DURHAM, N.C.—Researchers from Duke University Medical Center have discovered that two beta-blockers, drugs frequently prescribed to patients who have experienced heart failure, can stimulate the chemical pathway that helps protect heart tissue—a finding that could lead to the development of drugs that repair or reverse some of the damage caused by heart failure, the researchers say.
The discovery, detailed in a study published online in Proceedings of the National Academy of Sciences (PNAS), is the first evidence that the two beta-blockers— alprenolol and carvedilol—have greater potential to repair the heart and protect it than other beta-blockers, says Dr. Howard Rockman, senior author of the study and chief of the Duke Cardiology Division.
"What we discovered is a complete paradigm shift in our understanding of the mechanism of action of beta-blockers," Rockman says. "We show a completely new concept, that a beta-blocker itself can actually stimulate the beta-adrenergic receptor to signal pathways in the cell that protect it in stressful situations."
Until now, scientists believed that all beta-blockers worked by binding to and blocking the beta-adrenergic receptor, a molecule on the cell surface that responds to the hormone adrenalin. Blocking the receptor moderates increases in heart rate and heart function that could be damaging to patients whose hearts are already overstressed.
According to the current study, alprenolol and carvedilol also serve to stimulate a different signaling beta-arrestin pathway, a protein known as an "off-switch" for beta-adrenergic receptors. These two drugs activated a beta-arrestin pathway that produces beneficial effects in the heart tissue.
"These two drugs were found to stimulate the pathway that produces certain proteins that are protective to the heart," Rockman says. "If you imagine a receptor in a three-dimensional form that sits in the membrane of a cell, there are some beta-blockers that bind to it, but there is no change to its structure. These two beta-blockers do something to the receptor to change its structure so that it activates the pathway."
The researchers will now work to test the drugs in animals to learn which beta-blocker might promote protection and which might cause more negative effects, Rockman says.
"Cell studies can be tricky to replicate in organisms and we will have to see what happens, but these cellular results are very exciting and encouraging and could be a boon to heart failure patients," he says.
Ultimately, the researchers hope to design drugs that strongly bind in this way and activate the pathway, Rockman adds. This will likely be done by Trevena Inc., a Philadelphia-based drug discovery company founded by Rockman.
"We call these drugs biased-ligands, or super receptor blockers, because they are designed to block the harmful actions of adrenalin at the beta receptor, but at a molecular level will activate other pathways that protect the cell," Rockman says.
The study, Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation, was funded by the National Institutes of Health (NIH) and co-authored by Il-Man Kim, Douglas Tilley, Juhsien Chen, Natasha Salazar, Erin Whalen and Jonathan Violin of the Duke Department of Medicine. DDN
The discovery, detailed in a study published online in Proceedings of the National Academy of Sciences (PNAS), is the first evidence that the two beta-blockers— alprenolol and carvedilol—have greater potential to repair the heart and protect it than other beta-blockers, says Dr. Howard Rockman, senior author of the study and chief of the Duke Cardiology Division.
"What we discovered is a complete paradigm shift in our understanding of the mechanism of action of beta-blockers," Rockman says. "We show a completely new concept, that a beta-blocker itself can actually stimulate the beta-adrenergic receptor to signal pathways in the cell that protect it in stressful situations."
Until now, scientists believed that all beta-blockers worked by binding to and blocking the beta-adrenergic receptor, a molecule on the cell surface that responds to the hormone adrenalin. Blocking the receptor moderates increases in heart rate and heart function that could be damaging to patients whose hearts are already overstressed.
According to the current study, alprenolol and carvedilol also serve to stimulate a different signaling beta-arrestin pathway, a protein known as an "off-switch" for beta-adrenergic receptors. These two drugs activated a beta-arrestin pathway that produces beneficial effects in the heart tissue.
"These two drugs were found to stimulate the pathway that produces certain proteins that are protective to the heart," Rockman says. "If you imagine a receptor in a three-dimensional form that sits in the membrane of a cell, there are some beta-blockers that bind to it, but there is no change to its structure. These two beta-blockers do something to the receptor to change its structure so that it activates the pathway."
The researchers will now work to test the drugs in animals to learn which beta-blocker might promote protection and which might cause more negative effects, Rockman says.
"Cell studies can be tricky to replicate in organisms and we will have to see what happens, but these cellular results are very exciting and encouraging and could be a boon to heart failure patients," he says.
Ultimately, the researchers hope to design drugs that strongly bind in this way and activate the pathway, Rockman adds. This will likely be done by Trevena Inc., a Philadelphia-based drug discovery company founded by Rockman.
"We call these drugs biased-ligands, or super receptor blockers, because they are designed to block the harmful actions of adrenalin at the beta receptor, but at a molecular level will activate other pathways that protect the cell," Rockman says.
The study, Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation, was funded by the National Institutes of Health (NIH) and co-authored by Il-Man Kim, Douglas Tilley, Juhsien Chen, Natasha Salazar, Erin Whalen and Jonathan Violin of the Duke Department of Medicine. DDN
