Better Circulation with Resveratrol

Resveratrol and Arterial
Health—Dual-Mode Benefits

Improved vascular function, achieved with or without
nitric oxide (NO), helps control blood pressure
By Will Block

lumbing is pretty basic—it’s not rocket science. Fluids (liquids or gases) flow through tubes or pipes, all of which, regardless of their composition or size, work the same, right? Right—unless they’re inside your body, in the form of arteries, veins, and capillaries. Now we’re talking about plumbing of a very different order, because the way blood vessels work is complicated indeed.

Blood vessels have all kinds of tricks up their sleeve. (You didn’t know they had a sleeve, did you? Well, they do; it’s called the tunica adventitia.) The one we’re interested in here is the ability of arteries to expand and contract automatically in order to regulate the flow of blood and, not incidentally, to control the pressure it exerts on the vessel walls. That’s a trick that iron, copper, and plastic have yet to learn.

This phenomenon is called vasodilation or vasorelaxation, meaning that the arterial walls dilate, or relax, making the tube’s diameter wider and allowing more blood to flow through it at a lower pressure. That’s often desirable, such as at times when you’re under stress, or when you want to have sex and an erection would come in handy. (Women have erectile tissue too, so this applies to them as well.)

With all the attention that vasodilation gets in regard to our health, it’s easy to forget that there must be an opposite: it’s vasoconstriction, or a narrowing of the arterial diameter. Vasoconstriction serves necessary purposes, of course, but if it becomes chronic, we have hypertension, or high blood pressure. That’s why vasodilation, induced by whatever means, is such a big deal.

Many things induce vasodilation—some that occur naturally with no effort on our part, some that require a bit of “effort,” such as meditation or cuddling with a pet, some that require substantial effort, such as physical exercise, and some that are induced by drugs, foods, or supplements. Or by wine—red wine.

Think . . . Resveratrol

If you’re a health-conscious person (and we know that you are, because we have spies everywhere), red wine probably makes you think of resveratrol, even when you’re not reading an article about resveratrol. That’s good, because resveratrol is the most important phenomenon in health and longevity in our lifetime—a lifetime that this amazing compound might be able to extend, if the results of experiments with a variety of lower organisms carry over to humans.

Few would dispute that drinking red wine (in moderation, of course—never more than two glasses a day) or eating food infused with garlic (mmm!) is life enhancement. Less enjoyable, but vitally important for life enhancement, because it allows us to be healthy, is controlling our blood pressure. Is there any connection between these approaches? Yes, there is. For the garlic connection, see the sidebar. For the red wine (resveratrol) connection, read on.

The Gasotransmitter Paradox

What is it about poisonous gases? First the scientific world was astounded to learn, in 1986, that nitric oxide (NO), a toxic industrial gas and a major air pollutant, was also a neurotransmitter and cell-signaling molecule when produced endogenously, i.e., inside our bodies. (That revolutionary discovery led to the 1998 Nobel Prize in medicine or physiology.) We now know that NO is an extremely important compound with many roles in our physiology beyond vasodilation.

Then in 1993, we learned that carbon monoxide (CO), a gas best known for killing people, is also an endogenous neurotransmitter and signaling molecule. It has roles in many neuronal activities, including learning and memory, as well as in vasodilation and cardioprotection, and it also functions in the immune, respiratory, reproductive, gastrointestinal, kidney, and liver systems.1

And then in 2001, hydrogen sulfide (H2S), of all things, became the third member of the exclusive club of compounds called gasotransmitters, or neurotransmitter gases, all of which are toxic when inhaled in significant quantities. Even if you’re not familiar with the notorious H2S from your days in the high school chemistry lab, you probably know it as the unforgettable smell of rotten eggs. It’s also often a component of your, uh, southern wind.

We’ve always known that H2S is produced naturally in our bowel. But we now know that it’s also produced by enzymatic action in cells throughout our bodies, where it seems to play a role in an astonishing variety of functions, including . . . vasodilation (that’s three for three).2 This may explain why garlic, a source of metabolic H2S, has cardioprotective effects.

