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Dr. David Robertson, principal investigator, is leading the team studying the pathophysiology of autonomic nervous system disorders. (photo by Dana Johnson)

VUMC team nets $9.5 million to study autonomic nervous system

BY: LEIGH MACMILLAN

8/02/2002 - Fortunately, there are some things we don’t have to think about doing. We don’t have to consciously keep our hearts beating steadily; we don’t have to change our blood pressure to avoid fainting when we stand. The autonomic nervous system takes care of these things for us.

But it can run into problems. A group of VUMC investigators has received a $9.5 million, five-year Program Project Grant (PPG) from the National Heart, Lung, and Blood Institute to study disorders of the autonomic nervous system. The grant is a renewal and expansion of a PPG that was first awarded in 1997.

“We doubled the size of our initial program, and the reviewers seemed to like it,” said Dr. David Robertson, professor of Medicine, Pharmacology, and Neurology, director of the Clinical Research Center, and principal investigator of the grant. “It is said to be the only fully patient-oriented research PPG in the heart institute.”

Program Project Grants support a group of investigators “with the idea that we can do more together than we could ever do on our own,” Robertson said. “We’ve put together a group of investigators with the mission of understanding the pathophysiology of autonomic nervous system disorders so we can treat these disorders more effectively.”

Disorders of the autonomic nervous system usually cause very high or very low heart rates or blood pressures, Robertson said. The most common of these disorders is orthostatic intolerance — a syndrome characterized by an increase in heart rate (at least 30 beats per minute) on standing. For someone who suffers from orthostatic intolerance, the simple act of standing causes a racing heart, nausea, headache, dizziness, and even fainting. The disorder affects more than 500,000 people in the United States.

“Orthostatic intolerance can be debilitating,” Robertson said.

Robertson and a core group of investigators formed the Vanderbilt University Autonomic Dysfunction Center in 1978 to treat and study patients with orthostatic intolerance and other disorders of the autonomic nervous system. “We were the first center to specifically focus on these disorders,” Robertson said, “so we have probably seen more patients than any other center in the world.”

The long history of patient care and research in this area provides an invaluable tool for Robertson and his co-investigators — a database of clinical information accumulated over the years. And now DNA data are being collected and added to the database, Robertson said. The large number of patients has allowed center investigators to identify previously unrecognized syndromes and develop new treatments.

“When we discover a new cause for one of these clinical autonomic syndromes,” Robertson said, “that rapidly leads to improved therapy, and in some cases, it leads to unique and specific therapy that can reverse the clinical symptoms.”

The overall goal of the current PPG is to achieve better understanding of how the brain exerts control over the autonomic nervous system, and how that control plays out in regulating the cardiovascular system. “This program should lead directly to improved therapy in cardiovascular disease,” Robertson said.

The projects and their leaders are:

• Project 1, led by Robertson, will focus on the changes that occur in human subjects when the norepinephrine transporter — a sort of molecular vacuum cleaner that removes neurotransmitter from the synapse — is blocked. Project 1 also will seek to understand why variable amounts of plasma leak out of the blood vessels when individuals stand, Robertson said.

• Project 2, led by Randy D. Blakely, Ph.D., Allan D. Bass Professor of Pharmacology and director of the Center for Molecular Neuroscience, will search for genetic alterations in the norepinephrine transporter in cardiovascular disorders linked to autonomic dysfunction. This project will be the first systematic attempt to find such genetic changes, Blakely said. The project will also look for evidence of disrupted cardiovascular function and transporter mutations in patients more typically evaluated in psychiatric medicine, for example patients with depression or attention deficit hyperactivity disorder.

• Project 3, led by Dr. Italo Biaggioni, associate professor of Medicine and Pharmacology, will study the role of nitric oxide — a chemical that relaxes smooth muscle and dilates blood vessels — in governing blood pressure control.

• Project 4, led by Dr. Rose M. Robertson, professor of Medicine, will examine baroreflex failure and its clinical manifestations. The baroreflexes maintain arterial blood pressure within a narrow range, in order to protect blood flow to critical organs like the brain. Baroreflex failure causes patients to have severe volatile high blood pressure.

• Project 5, led by Dr. Stephen N. Davis, Rudolph H. Kampmeier Professor of Medicine, will study the mechanism by which hypoglycemia (low blood sugar) and other stressors can lead to autonomic dysfunction in patients with diabetes.

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