Dr.NO
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NO has been used therapeutically to treat certain diseases characterized by NO insufficiency , including hypertension, angina and impotence. There is evidence that the L-arginine / NO system is defective in patients with hyper tension and possibly angina. NO has actually been used to treat angina for over 100 years in the form of nitroglycerin. Only recently have researchers determined that it is the NO releases by the Nitoglycerin (NG)in the vascular wall that is responsible for the activity of the NG. Inhaled NO has also proved effective, after cardio pulmonary bypass surgery, for pulmonary hypertension common in neonatal and adult respiratory distress syndrome.
One of the most relevant studies on NO ” Detection of Nitric Oxide in Mice by Electreon Paramagnetic resonance techniques” has been conducted essentially to detect, to quantify nitric oxide and to assess the role nitric oxide plays in certain neurological disease, including Huntington’s disease. It is the investigation of NO’s ties to the other closely related neurons ahat helped shed some light on its functions. A comparison on the amount of Nitric oxide present in a healthy, control mouse and a mouse with a neurological disease was carried out so as to determine whether increase nitric oxide levels are associated with the disease state.
DISCOVERY OF A ROLE FOR NITRIC OXDIE
Nitric oxide was first identified as a gas by Joseph Priestly in 1772 and is a simple molecule consisting of just one atom of oxygen and one atom of nitrogen. For much of the time since this discovery nitric oxide, or NO, has been thought of simply as an atmospheric pollutant.
In the 1980’s researchers were investigating how blood vessels dilate (or relax). Dilation of blood vessels, also known as vasodilation, is extremely important for controlling blood pressure as dilated blood vessels have a larger diameter which allows blood to flow with lower pressure. Conversely, constriction of blood vessels narrows their diameter and increases blood pressure.
At the time drugs such as nitroglycerin were given to patients for heart conditions like angina in order to promote vasodilation and reduce blood pressure, but no-one knew how these drugs worked.
In 1980 Robert Furchgott investigated the role of a drug called acetylcholine on vasodilation and found that relaxation of blood vessels only occurred if a special class of cells called endothelial cells were present. Endothelial cells are the cells that line the insides of blood vessels and are in direct contact with the blood (see animation below). Behind the endothelial cells are another specialised type of cell known as smooth muscle cells. The contraction and relaxation of these muscle cells is thought to be responsible for constricting or dilating the blood vessels.
Robert Furchgott and his group found that without the endothelial cells the smooth muscle cells were not able to cause vasodilation. This suggested that there was some kind of factor produced by the endothelial cells that was required for relaxation of the blood vessels. This factor was termed Endothelial Derived Relaxing Factor or EDRF and the search to find and identify EDRF began.
Independently, in 1977 Ferid Murad was investigating how nitroglycerin works and discovered that it can release nitric oxide which in turn was able to cause relaxation of smooth muscle cells.
The pieces of the puzzle were finally put together in 1986 when Louis Ignarro identified EDRF and found that it had identical properties to the gas nitric oxide. This was the first time that a gas had been shown to play an important role in regulating biological functions in humans. For their role in this discovery Furchgott, Murad and Ignarro were awarded the Nobel Prize for Medicine or Physiology in 1998.
Since the discovery of this role for nitric oxide it has been shown to be involved in a large number of other roles, some of which are described here. It has also been shown to be important in s wide variety of different species from plants, to insects and mammals. Only a small number of other gases have been shown to play a role in mammalian cells. These are carbon monoxide and hydrogen sulphide, although these two gases appear to have far fewer role than nitric oxide.
SYNTHESIS OF NITRIC OXIDE
Nitric oxide is produced by a group of enzymes called nitric oxide synthases. These enzymes convert arginine into citrulline, producing NO in the process. Oxygen and NADPH are necessary co-factors. There are three isoforms of nitric oxide synthase (NOS) named according to their activity or the tissue type in which they were first described. The isoforms of NOS are neuronal NOS (or nNOS), endothelial NOS (or eNOS) and inducible NOS (or iNOS). These enzymes are also sometimes referred to by number, so that nNOS is known as NOS1, iNOS is known as NOS2 and eNOS is NOS3. Despite the names of these enzymes, all three isoforms can be found in a variety of tissues and cell types. The general mechanism of NO production from NOS is illustrated below.
Two of the enzymes (nNOS and eNOS) are constitutively expressed in mammalian cells and synthesise NO in response to increases in intracellular calcium levels. In some cases, however, they are able to increase NO production independently of calcium levels in response to stimuli such as shear stress.
iNOS activity is independent of the level of calcium in the cell, however its activity – like all of the NOS isoforms – is dependent on the binding of calmodulin. Increases in cellular calcium lead to increases in levels of calmodulin and the increased binding of calmodulin to eNOS and nNOS leads to a transient increase in NO production by these enzymes. By contrast iNOS is able to bind tightly to calmodulin even at very low cellular concentration of calcium. Consequently iNOS activity doesn’t respond to changes in calcium levels in the cell. As a result the production of NO by iNOS lasts much longer than from the other isoforms of NOS, and tends to produce much higher concentrations of NO in the cell.
The production of NO by iNOS can, however, be controlled through transcription. In most cell types iNOS protein levels are either very low or undetectable. However, stimulation of these cells with, for example, cytokines or growth factors, can lead to increased transcription of the iNOS gene, with subsequent production of NO.
