Heart Failure Drugs May Target Both Beta-Adrenergic and Angiotensin II Receptors

Laurie Barclay, MD

September 08, 2003

Sept. 8, 2003 — Beta-adrenergic receptors and angiotensin II type 1 receptors join to form receptor complexes, allowing single antagonist drugs used to treat heart failure to have a dual effect, according to the results of a basic science study published in the Oct. 7 issue of Circulation, published online ahead of print on Sept. 8. The investigators suggest that some heart failure patients could be treated more effectively with fewer drugs and better tailored therapies.

"We have known that beta receptors and angiotensin receptors talk to each other at the systemic level through the sympathetic nervous system," lead author Liza Barki-Harrington, PhD, from Duke University Medical Center in Durham, North Carolina, says in a news release. "We wanted to know if they also talk to each other at the cellular level through direct receptor-receptor interaction."

When treated with beta-blockers, mouse cardiomyocytes contracted less than normal in response to angiotensin receptor agonists. Similarly, the heart rates of live mice given an angiotensin receptor blocker failed to increase in response to beta-receptor agonists, a response previously thought to occur only with a beta-blocker.

Drugs that block the function of one receptor type therefore reduce the activity of both simultaneously, thanks to the physical interaction between beta receptors and angiotensin receptors in linked receptor pairs in cardiomyocytes.

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

According to senior author Howard Rockman, MD, also from Duke, the physical linkage of the receptors could allow physicians more flexibility in heart failure treatment. Because angiotensin blockers are better tolerated, they could be given alone to patients too sick to take beta-blockers. A single, potent drug targeting both receptors could reduce the need for multiple medications with increased potential for drug interactions and adverse events.

"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," Dr. Rockman says.

These findings could also facilitate tailored drug therapies for individual patients with heart failure. The complement of different receptors varies among patients and with the severity of disease, so a blood test identifying the patient's unique receptor makeup could allow the physician to prescribe the most appropriate medications.

"Better understanding of the complex interactions between different G-protein coupled receptors in vivo may therefore have important implications for the development of highly specified pharmacological treatment for a wide range of cardiovascular disorders," the authors write.

The National Institutes of Health and the Burroughs Wellcome Fund funded this study.

Circulation. Published online Sept. 8, 2003.

Reviewed by Gary D. Vogin, MD