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Targeting flight-or-fight hormone response to combat heart failure
Date:6/24/2010

reases adrenalin in teens and young adults to a higher risk of heart disease or heart attack later in life.

Blaxall's lab is part of a nationwide effort that has linked adrenalin's ability to propel heartbeat strength to a key protein, the beta adrenergic receptor. When adrenalin combines with this receptor it orders heart muscle cells to contract with greater speed and force. The problem in heart failure patients is that these receptors are chronically desensitized they no longer respond to adrenalin, so the heart grows weak and does not pump as forcefully as it should.

"While adrenalin desensitization has been studied extensively, this is the first report of compounds that effectively target this specific process to reduce heart failure," said Blaxall. The desensitization is caused in large part by elevated levels of a particular enzyme (G-protein-coupled receptor kinase 2 or GRK2) when it interacts with G-proteins.

This research was conducted in collaboration with Alan Smrcka, Ph.D., professor in the Department of Pharmacology & Physiology at the Medical Center whose laboratory discovered compounds that could block GRK2 regulation by G proteins. Smrcka's research team conducted extensive screening and testing to identify these experimental compounds. Two such compounds, M119 and Gallein, were identified and put to the test.

"In this study we took an entirely new pharmacological approach by altering signaling pathways after the beta adrenergic receptor rather than altering the receptor itself. In this way the actions of adrenalin are modified rather than blocked as with other therapies, such as beta blockers," said Smrcka. "This novel approach is applicable in heart failure and may be useful in other conditions as well."

Blaxall's team found that Gallein not only slowed, but halted heart failure progression when delivered to mice with pre-existing heart failure. Similarly, M119 reduced two characteristics of the
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Contact: Emily Butler
emily_butler@urmc.rochester.edu
585-273-1757
University of Rochester Medical Center
Source:Eurekalert

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