n this essay, Dr. Salvador Moncada discusses the impact his highly cited review, "Nitric oxide – physiology, pathophysiology, and pharmacology," (Pharmacol. Rev., 43[2]: 109-42, June 1991) has had on the scientific community, as well as what it means to be highly cited. This review has now been cited 6,655 times, making it one of the top-cited papers in scientific research of the 1990s. Dr. Moncada has authored 12 highly cited papers, which have received a total of 14,408 citations to date. Dr. Moncada is the Director of The Wolfson Institute for Biomedical Research at University College London.

Citation in the literature is the most objective and honest form of peer review. It gives a clear indication of the impact of the results and the appreciation by the scientific community of priority of observation, leadership or true innovation. Because of this, I was very pleased to hear from ISI that a review we wrote in 1991¹ has been cited in the literature more than 6,500 times. The speed at which generated knowledge becomes obsolete is accelerating to the point where almost any piece of scientific information is rapidly superceded by another one produced by the enormous amount of high-quality research which is being carried out in the world at present. Thus it is a further cause for celebration that our review has survived in the cited literature for almost a decade, since nearly 1,000 of its citations were in 1999.

I have been asked to give my opinion on why this article has been so highly quoted. This is a dangerous exercise in which the author can make errors of judgment based on wishful thinking—indeed, a publication may be highly cited for the wrong reasons! However, I will take up the challenge.

Firstly, I think that this review represented the consolidation of a field of research which was initiated by the discovery of endothelium-dependent relaxation and endothelium-derived relaxing factor², its identification as nitric oxide (NO) ^3-5 and the elucidation of the metabolic pathway leading to its synthesis from L-arginine ⁶. Although there had been reviews on the subject of NO prior to 1991, and many more appeared afterwards, this one was both in-depth and comprehensive; and because of this; was pivotal in the development of the field for which we coined the now widely-accepted name, the L-arginine:NO pathway.

The second reason is that in this review we not only attempted to cover the research that led to the discovery of the field and its status at the beginning of the 1990s, but we also made an effort to forecast the developments that might take place in the future. I think that the functions of a review are to describe the past objectively and analyze the present accurately. This defines the review as a historical platform describing the stage of development of a field of research and a vantage point from which the writer can interpret the evidence and, as lucidly as possible, extrapolate into the future. This extrapolation, although always incomplete and often wrong in relation to what proves to be reality, has the advantage of nurturing new ideas and lines of inquiry. As it turned out, the future held far more than we could predict; however, on rereading the review, I am pleased to see that we planted productive seeds.

The third and very significant reason for the popularity of the review is the clarity of style in which it was written. We spent a long time debating the nature of the statements we were making because of the responsibility that such a review carried. A great deal is owed to my collaborators for the zeal and attention to detail and accuracy which also characterizes the review. Not often does one have the privilege of working with such an enthusiastic and effective team. Many thanks are due to both Richard Palmer and Annie Higgs for their contribution to this valued and enduring achievement.

References:

1. Moncada, S., Palmer, R.M. & Higgs, E.A. "Nitric oxide: physiology, pathophysiology and pharmacology." Pharmacol. Rev., 43(2): 109-42, June 1991.

2. Furchgott, R.F. & Zawadzki, J.V. "The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine." Nature, 288(5789): 373-6, 1980.

3. Palmer, R.M., Ferrige, A.G. & Moncada, S. "Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor." Nature, 327(6122): 524-6, 11 June 1987.

4. Furchgott, R.F. "Studies on relaxation of rabbit aorta by sodium nitrite: The basis for the proposal that the acid-activatable inhibitory factor from retractor penis is inorganic nitrite and the endothelium-derived relaxing factor is nitric oxide." In: Vanhoutte, P.M., ed. Vasodilatation: Vascular Smooth Muscle, Peptides, Autonomic Nerves and Endothelium, New York, Raven Press: 401-14, 1988.

5. Ignarro, L.J., Byrns, R.E. & Wood, K.S. "Biochemical and pharmacological properties of endothelium-derived relaxing factor and its similarity to nitric oxide radical." In: Vanhoutte, P.M., ed. Vasodilatation: Vascular Smooth Muscle, Peptides, Autonomic Nerves and Endothelium, New York, Raven Press: 427-36, 1988.

6. Palmer, R.M., Ashton, D.S. & Moncada, S. "Vascular endothelial cells synthesize nitric oxide from L-arginine." Nature, 333(6174): 664-6, 16 June 1988.

Dr. Salvador Moncada
University College London
Wolfson Institute for Biomedical Research
London, England