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Press Release: The 1998 Nobel Prize in Physiology or
Medicine
NOBELFÖRSAMLINGEN KAROLINSKA INSTITUTET
THE NOBEL ASSEMBLY AT
KAROLINSKA INSTITUTET
October 12, 1998
The Nobel Assembly at Karolinska
Institutet has today decided to award the Nobel Prize in
Physiology or Medicine for 1998 jointly to
Robert F.
Furchgott, Louis J. Ignarro and Ferid Murad
for
their discoveries concerning "nitric oxide as a signalling molecule
in the cardiovascular system".
Summary
Nitric oxide (NO) is a gas that transmits
signals in the organism. Signal transmission by a gas that is
produced by one cell, penetrates through membranes and regulates the
function of another cell represents an entirely new principle for
signalling in biological systems. The discoverers of NO as a signal
molecule are awarded this year's Nobel Prize.
Robert F Furchgott, pharmacologist in New
York, studied the effect of drugs on blood vessels but often
achieved contradictory results. The same drug sometimes caused a
contraction and at other occasions a dilatation. Furchgott wondered
if the variation could depend on whether the surface cells (the
endothelium) inside the blood vessels were intact or damaged. In
1980, he demonstrated in an ingenious experiment that acetylcholine
dilated blood vessels only if the endothelium was intact. He
concluded that blood vessels are dilated because the endothelial
cells produce an unknown signal molecule that makes vascular smooth
muscle cells relax. He called this signal molecule EDRF, the
endothelium-derived relaxing factor, and his findings led to a quest
to identify the factor.
Ferid Murad, MD and pharmacologist now in
Houston, analyzed how nitroglycerin and related vasodilating
compounds act and discovered in 1977 that they release nitric oxide,
which relaxes smooth muscle cells. He was fascinated by the concept
that a gas could regulate important cellular functions and
speculated that endogenous factors such as hormones might also act
through NO. However, there was no experimental evidence to support
this idea at the time.
Louis J Ignarro, pharmacologist in Los
Angeles, participated in the quest for EDRF's chemical nature. He
performed a brilliant series of analyses and concluded in 1986,
together with and independently of Robert Furchgott, that EDRF was
identical to NO. The problem was solved and Furchgott's endothelial
factor identified.
When Furchgott and Ignarro presented their
conclusions at a conference in July, 1986, it elicited an avalanche
of research activities in many different laboratories around the
world. This was the first discovery that a gas can act as a signal
molecule in the organism.
Background
Nitric oxide protects the heart, stimulates
the brain, kills bacteria, etc.
It was a sensation that this simple, common air
pollutant, which is formed when nitrogen burns, for instance in
automobile exhaust fumes, could exert important functions in the
organism. It was particularly surprising since NO is totally
different from any other known signal molecule and so unstable that
it is converted to nitrate and nitrite within 10 seconds. NO was
known to be produced in bacteria but this simple molecule was not
expected to be important in higher animals such as mammals.
Further research results rapidly confirmed that
NO is a signal molecule of key importance for the cardiovascular
system and it was also found to exert a series of other functions.
We know today that NO acts as a signal molecule in the nervous
system, as a weapon against infections, as a regulator of blood
pressure and as a gatekeeper of blood flow to different organs. NO
is present in most living creatures and made by many different types
of cells.
- When NO is produced by the innermost cell layer of
the arteries, the endothelium, it rapidly spreads through the cell
membranes to the underlying muscle cells. Their contraction is
turned off by NO, resulting in a dilatation of the arteries. In this
way, NO controls the blood pressure and its distribution. It also
prevents the formation of thrombi.
- When NO is formed in nerve
cells, it spreads rapidly in all directions, activating all cells in
the vicinity. This can modulate many functions, from behaviour to
gastrointestinal motility.
- When NO is produced in white blood
cells (such as macrophages), huge quantities are achieved and become
toxic to invading bacteria and parasites.
Importance in medicine today and tomorrow
Heart: In atherosclerosis, the
endothelium has a reduced capacity to produce NO. However, NO can be
furnished by treatment with nitroglycerin. Large efforts in drug
discovery are currently aimed at generating more powerful and
selective cardiac drugs based on the new knowledge of NO as a signal
molecule.
Shock: Bacterial infections can lead to
sepsis and circulatory shock. In this situation, NO plays a harmful
role. White blood cells react to bacterial products by releasing
enormous amounts of NO that dilate the blood vessels. The blood
pressure drops and the patient may become unconscious. In this
situation, inhibitors of NO synthesis may be useful in intensive
care treatment.
Lungs: Intensive care patients can be
treated by inhalation of NO gas. This has provided good results and
even saved lives. For instance, NO gas has been used to reduce
dangerously high blood pressure in the lungs of infants. But the
dosage is critical since the gas can be toxic at high
concentrations.
Cancer: White blood cells use NO not only
to kill infectious agents such as bacteria, fungi and parasites, but
also to defend the host against tumours. Scientists are currently
testing whether NO can be used to stop the growth of tumours since
this gas can induce programmed cell death, apoptosis.
Impotence: NO can initiate erection of
the penis by dilating the blood vessels to the erectile bodies. This
knowledge has already led to the development of new drugs against
impotence.
Diagnostic analyses: Inflammatory
diseases can be revealed by analysing the production of NO from e.g.
lungs and intestines. This is used for diagnosing asthma, colitis,
and other diseases.
NO is important for the olfactory sense and our
capacity to recognise different scents. It may even be important for
our memory.
Nitroglycerin
Alfred Nobel invented dynamite, a product in
which the explosion-prone nitroglycerin is curbed by being absorbed
in kieselguhr, a porous soil rich in shells of diatoms.
When
Nobel was taken ill with heart disease, his doctor prescribed
nitroglycerin. Nobel refused to take it, knowing that it caused
headache and ruling out that it could eliminate chest pain.
In a
letter, Nobel wrote: It is ironical that I am now ordered by my
physician to eat nitroglycerin.
It has been known since last
century that the explosive, nitroglycerin, has beneficial effects
against chest pain. However, it would take 100 years until it was
clarified that nitroglycerin acts by releasing NO
gas. | 
