High blood pressure in the U.S. has reached epidemic proportions. According to the Centers for Disease Control and Prevention, 30 percent of adult Americans have it, 277,000 Americans died from it in 2002 and 90 percent of middle-aged adults will develop it before they die.
Obvious need has pushed scientists to better understand high blood pressure's causes and to find some effective therapies.
To this end, a group of Hopkins researchers, led by Rajini Rao at the School of Medicine, believe they've identified a gene linked to the most common form of high blood pressure.
Most of the time, high blood pressure - the technical term is hypertension - is called "essential" or "primary."
Unlike a related disorder called secondary hypertension, which usually arises from some other underlying condition, essential hypertension has no specific, treatable cause and is generally thought to be influenced by both behavioral choices and genetic predispositions.
Hypertension is a problem of balance. For their cells to function properly, all animals - from the lowliest nematode to the haughtiest human - have to maintain a balance between fluids and electrolytes (dissolved, positively-charged ions) in and around every cell.
Primarily, this is accomplished by transporting electrolytes from inside the cells out into the bloodstream or vice versa.
It's not surprising, then, that people with essential hypertension almost always have malfunctions in electrolyte transport, while those with secondary hypertension are generally normal.
What's more, a particular type of transport - called sodium-lithium countertransport (SLC) - is strikingly correlated with essential hypertension.
Indeed, the presence of increased SLC activity in red blood cells has been relied on for almost 20 years as a tool in diagnosing essential hypertension.
During SLC, one lithium ion from inside a cell is exchanged for one sodium ion from outside the cell. This is mediated by a specialized protein called an antiporter, which is inserted in the cell's membrane.
Until the present study, it was unclear which type of antiporter was involved in SLC.
Many scientists viewed SLC as a modification of another electrolyte-transport process that exchanges protons and sodium ions and is used to regulate a cell's pH. (The antiporter in that case is called the sodium-hydrogen antiporter or NHA.)
Lithium ions, the theory went, would simply replace protons in the exchange with sodium.
More recent evidence, however, suggested that SLC and sodium-hydrogen transport don't actually involve the same antiporter protein.
The drug amiloride, which is known to act on certain antiporters, blocks sodium-hydrogen transport but not SLC.
The objective of Rao and her team, then, was to find an amiloride-insensitive antiporter protein.
To do so, they analyzed over 550 genes whose codes they conjectured could produce the desired protein.
They came across two previously undescribed genes, now called NHA1 and NHA2, which bore striking similarities to sodium-hydrogen exchangers already identified in E. coli.
What's more, the team found that versions of NHA1 and NHA2 exist in all animals, including nematodes, flies, puffer fish and mice.
The researchers hypothesized that the human version of NHA2 was the antiporter responsible for SLC in our bodies, and they uncovered some convincing evidence to that end.
By inserting the NHA2 gene into blank yeast cells, they observed that the protein it produced resided in the plasma membrane (as any antiporter is obliged to do) and, more importantly, that its function was entirely insensitive to amiloride.
In addition, they detected the presence of human NHA2 in red blood cells, where increased SLC is associated with essential hypertension.
Nonetheless, the NHA genes are still considered "candidate" genes for essential hypertension.
Many points remain unclear. Are there simply more NHA2 proteins in people with the disorder, or are those proteins merely overactive in hypertension?
Understanding genetics and molecular biology could also help answer questions about lifestyle. What effects do behavior and diet have on SLC activity? The country's blood pressure continues to rise, but only time will tell.
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