Blood pressure control suggests new approach to hypertension therapy

Apr 3 2005

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.