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November 2005 Issue

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Hormone Might Cause Serious Pregnancy Compications

Published November 2005

UC researchers have found evidence of a hormone they say is responsible for certain types of high blood pressure (hypertension), and could also cause preeclampsia, a potentially dangerous condition that occurs during pregnancy.

Work is now under way to locate and identify the hormone, believed to be produced in very small, but highly potent amounts, so that its hypertension-causing action can be blocked.

Finding and neutralizing this "new player" in the mechanism of hypertension, the UC scientists say, could provide a breakthrough in the prevention of preeclampsia--which so far has been essentially untreatable--and other hypertensive conditions.

The researchers, Jerry Lingrel, PhD, chair of the UC Department of Molecular Genetics, Biochemistry and Microbiology, and postdoctoral fellow Iva Dostanic-Larson, PhD, report on their three-year study in the Oct. 17, 2005, online edition of the Proceedings of the National Academy of Sciences.

The work was funded by grants from the U.S. National Institutes of Health and the Heart and Stroke Foundation of Ontario.

The focus of their research, says Dr. Lingrel, the principal investigator, is an area in the human cell known as the "sodium pump," an enzyme (Na, K-ATPase) long known to be involved in the regulation of blood pressure.

The sodium pump contains the target or "binding site" of a group of drugs called cardiac glycosides, commonly used to control congestive heart failure by increasing blood pressure.

The survival of this site in the cell over thousands of years of evolution, however, has led scientists to believe that it must also be present to react to something other than externally derived, man-made medications.

The UC scientists say in their report that they have found "conclusive evidence" that the cardiac glycoside binding site is also the receptor for an agent that occurs naturally in the body. This finding in turn supports a long-held hypothesis that there must be a hormone in the body that regulates blood pressure by interacting with the binding site.

The next step, the researchers say, is to positively identify the hormone, so that its levels can be manipulated to control blood-pressure problems like preeclampsia.

"For centuries physicians have controlled cardiac function using drugs like digitalis, from the foxglove plant, which are chemically closely related to compounds from frog skin and an African tree that were used to make poison arrows," says Dr. Lingrel. "They all worked on the sodium pump binding site. "It turns out that almost all species, from fruit flies to humans, have a site that responds to these medications.

The question is, did nature somehow keep the site all through evolution just so that people who manufacture drugs or isolate them from plants, can use it as a target?

"No one would ever believe that," Dr. Lingrel says. "They'd say if it's been so highly conserved, it has a real role in biology. And that's what we have shown."

Dr. Dostanic-Larson genetically engineered a mouse model specifically for this project. By identifying and replacing just two nucleotides among the 3.2 billion "building" blocks in mouse DNA, she was able to knock out the binding site's ability to function without altering the enzyme's other essential functions.

By altering the two nucleotides, the normally glycoside-sensitive target area in the sodium pump was made resistant to the glycoside drug ouabain.

The researchers found that administration of the human hormone ACTH (adrenocorticotropic hormone) caused hypertension in wild-type control mice, but not in the ouabain-resistant animals.

This, the researchers say, demonstrates for the first time that some substance produced naturally by the body must be a major regulator of blood pressure.

"The 'breakthrough,' if you like," says Dr. Lingrel, "is in saying that the binding site not only interacts with drugs, but there must be some substance the body makes that interacts with this site. That's the bottom line of this research."

"This new player, when we identify it," says Dr. Dostanic-Larson, "is highly likely to be overproduced in preeclampsia. The next step is to chase down the hormone."

Also on the research team were James Van Huysse, of the University of Ottawa, Canada, and John Lorenz, of the UC Department of Molecular and Cellular Physiology.

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