New Information About Heart Enzymes Could Lead to Better Treatments

April 2, 2004

New evidence in animals about hormones that regulate blood pressure and heart function could lead to better treatments for humans after heart attacks, say researchers from Wake Forest University Baptist Medical Center.

“We’ve learned more about the complex system of enzymes and hormones that regulates the cardiovascular system,” Carlos Ferrario, M.D., director of the Hypertension and Vascular Disease Center and lead author of the study, reported in the on-line edition of Hypertension. “We believe this new knowledge could lead to more effective drugs with fewer side effects.”

In rats, the researchers found that the drugs olmesartan and losartan helped reverse changes in the heart that can lead to heart failure, a condition in which the heart doesn’t pump enough blood to meet the body’s needs. These two drugs have fewer side effects than the standard therapy currently given to humans.

After a heart attack, the damaged area of heart muscle often becomes thin and the remainder of the heart muscle becomes thick and flabby. These changes, which are known as remodeling, can lead to heart failure.

To prevent remodeling, patients are currently given drugs called ACE (angiotensin converting enzyme) inhibitors that prevent the formation of angiotensin II, a hormone that promotes remodeling. By studying rats after heart attacks, the investigators learned more about angiotensin II – information that may be used to develop more targeted medications.

The investigators studied rats with normal blood pressure. Three groups of rats had surgery to simulate a heart attack. These animals were then given either losartan, olmesartan or an inactive saline solution for 28 days. A fourth group of animals got a sham operation and no treatment.

While ACE inhibitors block the production of angiontensin II, losartan and olmesartan are both designed to block its function and have fewer side effects. Researchers found that losartan and olmesartan were both effective in the rats at reversing changes that cause remodeling.

The researchers also found that rats in the active treatment groups had increased levels of ACE2 and angiotensin 1-7, which both benefit heart function

ACE2 was discovered in the hearts of mice in 2002 by Wake Forest Baptist researchers and colleagues at other research centers. Mice that were bred without the enzyme had infrequent heart beats by middle age, leading researchers to believe it played an important role in heart function. ACE2 has since been identified in the human heart.

Angiotensin 1-7, a hormone that can dilate blood vessels, prevent remodeling and oppose the action of angiotensin II, was discovered by Ferrario and colleagues about 12 years ago.

“We believe that ACE2 may be a natural mechanism for protecting the heart,” said Ferrario. “It seems to limit levels of angiotensin II by degrading it into angiotensisn 1-7. This research was the first demonstration to show that by blocking the receptor for angiotensin II, we can stimulate the production of ACE2.”

Ferrario said the finding could one day lead to new therapies that will be based on the increasing the levels of angiotensin 1-7 by targeting the production of ACE2.

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