June 18, 1999 DALLAS, June 15 -- A drug used to lower high blood pressure can stimulate the growth of new blood vessels in laboratory animals.
The findings, reported in today's Circulation: Journal of the American Heart Association, suggest that the drug, quinaprilat, may prove useful for treating people with severe chest pain (angina) and others at high risk of suffering a heart attack, says the study's senior author Jeffrey M. Isner, M.D., professor of medicine and pathology at Tufts University School of Medicine in Boston.
Quinaprilat, marketed as Acupril, is one of several drugs known as angiotensin-conversion-enzyme (ACE) inhibitors, which are used primarily to treat high blood pressure and congestive heart failure. These drugs block the activation of angiotensin, which in its active form causes blood vessels to constrict. When blood vessels are constricted, the heart has to pump harder to force blood through the body.
"The study demonstrates an unexpected function of a class of drugs that is commercially available and already has been shown to be safe to use. Quinaprilat deserves to be investigated for its potential use for promoting blood vessel growth," says Isner.
The study findings may explain previous reports that ACE inhibitors can benefit individuals who have reduced blood flow to their hearts that can cause chest pain, or angina, says Isner.
"One reason for the interest in this approach is that ACE inhibitors are drugs that can be taken orally," he adds. "If they work out for this kind of application, they would be easy for patients to use and potentially would be among the simplest strategies one could devise for promoting new blood vessel formation."
The growth of new blood vessels is called angiogenesis. In recent years, scientists have focused considerable attention on drugs and natural molecules in the body that promote or inhibit angiogenesis. Pro-angiogenesis treatments also could help people when leg blood vessels are obstructed by the fatty deposits of atherosclerosis. Many people now lose their legs due to poor circulation caused by atherosclerosis.
In heart disease, the goal is to grow new blood vessels to the heart as a way to route blood around arteries choked by fatty deposits that prevent the heart from getting enough oxygen-rich blood. Heart attacks occur when the heart is deprived of blood.
"This finding adds another class of agents that is capable of promoting angiogenesis," says Isner, chief of cardiovascular research at St. Elizabeth's Medical Center in Boston. "How it does that is not yet clear."
Isner and his colleagues wanted to determine if ACE inhibitors have a protective effect on the thin layer of cells that lines blood vessels. These endothelial cells play a major role in new vessel growth. "We wondered whether an agent that has a protective property could have a favorable effect in terms of promoting angiogenesis," he says.
Using rabbits, the team compared quinaprilat, another ACE inhibitor called captopril (Capoten), and vascular endothelial growth factor (VEGF) -- which the body produces to generate new blood vessels. A group of animals that received no treatment served as the comparison to the treated group.
Evidence of new vessel growth was obtained on the 10th and 40th days of the experiment. After 40 days a significant difference was found in the amount of tiny vessels known as capillaries in the legs of the rabbits treated with quinaprilat and VEGF, compared to the other animals.
The eight rabbits that received quinaprilat had an average capillary density of 214 per square millimeter, and the six animals that got VEGF had an average density of 228.8 capillaries per square millimeter. In contrast, the seven rabbits injected with captopril and the six given no treatment had significantly lower average capillary densities of 147.2 and 140.5 per square millimeter, respectively.
Although the mechanism by which some ACE inhibitors might stimulate blood vessel growth remains unknown, some research suggests that nitric oxide, a chemical produced by blood vessels that helps relax them, might be involved.
"It turns out that the ACE inhibitors, quinaprilat in particular, are a very potent means of augmenting nitric oxide availability," Isner says. "So the increased availability of nitric oxide may account for part of the effect we are seeing."
Why the quinaprilat-treated rabbits showed significantly greater vessel growth than those given captopril also remains uncertain. However, Isner suspects the two drugs act somewhat differently in the body. Although 10 percent of the body's angiotensin circulates in the bloodstream, the other 90 percent exists within certain tissues, including the endothelial cells.
Both ACE inhibitors were equally effective in blocking the activation of angiotensin in the bloodstream. However, it may be that quinaprilat has a much greater attraction for cells that bind angiotensin than does captopril. If so, quinaprilat would be more effective in raising nitric oxide levels in endothelial tissue than would captopril.
Previous work from Isner's lab has suggested that nitric oxide may be an important mediator of VEGF induced angiogenesis. VEGF may require nitric oxide to produce blood vessel growth. If ACE inhibitors promote availability of more nitric oxide, this increase of mediator may promote angiogenesis.
One unresolved issue is whether using ACE inhibitors to promote blood vessel growth in heart patients might also promote the growth of budding cancers. Solid tumors do not enlarge unless blood vessels grow into them to supply nutrients. Some compounds that inhibit angiogenesis are currently in testing as anticancer drugs.
"There is not yet any evidence that ACE inhibitors promote tumor growth or tumor metastasis," says Isner. "On the other hand, it hasn't been tested adequately, and that is something that will certainly deserve serious investigation."
Co-authors are Jean-Etienne Fabre, M.D.; Alain Rivard, M.D.; Meredith Magner, B.A.; and Marcy Silver, B.S.
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