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Finding of Heart Drug Interaction Suggests Path to More Effective Treatment

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Duke Health News 919-660-1306

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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