© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo
Director, Centre for Clinical Pharmacology, University College London Medical School, Fourth Floor, St Martin's House, 140 Tottenham Court Road, London W1P 9LN, UK
* Tel.: +44-0171-209-6340; fax: +44-0171-209-6351 patrick.vallance{at}ucl.ac.uk
KEYWORDS Endothelial factors; Endothelial function; Nitric oxide; Shock; Veins
I am delighted that this particular paper has been so highly cited as I always assumed that it had been rather overshadowed by its sibling paper that we published in The Lancet [1]. In 1987 I started work with Joe Collier trying to determine whether endothelium-dependent relaxation occurred in human vessels in vivo. We worked in the veins since we wanted to damage the endothelium experimentally and to do so in arteries would have been risky. By infusing distilled water into the lumen of a vein on the back of the hand we managed to denude the vessel of its endothelium and this procedure was associated with loss of responsiveness to acetylcholine. Soon after this experiment, Salvador Moncada's group published in Nature [2] that Furchgott's endothelium-derived relaxing factor (EDRF) was nitric oxide synthesised from L-arginine and that the synthetic process could be inhibited by the arginine analogue, NG monomethyl-L-arginine (L-NMMA). It seemed obvious that we should explore the effects of L-NMMA in the hand vein model. I had never met Salvador Moncada before but he did not need much persuasion. We had little in the way of formal toxicology for L-NMMA but there was a significant amount of animal pharmacology available and we planned to give doses of L-NMMA that would produce an effective concentration in a single hand vein, but which would be far below a systemically-effective concentration.
The initial studies were a disappointment; L-NMMA did nothing on its own and did not enhance the constrictor response to noradrenaline. However, when we got on to the dilator studies everything fell into place. L-NMMA abolished the dilatation to acetylcholine, blunted the dilatation to bradykinin but did not affect the response to glyceryl trinitrate. Nitric oxide was a mediator of endothelium-dependent dilatation in human vessels! To be certain, we tested the effects of the D-enantiomer – it was devoid of activity – and showed that the effects of L-NMMA could be reversed by L-arginine but not by D-arginine. At the time this was exciting because it was the first demonstration of the existence of the L-arginine:nitric oxide pathway in humans. Later it became interesting to us in a different way when we realised that the arterial circulation constricted to L-NMMA, and it thus became clear that basal nitric oxide-mediated dilatation was a feature of the arterial circulation but was not evident in veins. This observation turned out to be relevant to understanding why nitric oxide donor drugs show venoselectivity. Similar observations had not been made in the animal or in vitro studies and the finding was a further justification for continuing to work in humans and in veins. Looking back, two things come to mind (i) this work was difficult to get funded and I remain grateful to the South West Thames Regional Health Authority for having the courage to fund it, and (ii) it was even more difficult to get it published. Indeed it is because of the delays and eventual rejection we encountered at the hands of another (nameless) journal, that our subsequent work on the effects of L-NMMA in the arterial circulation was published in The Lancet before this paper appeared in Cardiovascular Research. Ten years on I am very pleased that it has been such a highly cited paper and I wouldn’t mind recapturing that sense of excitement with another project.
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- Vallance P., Collier J., Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet (1989) 2(8670):997–1000.[Web of Science][Medline]
- Palmer R.M., Ferrige A.G., Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature (1987) 327:524–526.[CrossRef][Medline]
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