LONDON - A study of almost 100 British Army recruits undergoing physical training has turned up clues as to why some people lose weight quickly when they exercise, and why others fail to shed their unwanted pounds despite spending hours in the gym. The research could lead to a large expansion in the use of two classes of drugs currently used to treat heart failure and high blood pressure: ACE inhibitors and AT1 receptor antagonists.

The commercial rights to the discoveries, which were made by a team led by a group at University College London (UCL), are held by Eurogene Ltd., an emerging pharmaceutical company. Eurogene has filed patent applications for a wide range of therapeutic uses for agents which inhibit angiotensin converting enzyme (ACE) or block the effects of its product. Since Eurogene's shareholders include UCL, much of the resulting income from commercial exploitation will be channeled back into medical research.

John Martin, professor of cardiovascular medicine at UCL and chief scientific officer of Eurogene, told BioWorld International: "Given the results we already have, we are optimistic that the company should be able to make available treatments that will be beneficial in a variety of disorders that are presently without adequate treatment."

Hugh Montgomery, a physician at the Centre for Cardiovascular Genetics at UCL, said the "study group was all male, all 18 years old and all eating an Army diet, so we can't say how our findings relate to 'Mr. and Mrs. Average.' I think it is still the case that if you want to lose weight, you take more exercise and you eat less, and that this may be more difficult for some people than for others."

The research sheds light on the work of the renin-angiotensin system, he said. "For years, we thought this system was only important in heart failure and blood pressure control," Montgomery said. "Our data now suggest that this system may be playing much wider roles in tissues."

The real importance of the work, he added, was that agents which affect this system might be able to improve the survival of cells affected by poor blood supply and low oxygen levels, in conditions ranging from stroke and myocardial ischemia to congenital heart disease and respiratory diseases.

"These are exciting times," said Montgomery. "The market for ACE inhibitors and agents that block the product of ACE could go through the roof."

ACE plays a key role in a system of molecules and enzymes known as the renin-angiotensin system. This has a well-known role in regulating blood pressure in humans. When the kidney senses that blood pressure is low, it produces renin. This acts on a substance produced by the liver, called angiotensinogen, which results in the production of angiotensin I, the substrate for ACE. ACE lops off two of the 10 amino acids of angiotensin I, to produce angiotensin II.

Angiotensin II causes constriction of the blood vessels and acts on the adrenal glands, causing them to release a hormone called aldosterone, which makes the kidneys retain salts and water. Both of these effects act to raise blood pressure.

About 10 years ago, however, scientists discovered that ACE was present in a huge variety of animals, from mosquitoes and worms to birds and fish. This raised the suspicion that ACE had other roles in metabolism, apart from the regulation of blood pressure in higher animals, but no one knew what these roles were. Other studies showed that the renin-angiotensin system, as well as angiotensinogen and ACE were virtually omnipresent in human cells and tissues. They were found in ovaries, testes, hair follicles, heart, fat, muscle, eyes and a huge range of other tissues.

Further research suggested that the renin-angiotensin system, and the other molecules involved with it, might play a role in regulating the response to injury, such as scarring and cell growth. For obvious reasons, these aspects were difficult to study in humans.

Investigations of this kind received a fillip, however, when researchers found that there was a natural genetic variation, a polymorphism, in the gene encoding ACE. Some people have a fragment of the gene, 287 base pairs long, missing. This is the deletion polymorphism, or D. In others, this fragment is present: the insertion polymorphism, or I. So everyone is either DD, ID or II for this allele. People who are II have low ACE levels in their tissues, while the DD allele is associated with high ACE levels.

Genotypes Correlated Strongly With Heart Growth

These findings opened the way for a host of studies, including several carried out by Montgomery and his colleagues. "We had good data from work on rats and pigs that the renin-angiotensin system and ACE system control growth of the heart," he said. "As it is well known that if you exercise hard, your heart grows, we decided to take a group of people who were embarking on an exercise program and see how the rate of growth of their hearts varied with their ACE gene polymorphism."

