Once in a great while a discovery is made that changes the face of medicine forever. In 1998, the Nobel prize for Medicine and Physiology was shared between Furchgott, Ignarro and Murad for their work in beginning to uncover the functions of nitric oxide in the body. This was such a milestone.
Nitric oxide (NO) is a very simple molecule, just one nitrogen and one oxygen. It is manufactured using the amino acid arginine. It exists as a gas, with a life within the body of only a few seconds, but in those few seconds the range of events this humble, simple gas can orchestrate is truly amazing.
In the years since it was first discovered that nitric oxide has biological functions, over 70,000 articles have been published, a journal exists devoted entirely to nitric oxide research and there is also a Nitric Oxide Society. Even plants and insects use nitric oxide systems in much the same way people and animals do.
Mammals have at least three different sets of enzymes for generating NO:
- eNOS – endothelial nitric oxide synthetase. This is located in the cells lining blood vessels
- iNOS – inducible nitric oxide synthetase. Located primarily in immune system cells.
- nNOS – neuronal nitric oxide synthetase. Inside nerves.
Nitric oxide performs different functions in various tissues and under different circumstances. In the normal course of affairs, low level production of NO by the eNOS system keeps vessels dilated and blood flowing smoothly. Hemoglobin inside the red cells readily binds the NO, which in turn makes the hemoglobin pick up more oxygen. Once the blood reaches the tissue level, the NO is released and helps dilate vessels to receive the oxygen rich blood. Releasing the NO also releases the hold hemoglobin has on the oxygen, freeing it up for the tissues to use.
In the nervous system, low levels of NO from the nNOS system allow nerve cells to communicate with each other and NO production is absolutely essential to learning and memory. White cells in the tissues and the blood are constantly on the look out for any invading organisms, which they promptly destroy using nitric oxide.
As is usually the case though, you can have too much of a good thing. Trauma/injury, hypertension, allergy, infection, even cancer and arthritis, are all characterized by very high levels of nitric oxide production from the iNOS enzyme system.
Nitric oxide is a free radical, a substance with a deficiency of electrons that will damage cell membranes in its quest to be electrically neutral. In the normal state of affairs, the low levels of nitric oxide are easily handled by the body. However, overproduction leads to cell damage, inflammatory reactions and pain.
High production of NO by these pathways also blocks the normal, beneficial effect of NO on blood vessel dilation. Vessels spasm and clotting is activated. Most of the research on nitric oxide has been done with human problems in mind but even a quick look through the list of the some of the things nitric oxide does, both good and bad, makes it obvious this substance is very important to the horse as well.
Nitric Oxide in Horses
Interest in nitric oxide in horses has already led to some discoveries and even therapies:
- Several studies have identified nitric oxide as the “signal” that makes joint cartilage respond to loading and that abnormally high nitric oxide levels occur with arthritis in horses just like it does in people
- A study from Sweden showed that delivery of small amounts of nitric oxide to the lungs during anesthesia improved blood distribution in the lung and oxygen uptake
- Ohio State studies have found that the cerebrospinal fluid of horses with severe signs of EPM contains significantly less nitric oxide than the CSF of horses with no or mild symptoms after infection. This could be the immune system defect that explains why only a small percentage of horses exposed to the EPM organism ever get the disease
- Increased activity of the iNOS enzyme has been associated with allergic lung disease/heaves, and this may lead to a simple diagnostic test that measures the level of exhaled NO gas
- A University of Florida study has demonstrated that breathing low concentrations of nitric oxide dilates the vessels in the lungs of foals and reduces pressure in the pulmonary artery, an effect that may be very beneficial to premature foals with pulmonary hypertension. This therapy for “premies” is already in use with human babies.
- Even a partial block in nitric oxide production produces profound reduction in exercise tolerance according to a Kansas State study.
- A University of Pennsylvania study showed that inhaled nitric oxide can help relieve bronchospasm induced by histamine.
