Zeroing in on the Causes of Hypertension

Concluding a more than decade-long search and fueling hopes of improved drugs to treat the disease, a team of researchers led by a Medical School professor has isolated and purified a substance suspected of causing high blood pressure.

Since 1977, scientists have sought a substance which experimental evidence had demonstrated prevents the proper functioning of the sodium-potassium pump, a cell regulatory mechanism which helps to maintain a proper balance of ions in the cell.

A team led by Garner T. Haupert '67, assistant professor of medicine at the Medical School and the Massachusetts General Hospital (MGH), has pinpointed the substance, known as the hypothalamic inhibitory factor (HIF).

HIF prevents the body from maintaining a proper balance of salts. By creating an altered chemical state and causing blood vessels to contract, the presence of the factor results in hypertension, or high blood pressure.

The research, performed in conjunction with scientists at Bristol-Myers Pharmaceutical Research Institute and Columbia University, was published earlier this fall in the Proceedings of the National Academy of Sciences.

HIF apparently slows pumps of kidney cells, causing the sodium buildup which characterizes high blood pressure.

Haupert, who describes the possibilities of future HIF research as "tempting," hopes that the research will help scientists better understand HIF's effects on the pump and, in turn, to refine existing drugs which combat high blood pressure. For example, one such drug might be comprised of chemicals which block the actions of HIF.

"[Further studies on HIF] would allow us to take new directions in attempts to find ways to treat hypertension," he says. Haupert is also hopeful that hypertension may be used as a model to study other diseases involving the cardiovascular system.

The next direction for HIF research will involve synthesizing and testing the HIF for purity, finding an antibody to HIF which might block its action by binding to it, and running clinical tests on patients with high blood pressure. Ideally, those patients who receive the antibody will show fewer symptoms of hypertension over time.

The concepts behind the search for what eventually turned out to be HIF, according to Haupert, have been developing for more than two decades. Twenty years ago, scientists speculated that an unknown substance increased sodium excretion in animal models. During the '60s, the substance was believed to be a circulatory factor--present outside of the cell--which caused cells to excrete additional sodium.

When research failed to yield positive results, some scientists began to ponder the problem from a different angle--"a much more philosophical point of view," according to Haupert.

The only known cell pump regulator at that time was digitalis, a plant substance currently used as a drug to treat heart conditions. But Haupert says he questioned the idea that only once substance exists to control such an integral aspect of homeostasis.

"Why should we as mammals have a pump of so much importance whose only regulator is...from the plant kingdom?" he queried.

Haupert and scientists at the MGH reasoned that an analogous substance could be present in mammalian cells, and began in 1977 to target organs in which the pump plays a key role.

Years later, their efforts were rewarded when they isolated and purified a factor--HIF--from the hypothalamus. Chemists at Columbia analyzed the chemical and determined that it differed from its plant counterpart only by the three-dimensional placement of certain atoms.

"[The exact chemical structure of the compound] is extremely important because once you know the structure it can be synthesized easily," says Columbia Centennial Professor of Chemistry Koji Nakanishi.

Like digitalis, HIF caused cardiac muscles to beat more strongly, increasing pressure and potentially causing hypertension. Scientists hope that discovering the reasons for the similarities between the two chemicals will lead to a better understanding of their function.