"These findings provide new insights into the cause of hypertension and how normal blood pressure is regulated," says lead investigator Kendall J. Blumer, Ph.D., professor of cell biology and physiology. "This may lead to a way of determining the underlying cause of a person's hypertension and the most effective treatment for that individual."
Blood pressure is the force exerted by the blood against artery walls. Nearly one in four adults in the United States are estimated to have above-normal blood pressure. The condition is most common in African Americans and the elderly. Uncontrolled high blood pressure greatly increases risk for stroke, atherosclerosis, heart attack and kidney failure, and it can aggravate symptoms of diabetes.
Several classes of drugs are available to treat high blood pressure, but there is no way to determine which drug will best help particular patients because the underlying cause of the disease is unknown in 90 to 95 percent of cases.
Scientists have long known that certain signaling substances – hormones and neurotransmitters – in the body cause tiny arteries known as arterioles to constrict, causing blood pressure to rise. These substances also help regulate blood pressure by altering electrolyte and fluid levels in the kidneys.
But the precise mechanism through which these signaling substances maintain normal blood pressure even under rapidly changing conditions -- such as quickly standing or suddenly running – remains poorly understood. Recent research has suggested that a protein known as regulator of G protein signaling 2 (RGS2) is involved in blood pressure regulation. Blumer and his colleagues studied mice lacking both copies of the rgs2 gene, which is responsible for RGS2 production, and mice lacking only one copy of the gene. They compared these to normal mice.
Both strains of RGS2-deficient mice were highly hypertensive. While normal mice had a mean arterial blood pressure of 84 millimeters of mercury (mm Hg), mice lacking both rgs2 genes had a blood pressure of 135 mm Hg and those missing one gene had a blood pressure of 134 mm Hg. The finding that mice with one copy of the functional gene still were highly hypertensive suggested that the RGS2 protein is crucial for controlling blood pressure.
The investigators also were able to reverse the hypertension by giving the RGS2-deficient mice substances that blocked the hormone angiotensin II, which normally causes arterioles to constrict and increase blood pressure.
The investigators concluded that RGS2 works by stopping the action of angiotensin II, enabling arterioles to relax and blood pressure to decline. When RGS2 is missing or present at low levels, the effect of angiotensin II is prolonged, causing blood pressure to remain high.
"We hypothesize that genetic defects or differences that affect the amount or function of this protein may increase the risk of developing hypertension," says Blumer. "Developing a test for these abnormalities may lead to new means of diagnosing or treating the disease."
Next, Blumer hopes to identify the tissues in which RGS2 most strongly affects blood pressure and to identify the biochemical pathways through which the protein works.
Heximer SP, Knutsen RH, Sun XG, Kaltenbronn KM, Rhee MH, Peng N, Oliveira-dos-Santos A, Penninger JM, Muslin AJ, Steinberg TH, Wyss JM, Mecham RP, Blumer KJ. Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. Journal of Clinical Investigation, February 2003.
Funding from the National Institutes of Health, National Science Foundation, Pharmacia/Washington University Biomedical Research Agreement and American Heart Association supported this research.
Journal
Journal of Clinical Investigation