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
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
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.
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
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 gate keeper 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.
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