Changing chemistry helps explain estrogen threat to the heart

Feb 16 2005

A piece of the topical puzzle of how estrogen goes from protecting women from heart disease to apparently increasing their risk later in life may have been found.

Medical College of Georgia researchers have found changes in blood vessel chemistry that may explain the dramatic flip-flop in estrogen’s function that occurs in older women, taking it from a dilator of vessels to a potentially dangerous constrictor, says Dr. Richard White, MCG pharmacologist.

Dr. White will present the findings at the American Heart Association’s Second International Conference on Women, Heart Disease and Stroke in Orlando, Fla., Feb. 16-19.

He hopes the findings will ultimately make hormone replacement therapy safer, possibly by adding to the mix compounds that enable estrogen’s protective role before menopause.

Hormone replacement therapy, touted for its ability to reduce the risk of heart attack and stroke in postmenopausal women, appears to increase the risk of those conditions, according to findings of the Women’s Health Initiative, a 15-year study of more than 161,000 women by the National Institute of Health’s National Heart, Lung and Blood Institute.

This bad news about estrogen and the heart puzzled Drs. White and Scott A. Barman, also an MCG pharmacologist, as much as it did many physicians who had long prescribed it.

They were studying estrogen’s effects on blood vessels, focusing on its impact on the smooth muscle cells that allow blood vessels to contract, thereby regulating blood pressure and blood flow. These researchers found that estrogen targets nitric oxide synthase 1, one of three versions of the enzyme that makes the powerful vasodilator, nitric oxide.

“What we were finding is that estrogen seems to be what you might call a natural nitroglycerin; nitroglycerin also works by making nitric oxide,” Dr. White says.

Then they tried to block estrogen’s activity by blocking nitric oxide. “What surprised the heck out of me was after we blocked nitric oxide production and added estrogen, we got a contraction,” says Dr. White. “Estrogen now had turned into a constrictor agent, an agent that would increase blood pressure.”

They looked further and found that normal aging decreases levels of the cofactors L-arginine and tetrahydrobiopterin – both critical to nitric oxide synthase’s production of nitric oxide.

Instead of making nitric oxide, estrogen was producing the powerful age-promoting – and apparently vasoconstricting – oxygen-free radical, superoxide.

“At first, I thought it was an artifact,” says Dr. White, who recently received a $1.2 million, four-year grant from the NHLBI to pursue his findings. But using a porcine heart that is very similar to the human heart, he and Dr. Barman, along with Dr. David J. Fulton, a pharmacologist in the MCG Vascular Biology Center, found that every time they blocked nitric oxide production, estrogen became a vasoconstrictor.

“Under normal conditions, such as a pre-menopausal woman, this enzyme, nitric oxide synthase, makes nitric oxide,” says Dr. White. “But if you block the production of nitric oxide, this nitric oxide synthase now has a secondary product that normally isn’t made in an appreciable form. Now it makes a compound called superoxide. It’s an oxidant, and oxidation is bad in general. It causes a lot of cellular damage. But what we also have found is that now, instead of causing relaxation, it causes constriction. So you completely flip-flop the response here.

“One of the things this means is that menopause is a good thing, a sort of revolutionary endocrinology idea,” says Dr. White. “Menopause is adaptive because a woman is not supposed to have as much estrogen when she gets older because it can kill her.” He holds up a graph plotting the dramatically dropping rates of tetrahydrobiopterin over a woman’s life, a drop that parallels the drop in estrogen levels.

“We have to confirm it,” he says of the new grant in which researchers will use different drugs to mimic aging, drugs that knock out L-arginine and tetrahydrobiopterin, to try to create an aged artery and restudy estrogen’s impact.

“Estrogen is so powerful; it affects every system in your body. We are looking with tunnel vision at its effect on blood pressure control. What would this do to bone? What would this do to Alzheimer’s? What happens to the brain is probably very similar,” he says as critical cofactors drop that enable estrogen to relax blood vessels. “This could be a mechanism that would affect practically every system in the body.”

Studies leading to the latest grant also were funded by the NHLBI as well as the American Heart Association.