Public Release: 

Study identifies hypertension patients who can benefit from the little used diuretic amiloride

An intriguing hypothesis surmises that higher incidence of hypertension in African Americans may be related to slave ship crossings

American Physiological Society

Bethesda, Md. (August 13, 2002) -- Hypertension is a common disorder with potentially devastating complications that disproportionately affects the black community. It accounts for approximately 25 percent of all cases of end stage renal disease in the African-American population. Since patients have no symptoms, it frequently goes undiagnosed. Excellent treatments are available; however, given that it is a chronic disease and that patients are asymptomatic, keeping patients on treatment can be difficult. The African American Study of Kidney Disease and Hypertension (AASK) has shown that hypertension can be successfully treated in this population, leading to the reduction in the rate of deterioration of kidney function, according to Denyse Thornley-Brown, M.D., Assistant Professor of Medicine at the University of Alabama at Birmingham and a co-principal investigator of the AASK trial.

Tied To Slave Ship Transport?
There is an intriguing hypothesis enumerated by Clarence E. Grim, M.D., from the Medical College of Wisconsin, Division of Cardiovascular Medicine, which may help to explain the high incidence of hypertension in African Americans. When Africans were transported to the Americas, they were sailed across an equatorial ocean. They were not fed, and they were given little or no water. Consequently, a high percentage of individuals died in transit. This could be thought of an unnatural selection process. As a direct result of this occurrence, the survivors are thought to be individuals that could retain salt and water most efficiently. To put it another way, the people that survived needed very little salt. Circumstances with respect to salt availability have changed. Today salt is ubiquitous, and thus, the overexposure to salt by individuals with a high salt retentive capacity may be one reason for the elevated blood pressures observed today in the descendants of these original survivors.

The Study
Recently, a team of Alabama researchers, led by James K. Bubien Ph.D., has utilized state of the art electrophysiological technology to identify individuals with a specific salt retentive disorder causing their hypertension, and to remove any uncertainty for individual patients. The authors of "Hyperactive ENaC Identifies Hypertensive Individuals Amenable to Amiloride Therapy," are Artensie R. Carter, Zhen Hong Zhou, David A. Calhoun, and James K. Bubien, all from the University of Alabama at Birmingham, Birmingham, AL. Their findings have recently been published in the American Journal of Physiology - Cell Physiology, a publication of the American Physiological Society (APS).

Background
Amiloride is a potassium-sparing diuretic (water pill), most often used to treat edema (swelling), thereby reducing the amount of fluid in the body without causing the loss of potassium. Some individuals with hypertension have benefited from this medication. However, identifying which patients will or will not benefit from this therapy has been difficult. Until now.

Inappropriate retention of salt water can lead to hypertension (high blood pressure). There is a powerful mechanism in the kidney designed to retain salt and water during times of high loss, such as heavy exercise, sustained heat and humidity, or water deprivation. If this control of this mechanism is not precise, excessive salt and water can be reabsorbed, leading to elevation of blood pressure. The high prevalence of high blood pressure that tends to run in African Americans families, and the discovery of mutations in the main protein responsible for this specific salt retaining mechanism have led researchers at the University of Alabama at Birmingham to consider the possibility that gene changes or other factors that regulate this process and this protein may underlie the high incidence of hypertension in African Americans. Awareness of this possibility is important because of the devastating health consequences to the African American community.

Methodology
The initial step was an assessment of whether peripheral blood lymphocytes expressing ENaC (epithelial Na+ channels) similar to the same expressed by renal cells could be linked to hypertensive etiologies. The second was to test the hypothesis that specific inhibition of hyperactive ENaC with amiloride could improve hypertension.

To test their assumption, the researchers obtained blood samples from patients with normal blood pressure and hypertensive patients. Volunteers were between ages 19 and 70 and were recruited from the University of Alabama-Birmingham Hypertension Clinic. Blood samples were taken from subjects diagnosed as normotensive (unmedicated blood pressure <140/90 mmHg and no family history of hypertension); controlled hypertensive (having a blood pressure <140/90 mmHg while taking a single hypertensive medication); and refractory hypertensive (blood pressure >140/90 mmHg despite ongoing therapy with three or more anti-hypertensive agents). Nine subjects with refractory hypertension were prescribed amiloride for a four-week period.

Subjects were assessed after two weeks and their dosage increased to five milligrams, twice daily. Lymphocytes were examined to determine whether ENaC was hyperactive. They were then divided into four samples and frozen at -84°C before undergoing electrophysiological examination. A determination of normal or abnormal ENaC regulation was based on the basal channel activity and a response to cyclic AMP. Blood pressure was compared before and after treatment.

Results
Cells from blood samples of 106 volunteers were examined using a whole cell patch clamp (a technique used in the study of ion channels in which the movement of ions across a small patch of isolated membrane is measured when the membrane is electrically polarized or hyperpolarized and maintained at that potential). The researchers found:

  • Constitutively activated ENaC in 25 percent of patients with refractory hypertension. On the other hand, Na+ channel activation was not found in any of the study subjects with normal blood pressure or controlled hypertension.
  • Results indicating that an abnormally functioning ENaC is associated with a hypertensive clinical phenotype similar to that produced in Liddle's disease.
  • ENaC lymphocyte function may be useful in identifying pseudohyperaldosteronism and effective anti-hypertensive therapy where others have failed.
  • A high percentage of individuals with pseudohyperaldosteronism will have a clinical status of severe hypertension that is resistant to antihypertensive therapy exclusive of amiloride or other compounds that inhibit ENaC.

Conclusions
This study best exemplifies the potential benefits of translational physiology, demonstrating that research performed in the laboratory has immediate benefits to the diagnosis and treatment of a wide range of chronic disorders that afflict Americans.

Presently, amiloride is not considered a first-option treatment for hypertensive patients. These findings will enable caregivers to target those patients who suffer from this deadly condition that will benefit from pharmaceutical products now available.

Findings Have High Impact for Research Overall
This research marks a new direction in physiology research. These investigators adhered to the principles of translational physiology, known as the transfer of knowledge gained from basic research to new and improved methods of preventing, diagnosing, or treating disease, as well as the transfer of clinical insights into hypotheses that can be tested and validated in the basic research laboratory. This process occurs from the bench to the bedside, as well as from the bedside back to the bench.

It is highly suitable for the post-genomic era, enabling physiologists to interact with other basic scientists, engineers, bioinformatics experts, and clinicians in translating the wealth of genetic and molecular information into a better understanding of how the human body functions in health and disease.

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Source: American Journal of Physiology - Cell Physiology

The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.

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