The general structure of the NOS
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ROLE OF NITRIC OXIDE IN BIOLOGY
Since it was first discovered to play a role in the dilation of blood vessels many new roles for Nitric Oxide (NO) have been discovered. Nitric oxide has been found to be produced by virtually every cell type in the body and plays an important role in controlling the normal function of cells as well as in regulating larger scale processes such as the nervous and immune systems. Some of these biological roles for NO are described in more detail below.
Nitric oxide plays many important roles in the immune system. It is produced in high amounts from specialised cells of the immune system called macrophages. Following a bacterial infection, for example, the body produces chemicals known as cytokines which activate the cells of the immune system, including macrophaes, and help guide them to the site of infection. The high amounts of nitric oxide produced by the macrophages is actually toxic to the bacteria and plays an important role in their destruction (see image on the right). The production of nitric oxide in this way also help protect against other types of infection including viruses and parasites.
However, too much nitric oxide production has also been implicated in conditions where the immune system is too active – diseases like arthritis and the so-called autoimmune diseases.
THE NERVOUS SYSTEM
Nitric oxide is involved in many aspects of reproduction. It is thought to play a role in the implantation of the early embryo in the uterus and it functions to relax blood vessels and thereby helps to regulate maternal blood pressure. During pregnancy nitric oxide may also play a role in promoting the formation of new blood vessels, a process known as angiogenesis. It is also known to be an important survival factor for specialist cells called trophoblasts which form the placenta. There is also evidence that complications of pregnancy such as preeclampsia may be associated with reduced production of nitric oxide.
In addition drugs such as Viagra help overcome erectile dysfunction by affecting nitric oxide signalling.
REPRODUCTIVE BIOLOGY
Nitric oxide is involved in many aspects of reproduction. It is thought to play a role in the implantation of the early embryo in the uterus and it functions to relax blood vessels and thereby helps to regulate maternal blood pressure. During pregnancy nitric oxide may also play a role in promoting the formation of new blood vessels, a process known as angiogenesis. It is also known to be an important survival factor for specialist cells called trophoblasts which form the placenta. There is also evidence that complications of pregnancy such as preeclampsia may be associated with reduced production of nitric oxide.
In addition drugs such as Viagra help overcome erectile dysfunction by affecting nitric oxide signalling.
CELLULAR FUNCTION
A wide range of cellular activity can be regulated by nitric oxide including cell division, cell survival and cell movement.
Most cells have an in-built self-destruct system or cell suicide mechanism. This mechanism, usually called apoptosis or programmed cell death, exists to prevent damaged or infected cells from affecting the proper functioning of the rest of the tissue. Once triggered the apoptotic pathway leads to the breakdown of the structure of the cell in an organised manner, leading to a cell that is smaller and more neatly “packaged” ready for removal by cell of the immune system.
Nitric oxide has been shown to inhibit apoptosis and therefore is important in promoting cell survival. However, high doses of nitric oxide have been reported as being toxic to many cell types and in these circumstances may promote cell death instead.
CELLULAR FUNCTION
A wide range of cellular activity can be regulated by nitric oxide including cell division, cell survival and cell movement.
Most cells have an in-built self-destruct system or cell suicide mechanism. This mechanism, usually called apoptosis or programmed cell death, exists to prevent damaged or infected cells from affecting the proper functioning of the rest of the tissue. Once triggered the apoptotic pathway leads to the breakdown of the structure of the cell in an organised manner, leading to a cell that is smaller and more neatly “packaged” ready for removal by cell of the immune system.
Nitric oxide has been shown to inhibit apoptosis and therefore is important in promoting cell survival. However, high doses of nitric oxide have been reported as being toxic to many cell types and in these circumstances may promote cell death instead.
EXPERTS ON NITIC OXIDE(NO)
In 1980, Dr.Robert F. Furchgott published his discovery of endothelium – derived relaxing factor (EDRF) a mysterious Chemical in the inner linings of arteries that controls the artery’s widening and narrowing.
By 1986, he had worked out EDRF’s nature and mechanism and, from his 6th floor lab at the SUNY Health science Center at Brooklyn, announced that EDRF was in fact the tiny molecule Nitric Oxide (NO).
Between those years, laboratories around the globe were detailing EDRF’s importance in the body’s physiology, from regulating blood pressure to preventing blood clots.
In 1996, Dr. Robert F. Furchgott received the Albert Lasker Basic ‘Medical Research Award for his work at SUNY Downstate Medical Center in discovering, Nitric Oxide.
The foremost is Dr. Robert F. Furchgott of Brooklyn Hospital, New York, who discovered Nitric Oxide (NO) in the human body for the first time in the world. For this discovery Dr. Furchgott received the1998 Nobel Prize for Medicine.
Nitric Oxide (NO) functions as a signaling molecule in the cardiovascular system. Dr. Furchgott made the breakthrough discovery in 1998 that blood vessels are widened by Nitric Oxide (NO) thereby relaxing the blood vessels and effecting good blood flow.
In 1998, another pioneer, Dr. John Garthwaite of the Liverpool Institute, London, discovered, for the first time ever, Nitric Oxide (NO) in the brain. He further discovered that Nitric Oxide (NO) plays a remarkable role as a messenger between brain cells, carrying information and improving connectivity.