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
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
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."