Hormone might cause dangerous pregnancy complication

October 17, 2005

CINCINNATI--Researchers at the University of Cincinnati (UC) Academic Health Center 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, which is 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 said, could provide a breakthrough in the prevention of preeclampsia--which so far has been essentially untreatable--and other hypertensive conditions.

One of the Cincinnati research team's areas of interest, preeclampsia is a leading cause of fetal complications, which include low birth weight, premature birth and stillbirth. It can lead to seizures, known as eclampsia, the second leading cause of maternal death in the United States.

The researchers, Jerry Lingrel, PhD, chair of the University of Cincinnati's Department of Molecular Genetics, Biochemistry and Microbiology, and Iva Dostanic-Larson, PhD, a postdoctoral fellow in the department, report the findings of their three-year study in the Oct. 17, 2005, online edition of the Proceedings of the National Academy of Sciences (PNAS).

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

The focus of their research, said Dr. Lingrel, the principal investigator, is an area in the human cell known as the "sodium pump," an enzyme (Na,K-ATPase) that has long been known to be involved in the regulation of blood pressure, excitability of muscle and nerve tissue and the uptake of a wide range of essential nutrients.

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

Cardiac glycosides, used by physicians for centuries to treat congestive heart failure, have largely been obtained from "external" sources like plants, and even frog skin.

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 for something other than externally derived, man-made medications. They have been looking for a naturally occurring, internal or "endogenous" control agent.

The University of Cincinnati scientists say in their PNAS 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 Na,K-ATPase binding site.

The next step, the Cincinnati researchers say, is to positively identify the hormone, which they believe should be a relatively routine although painstaking procedure, so that its level can be manipulated to control blood-pressure problems such as preeclampsia.

"For centuries physicians have controlled cardiac function using compounds like digitalis from the foxglove plant, which are closely related to compounds found in the skin of a poisonous frog and the bark of an African tree once used to make poison arrows," said Dr. Lingrel, "and 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 said. "They'd say if it's been so highly conserved, it has a real role in biology. And that's what we have shown.

"The site, with its ability to regulate blood pressure, is there to respond to something that occurs naturally in the human body. We're now very close to finding it."

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 long-term, low-dose 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 point," Dr. Lingrel explained, "is that when the binding site is removed, the compound produced by the body can't interact with it, and therefore blood pressure is not regulated. In the logic of biochemistry, the compound interacting with the site has to be a steroid, and most probably a steroid hormone."

"The 'breakthrough,' if you like," said 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.

"Once you know that blood pressure regulation occurs as a result of interaction between the binding site and a hormone--or one of several hormones--you can neutralize the hormone, probably with a monoclonal antibody (an antibody engineered in a laboratory to react with a specific target), and then the hypertension patient is going to be in good shape."

A degree of hypertension is necessary in normal pregnancy, said Dr. Dostanic-Larson, so that enough blood gets to the baby. In some women, however, the hormone regulation goes wrong, increasing blood pressure too much and causing preeclampsia.

"This new player, when we identify it," Dr. Dostanic-Larson said, "is highly likely to be overproduced in preeclampsia. The next step is to chase down the hormone. But in the meantime, we have a backup, because we know where the receptor is, and an alteration that changes the reaction between the hormone and the receptor will abolish this kind of hypertension."

Preeclampsia typically starts after the 20th week of pregnancy, mostly in first-time pregnancies, and is related to increased blood pressure and protein in the mother's urine, resulting from kidney problems. It affects the placenta, and can affect the mother's kidney, liver and brain.

In a commentary on the research, Jack Kaplan, PhD, chair of the Department of Biochemistry and Molecular Genetics at the University of Illinois at Chicago, said this "important work" provides a first clear demonstration that some substance within the body binds to Na,K-ATPase and is one of the regulators of blood pressure.

According to the National Heart, Lung and Blood Institute (NHLBI) of the NIH, there has been no proven way to prevent preeclampsia, and the only "cure" is to deliver the baby. More than 146,320 cases of preeclampsia were diagnosed in the United States in1998, the NHLBI says.
Also on the research team were James Van Huysse, of the Heart Institute Hypertension Unit and the departments of medicine and biochemistry and microbiology and immunology at the University of Ottawa, Canada, and John Lorenz, of the Department of Molecular and Cellular Physiology at the University of Cincinnati Academic Health Center.

University of Cincinnati

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