Nitric Oxide: An Emerging Miracle Molecule

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Once in a while a discovery is made that changes the face of medicine forever: Bacteria as a cause of infections, effective anesthetics, penicillin and the first vaccine are examples. In 1998, Americans Robert F. Furchgott, Louis J. Ignarro and Ferid Murad earned the Nobel Prize for Medicine and Physiology for their work on the functions of nitric oxide in the body. We believe this is another one of those scientific milestones.

We’re not talking about nitrous oxide, commonly called “laughing gas.” Nitric oxide (NO) is a simple molecule (one nitrogen, one oxygen). It exists as a gas, with a life within the body of only a few seconds, but in that blink of an eye this humble, simple gas can orchestrate a truly amazing change of events. Interest has risen so quickly that there’s a journal devoted entirely to nitric-oxide research and a Nitric Oxide Society.

We’ve learned that plants and insects use nitric oxide systems in much the same way people and animals do, and more research about how nitric oxide is involved in health and disease is appearing at an astounding rate. It has improved our understanding of both the actions and side effects of common drugs and even resulted in the development of new drug classes.

Perhaps most importantly, now research is driving home the lesson that the difference between health and disease at the most basic level is about balance between body systems. It’s clear that the most effective treatments are going to be those that work to restore that balance.

The Horse Connection
Most of the research on nitric oxide has been done with human problems, but equine research is rapidly expanding with promising results in several areas:

• Arthritis. 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.

• Oxygen Uptake. A study that was done in Sweden showed that delivery of small amounts of nitric oxide to the lungs during anesthesia improved blood distribution in the lung and oxygen uptake.

• EPM. Ohio State studies found that the cerebrospinal fluid (CSF) 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 finding could be the immune-system defect that explains why only a small percentage of horses exposed to the EPM organism ever get the disease.

• COPD/Heaves. Increased activity of the iNOS enzyme has been associated with allergic lung disease/heaves, which may lead to a simple diagnostic test that measures the level of exhaled nitric-oxide gas. In addition, a University of Pennsylvania study showed that inhaled nitric oxide can help relieve bronchospasm induced by histamine.

• Premature Foals. 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 beneficial to premature foals with pulmonary hypertension. Nitric oxide is already in use with human babies.

• Exercise Tolerance. A Kansas State University study found even a partial block in nitric-oxide production produces profound reduction in exercise tolerance.

• Anhidrosis. A study performed in the United Kingdom showed that blocking nitric-oxide production during exercise caused anhidrosis and elevated body temperature.

New Drugs
Nitric oxide explains why common NSAIDs like phenylbutazone and flunixin meglumine (Banamine) 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 block the normally present low levels of nitric oxide from the eNOS system that are important in triggering the tissues to repair minor injuries.

However, this finding gave researchers the information they need to develop safer drugs. In fact, they’re 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’re 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 used by veterinarians to encourage 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.

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