Stanford Report, October 25, 2000
|Study sheds light on the
molecular causes of hypertension
BY CHARLES CLAWSON
A study published in the October 19 issue of Nature pinpoints a molecular component that regulates arterial muscle tone and may be vital in understanding and perhaps improving treatment of chronic high blood pressure. The Stanford and Vermont University researchers conducting the study report that the component may be a potential target for blood pressure treatments, and its gene is likely accountable for some forms of hereditary hypertension.
Chronic high blood pressure is dangerous because it can lead to stroke, heart disease and renal disease. Blood pressure is regulated in large part by the constriction of muscles along the walls of blood vessels.
"An understanding of the molecules involved in regulating arterial muscle tone is crucial to understanding hypertension," said Richard Aldrich, PhD, an investigator at the Howard Hughes Medical Institute at Stanford and lead author on the study. The results of the study further our understanding of how the contraction of blood vessels is controlled, Aldrich says.
"We now know from the basic molecular level all the way up through the pathology what's going on regarding smooth muscle cell contraction and thereby arterial tension," he notes. In an arterial muscle cell, calcium levels control both constriction and relaxation. While calcium throughout the cell causes constriction, calcium released from stores near potassium channels cause the cell to relax.
"Arterial tone therefore results from the interplay of opposing calcium-dependent processes: constriction, which is driven by global increases in calcium, and relaxation, which is driven by localized calcium concentrations," Aldrich said.
The recent study focuses on arterial relaxation initiated by potassium channels. In arterial muscle cells the main potassium channels are made up of two proteins, termed the alpha and beta subunits. From previous work the researchers theorized that the beta subunit made the system much more sensitive to calcium, and that without this component there would be no relaxation triggered by calcium. Aldrich and his colleagues confirmed that view with this study.
"What we've done is get rid of the beta subunit, which led to increased blood pressure [in mice]," Aldrich said. "Without the beta subunit involved, there's no way this relaxation pathway can take place, and the cells are constricted all the time."
"Our findings suggest that the beta-1 subunit may be a potential locus for some forms of genetic hypertension," Aldrich said. "Also, the findings suggest that the beta-1 subunit may be a good potential drug target for treating blood pressure." No drugs currently target the beta subunit.
The study, which was performed on mice, also is expected to provide subjects for future investigations. "This gives us a genetically hypertensive mouse model," said Aldrich. "In mouse the genetics is highly developed, so now we can study what happens with chronic blood pressure problems, with enlargement of the heart, kidney failure, strokes and things like that."
"These particular potassium channel molecules are important for very many physiological functions other than blood pressure regulation," Aldrich said. "They have an important role in being able to discriminate different sound frequencies in the ear, for instance.
Aldrich adds that there are likely interesting things going on with the same beta subunit in some of the other smooth muscle tissues, like the bladder, lungs, and gut. "Smooth muscle regulation is very important to clinical medicine, for things ranging from incontinence to asthma," Aldrich said.
While in other cell types the beta subunits don't function in precisely the same manner -- some beta subunits make the pathway less sensitive to calcium -- it's believed that a similar tuning mechanism is in effect, Aldrich said.
addition to Aldrich, the Stanford team includes, research associate
Robert Brenner, Assistant Professor Andrew Patterson from the
department of anesthesia, Professor Jon Kosek from the department
of pathology, and research technician Steven Wiler. Funding for
this study came from the Howard Hughes Medical Institute, the
Federation for Anesthesia Education and Research, the National
Institutes of Health, the National Science Foundation, the Totman
Medical Trust for Cerebrovascular Research, and the American Heart