- A study performed in the UK showed that blocking NO production during exercise caused anhidrosis and elevated body temperature
Drugs Affecting Nitric Oxide
Nitroglycerin has been used by human doctors to control chest pain (angina) in people with heart disease for well over a 100 years, although no one had a clue as to why it worked.
Studies being performed by two of the 1998 Nobel prize winners, working in different laboratories, finally put it all together. One showed that nitroglycerin releases nitric oxide while the other proved that nitric oxide is naturally produced by the cells lining blood vessels and causes them to relax. Mystery solved.
The discovery of nitric oxide has also explained why common NSAIDs like phenylbutazone and flunixin meglumine can cause stomach ulcers. A key effect in reducing inflammation is their ability to shut down the iNOS enzyme system. Unfortunately, in the process they also shut down the beneficial eNOS system, and do such a good job in shutting down iNOS that they also block the normally present low levels of NO from the iNOS system that are important in triggering tissues to repair minor injuries.
Researchers now have the information they need to develop safer drugs. In fact, they’re already on the way. The newest class of anti-inflammatory drugs being developed combines the traditional NSAIDs with a nitric oxide donor to replace the low level nitric oxide production they are blocking. These drugs are already being tested in people and have been shown to greatly reduce the likelihood of stomach damage when taking NSAIDs.
Pentoxifylline (Trental) is a drug that is being used by veterinarians in hopes of encouraging circulation to the feet (for treatment of laminitis and navicular disease), and to both relax and encourage good blood flow in the uterus. A Canadian study found that high dose pentoxifylline given to horses with COPD (“heaves”) improved breathing, and a University of Georgia study showed that pentoxifylline can help block inflammatory responses to endotoxins. Turns out pentoxifylline works by influencing the nitric oxide producing enzyme systems. It slows breakdown of a substance called cAMP, which is the trigger for production of nitric oxide inside blood vessels and low level production of nitric oxide by other NO enzyme systems. High levels of cAMP inhibit overproduction of nitric oxide by inflammatory pathways at the same time, so the end effect is to “balance” the enzyme systems so that they stay more at normal levels rather than getting carried away and producing the high, damaging levels of nitric oxide characteristic of disease. Unfortunately, it doesn’t work too well in improving blood flow in laminitis.
Jiaogulan to Help Laminitic Horses
What does help laminitic horses is use of the herb Gynostemma pentaphyllum, aka Jiaogulan. This Chinese herb has been shown to support production of eNOS enzyme while suppressing activity of the inflammatory iNOS.
Jiaogulan in combination with the arginine donor AAKG (arginine alpha-ketoglutarate) also helps relieve symptoms, delay progression and improve tissue quality of horses with DSLD, degenerative suspensory ligament desmitis, a body wide disorder of connective tissue. Nitric oxide also helps degenerative tendon and ligament problems in humans and nitric oxide production has been proven to be critical to all stages of healing of these tissues.
Research both in horses and other species continues to uncover details regarding how nitric oxide is involved in health and disease at an astounding rate, has improved our understanding of both the actions and side effects of common drugs and even resulted in the development of new classes of drugs. Perhaps most importantly of all, it’s helping to drive home the lesson that the difference between health and disease at the most basic levels is about balance between body systems and that the most effective treatments are going to be those that work to restore that balance.
Beneficial Functions of Nitric Oxide
- Keeping blood vessels open and blood flowing smoothly
- Uptake of oxygen by hemoglobin and delivery of oxygen at the tissue level
- Signaling molecule in the nervous system
- Destruction of invading micro-organisms by the primitive immune system
- Maintenance of skeletal muscle sensitivity to insulin
- Release of insulin from the pancreas
- Release of “growth factors”, local hormones responsible for the growth of all tissues and healing after injuries
- Control of fluid and electrolyte balance by the kidney
- Activation of T cells
- Ability to smell
- Essential for memory and central nervous system control of movement
- Penetration of egg by sperm
- Control of tone in the intestinal tract
- Protection of the lining of the stomach from ulcer formation
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