Studies by University of Maryland scientists and others suggest new treatment approaches
Mordecai P. Blaustein, M.D.
Collaborating scientists in the United States and Japan have identified how excess salt in the diet can lead to high blood pressure, by uncovering key steps in the physiological process. Their findings, which suggest new approaches for the prevention and treatment of hypertension, will be reported on February 16, 2004, at the annual Biophysical Society meeting at the Baltimore Convention Center.
"We've known for decades that eating too much salt can lead to high blood pressure, but until now, we did not understand exactly how it happens," says Mordecai P. Blaustein, M.D., professor of physiology and medicine at the University of Maryland School of Medicine, and lead author of one of the two related studies that demonstrate the process. Research collaborators include Takahiro Iwamoto, Ph.D., lecturer, Fukuoka University in Japan, and Jerry B. Lingrel, Ph.D., professor and chair of the Department of Molecular Genetics, Biochemistry and Microbiology at the University of Cincinnati.
The key to the newly identified physiological process is ouabain (pronounced wah-bane), a naturally occurring hormone secreted by the adrenal gland. Eating excess salt stimulates the secretion of too much ouabain. The hormone has a dramatic effect on two proteins that together, regulate the amount of sodium and calcium within the smooth muscle cells of the arteries.
The first protein, known as the Alpha-2 Sodium Pump, is responsible for removing excess sodium from artery cells. The second protein, called the Sodium-Calcium Exchanger, replaces sodium with calcium. The proteins, located in the cell membrane, work together to maintain a healthy balance of sodium and calcium inside the cell. Researchers in Baltimore and Ohio determined that the Alpha-2 Sodium Pump in artery muscle cells is the target of ouabain's action.
In a separate study at Fukuoka University in Japan, Dr. Takhiro Iwamoto, Ph.D., examined the role of the Sodium-Calcium Exchanger. Dr. Iwamoto's study will also be presented at the Biophysical Society meeting. "The combination of our research and Dr. Iwamoto's findings have enabled us to put together the pieces of this physiological puzzle," says Dr. Blaustein.
Excess ouabain upsets the balance by disabling the Sodium Pump, causing sodium to accumulate in artery cells. The additional sodium causes the Sodium Calcium Exchanger protein to bring in too much calcium, which triggers artery constriction and hypertension. "The process that leads to high blood pressure is a vicious cycle," says Dr. Blaustein. "Too much sodium in the blood stimulates ouabain secretion. The ouabain interacts with the Sodium Pump, causing sodium and calcium to accumulate in the cells."
"Understanding the sequence of events that leads to salt-related high blood pressure is vital to the development of new treatments and medications," says Dr. Blaustein. "In the future, it may be possible to stop or interfere with the secretion of ouabain, protect sodium pumps from the effects of ouabain, or develop a diagnostic tool to detect high ouabain levels in the bloodstream."
Previous research has established the link between ouabain and high blood pressure. In one study, mice injected with ouabain became hypertensive. And in humans, a high salt diet caused ouabain levels to rise in the bloodstream. In addition, half of patients with essential hypertension (high blood pressure of unknown cause) have significantly elevated levels of ouabain.
The research was supported by funds from the National Heart, Lung and Blood Institute, the National Institute of Neurological Diseases and Stroke, the American Heart Association Mid-Atlantic Affiliate, the Ministry of Education, Science and Culture of Japan, the Salt Science Research Foundation in Japan, and Fukuoka University in Japan.
Contributing investigators include Paul F. James, Ph.D., assistant professor of zoology at the Miami University of Ohio, Jin Zhang, a post doctoral fellow at the University of Maryland, and Satomi Kita, Ph.D., a postdoctoral fellow at Fukuoka University.
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