feature of endotoxaemia and sepsis. We have tested directly the hypothesis that three cytokines (IL-1 beta, TNF alpha a nd IL-6) generated during endotoxaemia affect venous tone in humans in vivo by increasing NO generation and explored whether the NO comes from the iNO S or eNOS isoform. Design and intervention: Cytokines were given into a sup erficial vein in very low doses sufficient only to produce changes in the s tudy vessel. The effects of cytokines on the response to noradrenaline were examined. Results: IL-I beta increased basal NO-induced dilatation in the study vein, and this was sufficient to attenuate the constrictor response t o exogenous noradrenaline or sympathetic stimulation. The effects were maxi mal at 6 h and both N-G-monomethyl-L-arginine and aminoguanidine caused sig nificant reversal of the IL-I beta effects. However, no induction of iNOS m RNA was detected in the tissue samples. Instead, mRNA encoding eNOS and GTP cyclohydrolase-1 was detected in all vessels. Conclusion: The simplest exp lanation of these results is that IL-I beta induces expression of GTP cyclo hydrolase-l which leads to increased generation of BH4 and activation of eN OS. This study identifies DL-I beta as a key cytokine causing physiological ly significant venodilatation in humans by increasing NO generation and sug gests that this can occur even in the absence of iNOS expression. (C) 1999 Published by Elsevier Science B.V. All rights reserved.