Finding of heart drug interaction suggests path to more effective treatment

September 08, 2003

Durham, N.C. -- Key cellular receptors that regulate the heart's response to stress interact much more closely than previously suspected -- a finding that suggests some heart patients could be treated more effectively with fewer drugs, Duke University Medical Center researchers say.

Rather than functioning independently, receptors that control normal heart function -- beta-adrenergic receptors and angiotensin II receptors -- join to form receptor complexes, the researchers found. What's more, drugs used to treat heart failure by blocking a single receptor actually have a dual effect, the Duke team reports in a forthcoming issue of the American Heart Association journal Circulation. Instead of only blocking the function of one form of receptor, the drugs -- known as beta blockers and angiotensin II receptor blockers -- restrict the activity of both.

The finding suggests that patients might not need the multiple blockers commonly prescribed to treat heart failure, said Howard Rockman, M.D., professor of medicine and senior author of the study. A single drug designed to efficiently block both receptors might do the job, he suggested. The National Institutes of Health and the Burroughs Wellcome Fund funded the research.

The activation of beta-adrenergic and angiotensin receptors both alter the activity of the heart. Beta-adrenergic receptors respond to the hormone adrenaline, while angiotensin receptors respond to the hormone angiotensin. Dysfunction of both receptor systems is a hallmark of heart failure, a progressive disorder that affects about 5 million people in the United States.

Cardiologists view the beta-adrenergic receptors as the "life-lines" of the heart, Rockman explained. These receptors control the amount of blood delivered to the tissues of the body in response to environmental situations such as exercise or stress. In heart failure patients, chronic stress leads the body to produce an excess of adrenaline, over-stimulating beta-adrenergic receptors to further weaken the heart in a kind of runaway process, Rockman said.

Angiotensin receptors regulate heart growth and are responsible, in part, for the enlargement of the heart seen in patients with heart failure, Rockman said.

Scientists believe that drugs that block these two kinds of receptors treat heart failure by preventing the heart from responding to the escalating adrenaline stress associated with heart failure, he said.

"We have known that beta receptors and angiotensin receptors talk to each other at the systemic level through the sympathetic nervous system," said Liza Barki-Harrington, Ph.D., a research associate in cardiology at Duke and lead author of the study. "We wanted to know if they also talk to each other at the cellular level through direct receptor-receptor interaction."

When the researchers treated heart muscle cells from adult mice with beta blockers, the cells contracted less than normal in response to a chemical that stimulates angiotensin receptors. Likewise, the heart rates of live mice given an angiotensin receptor blocker failed to increase in response to a chemical that activates beta receptors, a response scientists believed occurred only with a beta blocker. Additional experiments revealed precisely how the two receptors interact to block each other's activity.

The results of the Duke study indicate that drugs that block the function of one receptor type reduce the activity of both simultaneously, said the researchers. The drugs' dual action stems from the fact that beta receptors and angiotensin receptors physically interact, forming linked receptor pairs in heart cells.

"It appears that the success of these drugs in treating heart failure is owed to the fact that they target not just one receptor but two," Rockman said.

Barki-Harrington added, "It's like getting two drugs for the price of one."

The finding of the receptors' physical linkage could influence how doctors prescribe medications for patients with heart failure. For example, since angiotensin blockers are more easily tolerated, physicians might prescribe them alone for those patients too sick to take beta blockers, Rockman said. The result also suggests that a single, potent drug targeting both receptors could eliminate the need for heart failure patients to take multiple medications having multiple potential side effects, he added.

The findings also might lead to tailored drug therapies for individual heart failure patients, said the researchers. The complement of different receptors varies among patients and with the severity of disease, Rockman said. A blood test could reveal a patient's unique receptor makeup and allow a physician to prescribe the best medications accordingly.

Similar interactions among receptors might well be important to the function of other organs in health and disease, the researchers suggest. Taking such interactions into account could lead to better treatment strategies for a variety of ailments.

Louis Luttrell, M.D., associate professor of medicine at Duke, also participated in the study.
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Duke University Medical Center

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