Preeclampsia: key role for a hormone

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, 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.

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, at the University of Cincinnati, and Iva Dostanic-Larson have reported the findings of their three-year study in the Proceedings of the National Academy of Sciences ( PNAS ).

The focus of their research, said 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.

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," 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" said 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, and then the hypertension patient is going to be in good shape."

A degree of hypertension is necessary in normal pregnancy, said 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.

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, 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 in 1998, the NHLBI says.

Source: University of Cincinnati, 2005



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