First gene-hypertension link found.

First Gene-Hypertension Link Found

Researchers have pinpointed a tiny genetic defect in a strain of rats prone to high blood pressure, suggesting that a similar mutation may underlie certain forms of hypertension in humans. The finding represents the first known link between a specific genetic error and high blood pressure.

Molecular geneticists performing the work caution that hereditary high blood pressure -- whether in rats or people -- almost certainly results from a combination of genetic defects and environmental factors. They say significant hurdles remain before they'll be able to sort out the various contributing factors.

Nontheless, the new finding confirms many scientists' suspicions that hypertension can result from defects in a critical molecular pump that regulates salt concentrations in cells. In the long run, it could lead to the development of genetic tests capable of spotting susceptible individuals, and possibly to novel therapies.

"This is very important finding," says Michael Horan, associate director for cardiology at the National Heart, Lung and Blood Institute in Bethesda, Md. "Whether this exact gentic flaw is important in humans remains to be seen. But finding it in an animal is a good first step."

Horan notes that high blood pressure--which affects 58 million Americans, or about one-third of the adult U.S. populations -- is a potent risk factor for stroke, heart disease and kidney disease. "If we can make inroads in hypertension, we'll be making inroads for a whole sphere of very serious diseases," he says.

The work was performed by Victoria L. M. Herrera and Nelson Ruiz-Opazo of the Boston University School of Medicine. They investigated and enzyme called sodium- and potassium-dependent adenosine triphosphatase ([Na.sup.+.,K.sup.+.-ATPase]) in two strains of rats -- one that becomes hypertensive in response to a high-salt diet and one that retains normal blood pressure despite a high-salt diet. [Na.sup.+.,K.sup.+.-ATPase] is a protein embedded within the cell membranes of many types of animal cells. It pumps sodium ions out of cells and hauls potassium ions in, creating a sort of ionic tension, or chemical gradient, across cell membranes. In addition to maintaining proper water volumes and acidity levels within cells, this gradient provides the electrochemical energy to drive a host of important cellular activities, including sugar transport, nerve firing and muscle contraction.

With its obvious role in maintaining salt balance and its abundance in blood-pressure-regulating organs such as the heart, kidney and blood vessels, some researchers have hypothesized that [Na.sup+.,K.sup+.-ATPase] might play a role in hypertension. Herrera and Ruiz-Opazo isolated segments of [Na.sup.+.,K.sup.+.-ATPase genes in hypertensive and nonhypertensive rats and analyzed the DNA sequences. They found one significant difference: Hypertensive rats bear a DNA mutation that leads to the amino acid leucine getting substituted for the amino acid glutamine at position 276 in the 1,023-amino-acid-long protein.

The change, while seemingly minor, apparently causes big problems. It occurs in a region of the protein that must regularly change shape to perform its ion transport work. The leucine substitution makes the protein segment water-repellent, interfering with its flexibility. In a series of experiments with radioactive ions, Herrera and Ruiz-Opazo showed that mutant [Na.sup.+,K.sup.+.-ATPase] pumps ions less efficiently than normal [Na.sup.+.,K.sup.+-ATPase.

The work, described in the Aug. 31 SCIENCE, provides a plausible genetic mechanism for some varieties of high blood pressure. "An alteration in [Na.sup.+.,K.sup.+-ATPase ion transport would affect the [sodium-potassium] electrochemical gradient and conceivably contribute to changes in renal function, vessel wall resistance, or cardiac rhythmogenicity and contractility," the researchers say.

The finding represents a "very significant" advance, says the University of Cincinnati's Jerry B. Lingrel, who led a successful effort to clone part of the human [Na.sup.+.,K.sup.+.-ATPase] gene in 1987. "To find a real defect in a gene like this that appears to correlate with differences in hypertension is very exciting."

The enzyme "may be important in some families and not in others," he says, adding that the discovery will spur a search for this or similar mutations in people with high blood pressure. About one-third to one-half of U.S. hypertensives have a form of salt-sensitive high blood pressure similar to that seen in the experimental rats.

Herrera says the mutant gene "might just contribute to salt sensitivity or it might contribute to hypertension [directly]." To clarify the extent to which the gene causes high blood pressure independent of other contributing factors, she plans to mix and match [Na.sup.+.,K.sup.+.-ATPase] genes in genetically engineered rats.

"Ideally, we'd like to put a mutant gene into a wild-type rat and see what happens to its blood pressure, or put a wild-type gene into a hypertensive rat and see if we can reduce blood pressure despite a high-salt diet," Herrera says. "Experiments like those...would really help nail this thing down."