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Carbon monoxide: Silent killer or potential life saver?

By David Bowkett
Target Discovery Institute, University of Oxford, UK

This summary was highly commended by the judges for Access to Understanding 2015

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The dangers of carbon monoxide are increasingly well known to the public, especially in relation to faulty gas central heating systems. Indeed, carbon monoxide accounts for more than 50% of all fatal poisonings. Carbon monoxide’s deadly toxicity arises when it binds to haemoglobin, stopping this protein from efficiently transporting oxygen around the body.

Recent research has suggested that the level of carbon monoxide typically found in built-up areas with lots of traffic may also be damaging to health. Long-term exposure has been linked to damage of the heart and brain, particularly in the elderly. Recently, researchers at Leeds University found that carbon monoxide interferes with a sodium channel called NaV1.5. This channel lets sodium ions move into the cell, which is an important part of sending a nerve signal. They showed that disruption of this sodium channel by carbon monoxide led to a disruption of the heartbeat known as a heart arrhythmia.

Less well known than carbon monoxide’s toxic effects, is the increasing scientific interest in the role played by carbon monoxide in everyday bodily functions across a wide range of organs, including the heart and brain. It will come as a surprise to many that the human body produces carbon monoxide. Dissolved carbon monoxide can move through bodily fluids very quickly, allowing it to be used by the body to send signals. There are even potential therapeutic uses for carbon monoxide, for example it has been suggested that carbon monoxide could be used to reduce the damage caused by restricted blood flow to the heart. This condition, known as myocardial ischemia, is caused by the build up of cholesterol-rich plaques in the coronary arteries, and is one of the largest causes of death in the Western world.

For carbon monoxide to be therapeutically useful, researchers will need to identify its ‘therapeutic window’. This is the point at which enough carbon monoxide is given to a patient to cause the desired therapeutic effect, but not so much as to cause side effects like arrhythmias. To help establish the therapeutic window, the team from Leeds have been conducting new investigations into the effects of low levels of carbon monoxide. They once again turned their attention to the sodium channel identified in their previous study.

The researchers modified a type of human embryonic kidney cell, commonly used in biological studies, to contain many more copies of the sodium channel NaV1.5 than usual. They then used a sensitive device called a patch clamp, which can measure the electrical current caused by the movement of sodium ions into the cell. NaV1.5 is a voltage-dependant sodium channel, which means that sodium only flows through it when a voltage is applied. In the body this voltage would come from a nerve signal. The researchers stimulated the channel by applying a small voltage for a time period as short as four hundredths of a second. A correctly functioning channel will only allow sodium ions to flow through it for less than a tenth of a second after the voltage has been applied, before closing and preventing the flow of any more sodium ions.

By using a chemical that slowly releases carbon monoxide, the team were able to study the effects of carbon monoxide on the flow of sodium ions. They found that carbon monoxide reduced the size of the current, but not the length of time that sodium ions flowed through the channel. Previous experiments had shown that carbon monoxide is able to induce an effect called a late current, meaning that the sodium channel is kept open for longer, however that was not seen in this study.

The team ruled out various possible causes for this discrepancy, before showing that the effect of lengthening the current only occurs in cells that can produce another important signalling molecule called nitric oxide (not to be confused with nitrous oxide, or ‘laughing gas’). They were able to show that a nitric oxide-producing enzyme called nNOS was required for carbon monoxide to cause a late current, but not for carbon monoxide to reduce the size of the current. This implies that carbon monoxide’s effects on the size and length of the current occur through different mechanisms.

It should be remembered that observations made in isolated embryonic kidney cells may not be entirely representative of native tissue. Nonetheless this research has begun to explore the effects of carbon monoxide on sodium channels. The team showed that carbon monoxide can reduce the size of the current that flows through NaV1.5, and the length of time the channel stays open for, however carbon monoxide does this by different mechanisms. If carbon monoxide is to be used for therapeutic purposes, further research will be required into its potential side effects.

This article describes the research published in:

Inhibition of the cardiac Na⁺ channel NaV1.5 by carbon monoxide
Elies, M. L. Dallas, J. P. Boyle, J. L. Scragg, A. Duke, D. S. Steele, C. Peer Biol. Chem. (2014) 289(23), 16421–16429
http://EuropePMC.org/articles/PMC4047409

This article was selected for inclusion in the competition by the British Heart Foundation.

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