But there’s more—much more. Endogenous H2S affects many biological functions (including the facilitation of erections) and diseases, including diabetes and neurological disorders. And administered in small amounts, it serves to protect organisms from major environmental stresses, such as low oxygen levels or high temperatures.3

Most intriguing of all, H2S acts as a longevity molecule, greatly extending the lifespan of certain roundworms (Caenorhabditis elegans) via a mechanism that involves the SIR2 gene—the same longevity gene that’s activated by caloric restriction and by . . . resveratrol!4 And guess what other molecule is intimately involved in lifespan extension through caloric restriction? NO. (See “Can Nitric Oxide Increase Lifespan?” in the January 2006 issue.)

That gets your attention, doesn’t it? By the way, there are still only three known gasotransmitters. Care to place a bet on whether more will be discovered, and whether they too will be poisons?

References

  1. Wu L, Wang R. Carbon monoxide: endogenous production, physiological functions, and pharmacological applications. Pharmacol Rev 2005; 57:585-630.
  2. Du J, Zhang C, Yan H, Tang C. A newly found gasotransmitter, hydrogen sulfide, in the pathogenesis of hypertension and other cardiovascular diseases. Curr Hypertens Rev 2006;2:123-6.
  3. Erdmann J. Rotten remedy: hydrogen sulfide joins the list of the body’s friendly, if foul, gases. Science News, March 8, 2008, p. 152.
  4. Miller DL, Roth MB. Hydrogen sulfide increases thermotolerance and lifespan in Caenorhabditis elegans. Proc Natl Acad Sci USA 2007;104: 20618-22.

Why Smoothness Matters

Red wine rocketed to public attention after “The French Paradox” was aired on 60 Minutes in 1991. Scientists soon discovered that the cardiovascular health benefits attributed to red wine were due primarily to resveratrol and other polyphenolic compounds found in red wine. These benefits are associated, in part, with improved vasodilation.

Vasodilation occurs via two main types of mechanisms: those that involve the vascular endothelium and those that do not. The vascular endothelium is the arteries’ inner lining. It consists of a single layer of smooth, flat, tightly tiled cells that provide a slippery surface for blood to flow over, thereby minimizing drag and turbulence (which would make the heart’s job of keeping the blood flowing that much harder). Beneath this thin layer of endothelial cells lies the layer of smooth muscle that enables the arteries to expand or contract as needed.

Nitric Oxide—Short-Lived but Potent

The dominant mechanism driving vasodilation—one that does depend on the vascular endothelium—involves the cell-signaling molecule nitric oxide (NO), which is synthesized in the endothelial cells from the amino acid arginine; the enzyme that catalyzes this reaction is endothelial nitric oxide synthase (eNOS). NO is a highly unstable molecule (a free radical, actually), which is to say that it’s highly reactive with many other molecules (and it’s toxic and corrosive if inhaled as a gas). Its lifetime in the body is about 1 second, so there are never any “supplies” of NO—it’s synthesized on demand and is quickly converted to nitrite and nitrate ions, which are eventually excreted in the urine.

When NO is synthesized in endothelial cells, it diffuses into the underlying muscle cells, where it induces chemical reactions that cause the muscles to relax—vasorelaxation. (Certain compounds used in treating cardiovascular disease and impotence induce or mimic this action.)

As noted above, there are other mechanisms that do not depend on NO or any other compound produced in the vascular endothelium. These mechanisms involve the smooth muscle cells in a manner called endothelium-independent vasodilation.

The Resveratrol Paradox

It turns out that resveratrol induces vasodilation by both kinds of mechanisms. Its ability to induce endothelium-dependent (NO-mediated) vasodilation in laboratory experiments with cell cultures or tissue samples has been known for many years. The concentrations used, however, have typically been thousands of times greater than those that can be achieved (and only very briefly at that) in the human bloodstream, even when the subjects take large supplemental amounts of resveratrol. The problem is that almost all the resveratrol is metabolized by the intestines and the liver before it has a chance to enter the circulation.

The obvious question is: If the laboratory experiments apparently require such large amounts of resveratrol, how can the cardiovascular benefits that resveratrol appears to provide in human beings be attributable to the tiny amounts contained in a few glasses of red wine (consumed daily for decades), especially when resveratrol’s bioavailability is so extraordinarily low?

