Press Release: The 1998 Nobel Prize in Physiology
or MedicineNOBELFÖRSAMLINGEN KAROLINSKA INSTITUTET
THE NOBEL ASSEMBLY AT KAROLINSKA INSTITUTET
October 12, 1998
The Nobel Assembly at Karolin's Institutet
www.nobelprize.org 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.
