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Two-Part Blood Pressure Control Suggests New Approach to Hypertension Therapy

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Duke Health News 919-660-1306

Durham, N.C. -- The kidneys have long been known to play a
major role in many cases of high blood pressure, but a new
study by researchers at Duke University Medical Center reveals
that the body's control of blood pressure depends as much on
other organs in the body. The researchers said the findings
about a "two-part system" may lead to improved methods for
treating high blood pressure, which affects nearly one in three
American adults.

The findings further suggest how the underlying causes of
high blood pressure may vary among patients, with some cases
resulting from kidney abnormalities and others from
abnormalities in other areas, such as the blood vessels,
researchers said. Such differences might lead to variability in
the response of patients to particular treatment regimens. For
example, it might explain why reductions in dietary salt
effectively lower blood pressure for some people, but not
others, they said.

Through a series of kidney transplantation experiments
involving both normal mice and mice in which a critical
molecular component of blood pressure regulation had been
rendered nonfunctional, the researchers found clear evidence
that the kidneys and other systemic tissues have distinct and
equally important roles in controlling blood pressure. The
researchers report their findings in the April 1, 2005, issue
of the Journal of Clinical
Investigation
.

The findings provide new insights into how the kidney
interacts with other organs to control blood pressure, said the
researchers. These insights may augment scientists'
understanding of how common blood pressure medications work and
lead to improved treatments for hypertension and its
complications, including stroke and organ failure, they
added.

"Our study provides the first direct evidence that the job
of blood pressure regulation is split into two parts – that
controlled by the kidneys and that controlled by other systems
throughout the body," said Thomas Coffman, M.D., chief of
nephrology at Duke University Medical Center and the Durham VA
Medical Center and lead author of the study.

"Many people with high blood pressure take multiple
medications -- each with its own side effects -- to control
blood pressure," Coffman added. "As we understand more
precisely the molecular basis for blood pressure control, we
might identify novel therapies for hypertension that better
prevent organ failure."

Scientists have long thought that blood pressure
abnormalities are tied closely to changes in the kidneys that
affect salt excretion.

"The prevailing view holds that the kidneys play a dominant
role in the maintenance of blood pressure," Coffman said.
"While abnormalities in other elements, such as the blood
vessels, might perturb the system, it's been thought that the
kidneys could adjust accordingly to normalize blood
pressure."

Within the kidney, evidence has shown that proteins called
type 1 angiotensin (AT1) receptors are integral to salt
excretion and blood pressure control, Coffman said. Mice
lacking the receptors exhibit low blood pressure and profound
salt sensitivity, he said. Furthermore, drugs that block the
function of AT1 receptors and their binding protein angiotensin
II – so-called angiotensin receptor blockers and ACE
inhibitors– effectively treat patients with hypertension.

However, the presence of AT1 receptors in tissues throughout
the body, including the heart, blood vessels and brain, has
made it difficult to pinpoint the proteins' roles in individual
tissues, Coffman said.

To clarify the function of AT1 receptors, the researchers
transplanted the kidneys of normal mice into mice in which the
AT1 receptor had been rendered nonfunctional, and vice versa.
Mice with AT1 receptor defects only in the kidneys exhibited
low blood pressure, they found.

However, mice with the opposite condition – having the AT1
receptor defect everywhere but the kidneys – exhibited a nearly
identical drop in blood pressure, the team reported.

Further study indicated that the receptors in the kidneys
versus other parts of the body carry out distinct, though
equally, important roles. For example, when fed a high salt
diet, mice without AT1 receptors in their kidneys exhibited a
significant increase in blood pressure. However, mice with
normal kidneys that lacked the receptors in other tissues
tolerated dietary increases in salt and maintained blood
pressures comparable to mice fed a normal diet.

"These findings indicate that angiotensin receptors in the
kidney have unique and non-redundant actions in blood pressure
control," Coffman said. "However, receptors outside the kidney
also make a unique contribution to blood pressure homeostasis
that is virtually equivalent to and independent of their
actions within the kidneys."

The results illustrate the complexity of blood pressure
regulation and suggest that maximal efficacy of hypertension
drugs, including ACE inhibitors and angiotensin receptor
blockers, requires complete blockade of receptors in both the
kidney and outside of the kidney.

The findings further suggest that the degree of salt
sensitivity exhibited by patients with high blood pressure
might be explained by the level of involvement of the kidneys
compared to other organs, Coffman said.

While the findings confirm an important role for both the
kidneys and other tissues in maintaining normal blood pressure,
further research is required to examine their relative roles in
mice with high blood pressure, the researchers said.

Collaborators on the study include Steven Crowley, Susan
Gurley, Michael Oliviero, A. Kathy Pazmino, Robert Griffiths,
Patrick Flannery, Robert Spurney and Thu Le, all of Duke;
Hyung-Suk Kim and Oliver Smithies, of the University of North
Carolina, Chapel Hill. The National Institutes of Health and
the Medical Research Service of the Veterans Administration
supported the research.

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