Hormone Aldosterone Is Promising Target For Stroke Treatment

“It costs about $56 billion a year to look after stroke patients, never mind the quality-of-life issues for these patients,” says Dr. Anne M. Dorrance, Medical College of Georgia physiologist and senior author of a review article on the cover of the November issue of Trends in Endocrinology and Metabolism.

Despite better management of blood pressure – the number-one risk factor for strokes – stroke incidence is not declining and aging baby boomers likely will cause rates to spike, says Dr. Dorrance.

She is among an increasing number of scientists who think the hormone, aldosterone, is part of the problem and blocking it may be part of the solution. Scientific momentum surrounding the hormone secreted by the adrenal gland prompted the journal to ask Dr. Dorrance to write the article, “Aldosterone: Good Guy or Bad Guy in Cerebrovascular Disease.”

She calls aldosterone “a double-edged sword” that helps maintain healthy blood pressure but also dangerously reshapes blood vessels and makes the heart fibrotic. Its conflicting roles in the body are clearly played out in the brain of hypertensives.

“What aldosterone does under normal circumstances is regulate sodium balance in the body,” says Dr. Dorrance. When sodium levels rise, aldosterone levels drop so the kidneys will eliminate more sodium to help maintain a healthy blood pressure and vice versa. “Ten years ago, we would have told you all aldosterone does is work on the kidneys,” she says.

In recent years, Dr. Dorrance and others have learned aldosterone works in many ways – many of them bad – inside blood vessels throughout the body and brain where there are many aldosterone receptors.

As with most things, too much aldosterone – resulting from an adrenal gland tumor or abnormal production for unknown reasons – is what causes problems, such as proliferation of the smooth muscle cells that make up the elastic walls of blood vessels. Instead of the middle filling up with plaque as it does in atherosclerosis, the middle, or lumen, of the blood vessel shrinks because the walls thickens. To further set the stage for stroke, the thicker walls are less stretchy, Dr. Dorrance says.

Conversely, after a stroke, emerging evidence suggests aldosterone helps neurons survive. “This is still a very big ‘perhaps,’ but perhaps at the time of a stroke, it may be beneficial, but only within the brain,” Dr. Dorrance says of high aldosterone levels. “There is a huge caveat because aldosterone does not get into the brain terribly well.”

Other good news emerging is that adolesterone blockers, such as spironolactone and a newer, more specific blocker eplerenone, may help turn the tide. Spironolactone was developed as an antihypertensive years ago but didn’t work very well, Dr. Dorrance says. Then, a University of Michigan study in the mid-1980s showed heart failure patients who got the drug in addition to standard treatment, such as beta blockers and ACE inhibitors, basically stopped dying, says Dr. Dorrance, who came from the University of Michigan to MCG as a postdoctoral fellow in 2000.

Unfortunately spironolactone also blocks testosterone so it increased men’s breast size. Last year, a more-specific second generation of the drug, eplerenone, received Food and Drug Adminstration approval.

Still neither version has become a medicine cabinet mainstay. However the potential for aldosterone blockers may still be unfolding as researchers such as Dr. Dorrance discover what the hormone does and what blocking it prevents.

In an animal model of stroke and hypertension, Dr. Dorrance and MCG graduate student Christine Rigsby, a paper co-author, have shown spironolactone won’t lower blood pressure but will reverse the wall-thickening effect of aldosterone, at least in males.

Within six weeks, “the blood vessels look like a normotensive animal, like the animal never had high blood pressure,” says Dr. Dorrance. “But when you block aldosterone in the females, there is no beneficial effect,” she says of the increasingly complex story. Her lab is looking at whether blockers become protective after menopause.

Gender difference hold up in aldosterone’s effect on the heart as well. One of the many findings of the Framingham Heart Study, a long-term study of thousands of residents in a Boston suburb, was that in women, higher levels of aldosterone correlate with worsening enlargement of the pumping chamber of the heart. “That does not mean aldosterone doesn’t impact a man’s heart in some way, but it’s definitely not as direct an effect,” says Dr. Dorrance.

“We are literally at the tip of the iceberg,” she says. Some scientists suspect the level of adolsterone receptors, not the hormone level, may be the real culprit.

Either way, there is little doubt aldosterone’s obscurity is over. “I think we are beginning an extremely complicated and terribly exciting 10 to 15 years of research as we try to unravel what is happening and why,” she says. “I think at the end, there will be better drugs and better information so clinicians will know when patients would benefit from these aldosterone blockers.”

Part of the excitement will come in identifying the pathways of aldosterone’s many actions. Dr. Dorrance thinks a relationship between aldosterone and epidermal growth factor, for example, causes the dangerous thickening of blood vessel walls in the brain. “It’s not just a blood pressure-dependent effect. This is something that is much more active than that. I do get up in the middle of the night wondering why it happens. It fascinates me.”

Dr. William E. Cannady, an MCG School of Medicine graduate who worked in Dr. Dorrance’s lab, also is a paper co-author.