February 21, 2005
Estrogen Becomes Vasoconstrictor In Old Age

Dr. Richard White and colleagues at the Medical College of Georgia have found that in older blood vessels estrogen ceases to be a vasodilator that opens blood vessels and instead becomes a vasoconstrictor that restricts blood flow.

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."

The dangers posed by estrogen replacement therapy in older women illustrate a point I've made here before: the reason many compounds decline or increase as we age may well be an adaptation to other changes that are caused by damage accumulation that is aging. Restoring those compounds to youthful levels may raise risks of a variety of diseases. For another case which I suspect is also an example of this same phenomenon see my warning that replacement of older blood with younger blood may reinvigorate many stem cell reservoirs but at the cost of increasing the risk of cancer. Some types of rejuvenating interventions may not be prudent before other types of rejuvenation can be accomplished first. Otherwise, as is illustrated with this report above, the net result can be harmful.

One practical question arises from this study: Can we at least partially prevent the decline in nitric oxide production capability in old bodies by eating more foods that contain L-arginine? Studies of the effects of supplementary L-arginine on the vasodilation of old blood vessels seem like a wise idea. It might be possible to cancel out some of the negative effects of hormone replacement therapy in older women by L-arginine supplementation or some compound that would enhance vasodilation.

If you want to boost your L-arginine intake on speculation that this will increase nitric oxide production then nuts are good sources of L-arginine and hazel nuts, brazil nuts, and walnuts are the richest sources (at least of those nuts listed). See the table 4 at that link for more nuts and their L-arginine content. The reported heart healthy benefits of nut consumption may be coming at least in part from the vasodilatory effects of the L-arginine in them.

Share |      Randall Parker, 2005 February 21 02:57 PM  Aging Studies

Robert Silvetz said at February 21, 2005 10:49 PM:

I really think the worry about cancer with restoration of youthful levels of compounds to be overrated.

For example, hormone replacement therapy in women: the lines of cancer incidence in iso-human hormone replacement, and non-replacement, are effectively on top of one another. However, in non-replacement groups, cardiovascular disease runs rampant. Women are bulletproof pre-menopausal, and almost bulletproof in iso-human hormone replacement.

We need to stop focussing on half of the equation. Sure, older cells are cancer prone. Yet, it's immune system surveillance that crushes the cancers we generate every day. Restoration of youthful levels of systemic signals typically should restore immune surveillance to maximal levels. In fact, makes one wonder if a technology to regenerate the thymus shouldn't be explored post-haste as a cancer treatment modality.

Now, having said that, it's a total mystery to me why L-arginine isn't first line hypertensive therapy in patients where L-arginine doesn't put TGF-beta through the roof. I've used L-arginine quite successfully to shave a few systolic points, and many diastolic points, off my blood pressure.

Tim Fitch said at May 26, 2005 4:40 PM:

To say something "targets" something else is not speaking clearly. "Targets" here means "affects", but affects how, in what direction? Increases the targeted item? Decreases and destroys it?

brenda howe said at January 22, 2006 5:21 AM:

HELLO HAVE READ YOUR PAGES ... AND CAN SEE THE VALUE OF L-arginine.... am asking are there any VITAMINS WORTH WHILE TAKING WITH L-arginine in them ... i am 70 years old am on quite afew tablets[medication ] ... now have added warfarin to these .. and did recently have an angina attack .... BUT must also say i am on estrogen patches and a vagina tablet in a plunger type ....i have low energy levels ..so am hoping perhaps vitamin tablets may help with this
thank you ..brenda howe

Anonymous said at September 27, 2014 7:32 PM:

Holy cow, is this the reason I am feeling tightness and pressure in the chest (angina?) every time I take a dose of estrogen replacement? No matter how small a microdose I make it, w/in the hour, it's cardiac symptoms and/or sensations. But without the estrogen I am nutty in the head. How to get it to my brain without affecting the heart?

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