The team used military recruits for the study because they exercise vigorously to a set protocol for 10 weeks. They found that recruits who were DD had heart growth about 25 times bigger than the men who were II. The left ventricles of II people, whose tissues had low ACE activity, only put on two or three grams of weight (as estimated from scans), whereas those who were DD put on about 50 grams.

This finding begged the question of whether people who were DD were naturally able to grow bigger muscles more easily. So, the team examined how long the recruits were able to go on lifting weights up to their chests, and looked to see how this correlated with their ACE gene genotypes.

"We found an 11-fold difference," Montgomery said. "But, interestingly, it was the II genotype, with low ACE activity, that did best. They were able to go on lifting these weights about 11 times longer than those who were DD. This was slightly against what we had expected, which was that if the DD allele makes your heart grow more, maybe it makes your muscles grow more, and maybe you do better. But, in fact, performance was 11 times better for those who were II rather than DD."

Perhaps, the researchers postulated, II people did better because their cells were more efficient, that is, able to do more work for less energy. If this was true, the group reasoned, you would expect to see an excess of II people among high-altitude mountaineers. This was exactly what they found. These results, and the ones on heart growth and weight-lifting, appeared in a paper in Nature last May.

How could the researchers find out if their hypothesis was correct: that the muscle activity of DD people was less efficient and that of II people more efficient? The next experiment they designed set out to compare the body composition and morphology of DD people and II people. Montgomery said: "We expected that the DD people, whom we were saying had less efficient muscle activity, would have to burn off more fat to do the same amount of work, and the II people, whose muscles we were saying were very efficient, would burn off fewer calories, less fat."

This is the study reported in last week's Lancet, titled "Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training." Again, the study population was military recruits.

The researchers examined the composition of the recruits' bodies using three different methods that allowed them to estimate the amount of fat, water and muscle. "All three methods showed the same thing," Montgomery said. "As we had hoped to find, the II people [with] low ACE activity put on muscle and put on fat, whereas DD people lost fat and lost muscle, suggesting that they were having to burn more calories to get the same amount of work done."

Where do ACE inhibitors fit in with all of this? They are currently used to treat high blood pressure and heart failure. They are very effective and have few side effects. But, Montgomery said, it has always been something of a mystery why they are so effective. "If all they were doing was making you lose salts and water and opening up your blood vessels, they really ought to be no better than other drugs with the same effects," he said. "But they are very much better than these other agents. Our data on military recruits, coupled with other discoveries on the biology of the mitochondrion, and by scientists at UCL, could help to provide a new understanding of why this is."

Patents Filed Covering Variety Of Uses

It is possible, he said, that if low angiotensin II levels make muscles more efficient, then giving the right agent could make it possible to get more work out of the skeletal muscles for the same amount of energy, and the heart would therefore need to do less work delivering the blood. Secondly, if the same theory was applied to the heart, the heart itself could do more work on less energy, and would therefore last longer.

"This means that, potentially, by giving ACE inhibitors to people with diseases in which blood supply and oxygen delivery is reduced, you might be able to improve the survival of the affected cells and their function," Montgomery said. "These drugs are well established and some may have huge benefits to large numbers of people. That is really very exciting."

To ensure that the profits from this discovery are mainly plowed back into research, Eurogene, working with Montgomery and his colleagues at UCL, has patented the use of agents that reduce angiotensin for a wide range of conditions.

Martin said the company has filed broad patents which "relate to mitochondrial efficiency and cellular metabolism in the musculoskeletal and cerebrovascular systems." The company is in discussion with a number of other firms regarding exploitation of the patents.

Montgomery said he and his colleagues want to examine the influence of polymorphisms in other genes relevant to the renin-angiotensin system (such as those encoding angiotensinogen and the angiotensin II receptor) on performance and body morphology. "We will have that answer within a few months," he said.

"We also need to see," he added, "whether we can intervene with ATII antagonists and ACE inhibitors to improve performance, to change body morphology and to change efficiency. This will involve two sets of work. In animals, we are looking to see if you can make a heart work more efficiently, and in humans we are looking to see how enhanced cellular metabolism might be beneficial to brain and muscle."

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