Jon O. Lundberg talks with
ScienceWatch.com and answers a few questions about
this month's New Hot Paper in the field of Pharmacology
& Toxicology.
Article Title: The nitrate-nitrite-nitric oxide
pathway in physiology and therapeutics
Authors: Lundberg,
JO;Weitzberg, E;Gladwin, MT
Journal: NAT REV DRUG DISCOV
Volume: 7
Issue: 2
Page: 156-167
Year: FEB 2008
* Karolinska Inst, Dept Physiol & Pharmacol, Sect
Anesthesiol & Intens Care, SE-17177 Stockholm,
Sweden.
* Karolinska Inst, Dept Physiol & Pharmacol, Sect
Anesthesiol & Intens Care, SE-17177 Stockholm,
Sweden.
(addresses have been truncated)
Why do you think your paper is highly
cited?
We are working in a young and exciting field which has many active groups.
The topic is of interest to a quite extensive group of scientists,
including biochemists, pharmacologists, physiologists, and toxicologists,
as well as clinically active researchers.
Does it describe a new discovery,
methodology, or synthesis of knowledge?
The paper summarizes the latest development in this rapidly emerging field
and we discuss the major new discoveries made over the past several years.
Would you summarize the significance of your
paper in layman's terms?
We and others have discovered and started to characterize a previously
unknown pathway for the generation of nitric oxide (NO) in mammals. NO is a
key messenger in mammalian biology and this free radical gas is classically
generated by specific enzymes—the NO synthases. These enzymes use
L-arginine and oxygen to generate NO, which has a key role in
vasoregulation, neurotransmission, immunity, and more. The bioactivity of
NO is acutely terminated by its rapid oxidation to nitrite (NO2-) and
nitrate (NO3-).
"From the recent research discussed
in our article, it is now clear that dietary
nitrate is not necessarily a threat to human
health."
These inorganic anions have generally been considered to be completely
inert. However, it has now become clear that various pathways exist for the
reduction of nitrate and nitrite back to bioactive NO again. Interestingly,
this pathway is greatly accelerated under hypoxic conditions, when the
oxygen-dependent NO synthase is malfunctioning. The physiological and
therapeutical implications of the nitrate-nitrite-NO pathway are just now
being revealed. As an example, nitrite mediates vasodilation via NO
formation, and it protects against ischemia-reperfusion injury in animal
models.
In humans, inorganic nitrate decreases blood pressure via NO generation.
This latter finding is very interesting from a nutritional point of view,
since nitrate is abundant in our diet (mainly in green leafy vegetables).
How did you become involved in this research,
and were there any problems along the way?
Our group and Ben Benjamin's group at Aberdeen University first described
NO-synthase-independent NO generation from nitrate and nitrite in 1994. A
year later, Jay Zweier's group at the Davis Heart and Lung Research
Institute in Columbus, Ohio, demonstrated nitrite reduction to NO in the
ischemic heart. The field was quite slow initially, likely because the NO
synthase pathway took all the focus at that time. Also, many researchers
would simply not believe that nitrate and nitrite can be biologically
active.
The dogma was that they are inert oxidation products of NO metabolism. The
field really took off during the years 2000-2003 when work by Mark Gladwin
of the Pulmonary and Vascular Medicine Branch, NHLBI, in Bethesda, MD,
along with ours at Karolinska, showed that low concentrations of nitrite
could elicit vasodilation, and then again in 2004-2005 when Amrita
Ahluwalia at the William Harvey Research Institute in London and Gladwin's
group went on to demonstrate the cytoprotective effects of nitrite.
Where do you see your research leading in the
future?
We hope to be able to convincingly show that the nitrate-nitrite-NO pathway
is an important complement to the L-arginine/NOS pathway for the generation
of bioactive nitrogen oxides within our bodies. In particular, we need to
better explore the physiological importance of this pathway and how it is
regulated, which is not a trivial task since there are no specific
pharmacological inhibitors available. In addition, it will be of great
interest to explore the therapeutic opportunities for nitrate and nitrite
in diseases such as hypertension, atherosclerosis, and ischemia-reperfusion
injury.
Do you foresee any social or political
implications for your research?
Nitrate and nitrite are found in our diet and, for over 50 years, they have
been linked to diseases in humans, most notably gastric cancer. Although
the link between nitrate in food and cancer has never been proven, the fear
of nitrate and nitrite is still widespread. This is reflected in the strict
regulation of nitrate levels in food and drinking water. From the recent
research discussed in our article, it is now clear that dietary nitrate is
not necessarily a threat to human health. In fact, we are hoping that it
will eventually be considered an essential nutrient.
Jon Lundberg, M.D., Ph.D. Professor of Pharmacology Department of Physiology and Pharmacology Karolinska Institutet Stockholm, Sweden