Small Amounts Can Work

Researchers at the University of Louisville School of Medicine in Kentucky have shed some light on this vexing question, in a laboratory study elucidating the biochemical mechanism by which small amounts of resveratrol increase eNOS activity in human endothelial cells, thereby increasing NO production.1 (The mechanism involves cellular estrogen receptors and is too complicated to describe here.)

The researchers showed that, at least in their experimental design, extremely high concentrations of resveratrol were not necessary for inducing NO production. On the contrary, very low concentrations, similar to those found in the human circulation after oral administration of 25 mg of this compound (about 125 times as much as is found in a typical glass of red wine), did, in fact, produce measurable increases in NO production. (Actual vasodilation was not measured in this study.) The authors stated,

. . . we hypothesize that because of its rapid metabolism, resveratrol’s acute effects in the vasculature may contribute to its vascular/cardioprotective effects through different mechanisms than chronic/high dose effects. . . . the data presented here demonstrate that nutritionally relevant (nanomolar) concentrations of resveratrol rapidly . . . [lead to] eNOS activation and NO production . . .

Note that by “nutritionally relevant (nanomolar),” they meant concentrations that can be achieved through supplementation, not by drinking wine. So the question of how, exactly, the long-term consumption of red wine provides vascular and cardioprotective benefits is still unanswered.

Bordeaux, Anyone? (The Rats Didn’t Get Any)

Another new laboratory study, this one conducted by researchers in Bordeaux, France (home of some pretty decent wines, we’re told), examined, separately, the effects of a red-wine polyphenols extract as well as numerous chemically distinct fractions and subfractions of the extract, and several individual compounds, including resveratrol, that were isolated from the extract.2 Here the objective was to measure the actual amount of vasodilation induced by these substances and to determine whether it was endothelium-dependent (NO-mediated) or endothelium-independent.

The researchers used rat arteries of two kinds: aorta and pulmonary arteries, both of which emerge directly from the heart.* The big difference between the aorta and the pulmonary arteries is that the former carries oxygenated blood from the heart to the rest of the body, whereas the latter carry deoxygenated blood from the heart to the lungs. There the blood releases its carbon dioxide and picks up a fresh load of oxygen; it then returns to the heart via the pulmonary veins and is pumped out through the aorta.


*The segments of pulmonary artery used in this study were actually intralobar (from within one of the lung’s lobes), not from the main pulmonary artery itself. The segments of aorta were taken from the thoracic portion of the aorta.


Resveratrol Behaved the Same in Both Kinds of Arteries

Thus the oxygen status of blood in the aorta and in the pulmonary arteries is very different—and so are some characteristics of the vascular endothelia in these arteries. These differences were dramatically evident in the French study, which showed different behaviors of the various substances in the two types of arteries: some were vasoactive (producing vasodilation) in one type but not in the other.

What was most interesting—and surprising to the researchers—was that the vasodilation mechanism was, for the most part, mediated by NO in the aorta but not in the pulmonary arteries, where the effect was endothelium-independent and hence unrelated to NO. The notable exception to this pattern was resveratrol, whose activity was endothelium-independent in both types of artery. Resveratrol also had the largest effect of all the substances examined.

How Is Your Blood Pressure?

Have you looked inside your arteries lately? There are imaging techniques that can do that (sort of), you know. You might want to talk to your doctor about it. Even if you don’t wind up having it done, you can still monitor your blood pressure regularly, with a home device or with the sit-down apparatus at one of the large chain drugstores. Your blood pressure is a vitally important facet of your health—don’t neglect it. And don’t neglect to take resveratrol!

References

  1. Klinge CM, Wickramasinghe NS, Ivanova MM, Dougherty SM. Resveratrol stimulates nitric oxide production by increasing estrogen receptor α-Src-caveolin-1 interaction and phosphorylation in human umbilical vein endothelial cells. FASEB J 2008 [online preprint].
  2. Leblais V, Krisa S, Valls J, Courtois A, Abdelouhab S, Vila AM, Mérillon JM, Muller B. Relaxation induced by red wine polyphenolic compounds in rat pulmonary arteries: lack of inhibition by NO-synthase inhibitor. Fundam Clin Pharmacol 2008;22:25-35.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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