Reporter: Aviva Lev-Ari, PhD, RN
On August 16, 2012 I received an e-mail on New@NEJM.org from this e-mail, I selected to post HERE, the
Cardiology Panel — NEJM Dialogue in Medicine, June 22, 2012
While listening to the 1:35 minutes of the Video of the Cardiology Panel, the Nobel Prize for Nitric Oxide was mentioned. In light of the thrust, this Scientific Web Site has related to Nitric Oxide in Health and in Disease, I decided to cite here the entire Letter from the Nobel Prize Web Site.
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.
MLA style: “Physiology or Medicine for 1998 – Press Release”. Nobelprize.org. 16 Aug 2012 http://www.nobelprize.org/nobel_prizes/medicine/laureates/1998/press.html
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.