August 10, 2007

Heart, blood pressure studies boosted

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David Robertson, M.D.

Heart, blood pressure studies boosted

Researchers at Vanderbilt University Medical Center have received a major federal grant to continue their studies of disorders that can disrupt control of blood pressure and heart rate.

The $9.6 million award from the National Heart, Lung, and Blood Institute extends the Vanderbilt Program Project Grant (PPG) in autonomic cardiovascular regulation for another five years. Initially funded in 1997 and renewed in 2002, it is the largest grant of its kind funded by the National Institutes of Health, and the only cardiovascular PPG that is based solely on clinical, patient-oriented research.

Given current limitations in federal funding, “this is kind of remarkable,” said David Robertson, M.D., the grant's principal investigator, the Elton Yates Professor of Medicine, Pharmacology and Neurology and director of the Clinical Research Center.

“This is very exciting news,” added Jeffrey Balser, M.D., Ph.D., associate vice chancellor for Research. “It will take us to 16 years of continuous funding for this program, making it one of the longest running PPGs at Vanderbilt.

“This is testimony to the many years of distinguished achievements by this internationally recognized team,” Balser said.

The autonomic nervous system is the crucial link between the brain and the cardiovascular system. It controls vital systems including blood pressure and heart rate for the most part without conscious control or sensation.

Part of the autonomic nervous system, the sympathetic nervous system, responds to stressors of various kinds by releasing the neurotransmitter norepinephrine. In turn, norepinephrine binds to adrenergic receptors to increase heart rate and blood pressure.

Vanderbilt researchers have made significant contributions — dating back 70 years — to current understanding of heart rate and blood pressure regulation.

They developed some of the first treatments for orthostatic intolerance, an autonomic dysfunction that causes a racing heart, nausea, headache, dizziness and fainting when a person stands up. The disorder affects more than 500,000 people in the United States.

In 1978, Robertson and his colleagues established the Vanderbilt Autonomic Dysfunction Center. With a current database of 2,900 patients, it may be the world's largest registry of autonomic disorders.

Eight years later, the Vanderbilt group reported that a rare, inherited deficiency in the enzyme that makes norepinephrine can cause orthostatic intolerance, and developed a successful drug therapy to treat the deficiency.

In 2000, three years after the first PPG was awarded, Robertson, Randy Blakely, Ph.D., Italo Biaggioni, M.D., and their colleagues described the first genetic defect in orthostatic intolerance — a mutation in the norepinephrine transporter, which regulates the supply of the neurotransmitter in the synapses, or spaces between nerve cells.

The researchers have since described the mechanisms of other autonomic disorders, including abnormalities in the choline transporter, which is essential to the production of the neurotransmitter acetylcholine.

The current PPG will fund five projects:

• Project 1, led by Robertson, will continue studies of orthostatic tolerance, including the “gastropressor response” elicited by the ingestion of water.

In 2000, he and his colleagues reported that drinking water profoundly increases blood pressure in patients with autonomic failure. Two years later, they determined that drinking water elicited a previously unrecognized physiological reflex and can be used to treat orthostatic intolerance and prevent fainting.

• Project 2, led by Blakely, the Allan D. Bass Professor of Pharmacology, will study whether genetic variations in the choline transporter may contribute to heart rhythm disorders.

• Project 3, led by C. Michael Stein, M.D., professor of Medicine and Pharmacology, will study the clinical effects of genetic variability in adrenergic receptors.

• Project 4, led by Biaggioni, professor of Medicine and Pharmacology, will study the role of the autonomic nervous system in the cardiovascular and metabolic alterations associated with obesity.

• Project 5, led by Stephen N. Davis, M.D., Rudolph H. Kampmeier Professor of Medicine, will study factors — including exercise — that affect the response of the autonomic nervous system to hypoglycemia (low blood glucose), a frequent consequence of insulin treatment in diabetes.