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 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.
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. | 
