© Whole Foods Magazine

November 2006

Vitamin Connection

The Science of ATP: Part 2, An Interview with ATP Pioneer Dr. Eliezer Rapaport

By Richard A. Passwater, Ph.D.


Last month we began our chat with adenosine triphosphate (ATP) research pioneer Dr. Eli Rapaport by discussing some of the basic chemistry of ATP. In this installment, we explore how Dr. Rapaport’s research led to important health findings for ATP supplements.


Passwater: Could you provide us with a background summary of your scientific activities.


Rapaport: Yes, I received a Ph.D. in organic chemistry from the Johns Hopkins University in 1971. Since that time I served on the faculties of Harvard Medical School at the Massachusetts General Hospital, Boston University School of Medicine and the Worcester Foundation for Experimental Biology. I was the first to make the seminal discovery that administration of adenosine 5’-triphosphate (ATP) to an animal or a human results in the immediate expansions of liver, blood and blood plasma (extracellular) pools (steady state levels) of ATP.


Passwater: The prevailing thought before that was that administered ATP, which is rapidly degraded to adenosine inside the vascular bed, yields only elevated levels of adenosine. Now that is a major discovery of importance, but I want to return to that discussion later. For now, let’s continue with your discoveries.


Rapaport: Well, I further discovered and characterized the physiological and pharmacological roles of normal and expanded pools of organ, blood and blood plasma ATP pools in the treatment of clinical indications and aging. Intravenous ATP treatment of advanced, refractory cancers is now in phase III clinical trials. I have identified physiological regulatory mechanisms of ATP and its catabolic (degradation) product in vivo, adenosine. I have established the therapeutic and nutritional applications of ATP (and adenosine) in benefiting cardiac, liver and skeletal muscle protection, circulatory functions, vascular health, glycemic (blood sugar) control, disposal of oxygen and nutrients at peripheral sites, regulation of weight loss and the treatment of type II diabetes and arthritic diseases.


Passwater: These discoveries must have been of interest to pharmaceutical companies. Did you patent any of them?


Rapaport: I have served as a consultant to biopharmaceutical companies as well as chairman and chief scientific officer of ATP Therapeutics. My research activities are described in 58 published original, peer-reviewed articles as well as meeting abstracts and a variety of issued U.S., European and Japanese patents. These issued patents and patent applications that are currently being prosecuted, dominate the ATP delivery field and are basic to ATP administration and delivery technologies. These issued and pending patents disclose and teach the administration of ATP in the maintenance of healthy physiological systems as well as in the treatment of diseases.


Passwater: Dr. Rapaport, last month we mentioned that your discovery of the luciferin/luciferase/ATP mechanism led to unsuspected uses that really advanced biochemistry in general and enzymology in particular. As I mentioned, we developed the Aminco Chem Glow photometer to enable scientists to follow up on your discovery. Are there other advances in the ATP detection technology that come to your mind?


Rapaport: The detection of extremely low levels of ATP by utilizing the luciferin/luciferase light reaction is sensitive enough to enable the quantitative determination of ATP released from cells. Examples are in identifying the defects in cystic fibrosis, a genetic disease where there is thought to be a deficiency in the release of ATP from epithelial cells, yielding increased cellular ATP pools and decreased extracellular ATP pools.

Another example of an advance that is based on the sensitive determination of ATP released from cells is the monitoring of ATP release at the carotid body. The carotid body is a chemoreceptor that, among other functions, monitors oxygen content in the blood and helps regulate breathing. When blood oxygen levels drop, cells in the carotid body release ATP, which in turn interacts with P2X ATP receptors on nerve endings in an afferent mechanism that transmits the signal to a specific part of the brain. The brain then initiates involuntary breathing in order to restore normal blood oxygen levels.


Passwater: Not too long after you helped elucidate the long-sought-after mechanism of the firefly light emission, I narrowed my antioxidant research and lost track of your research for a while. Please tell us more about your seminal discovery related to the actions of oral ATP.


Rapaport: The systemic and oral administrations of ATP result in the expansions of liver, blood (red blood cells) and blood plasma (extracellular) pools of ATP. Administration of ATP, or any other adenine nucleotide, in a suitable formulation, results in a rapid degradation to adenosine and inorganic phosphate. Oral administration of ATP produces adenosine and inorganic phosphate in the small intestine and the portal circulation. Both adenosine and inorganic phosphate are then incorporated into the liver ATP pools, yielding expansions of these pools.

Detailed studies in animals have shown that the turnover of the expanded liver ATP pools, supply the adenosine precursor, in the hepatic sinusoids, for increased synthesis of ATP in red blood cells. Mature red blood cells utilize only a salvage precursor (adenosine) in the synthesis of ATP by a glycolytic pathway only. The elevated red blood cell ATP pools slowly release ATP into the blood plasma by a non-hemolytic mechanism. Red blood cells (mature erythrocytes) are not only carriers of oxygen, which is released to peripheral tissue such as skeletal muscle, only when and where it is needed. Red blood cells are also carriers of ATP, which is released in order to stimulate blood flow to oxygen-poor (hypoxic) tissue when and where stimulation of blood flow is needed to answer the metabolic demands of the tissue.

All of the methods and processes establishing the expansions of ATP pools in organs, red blood cells and blood plasma after oral administration of ATP, are protected by claims of my issued U.S. Patents Nos. 5,049,372 and 5,227,371. The half-life of elevated ATP pools in red blood cells is about six hours. The slow release of ATP from red blood cells yields elevated ATP and its blood plasma degradation product, adenosine, extracellularly in the blood plasma. This process is regulated by physiological mechanisms that produce these agents inside the vascular bed at sites where they are needed.

ATP and adenosine are powerful vasodilators inside the vascular bed, acting through interactions with P2Y (ATP) and A2 (adenosine) receptors present on vascular endothelial cells. In addition to their powerful vasodilatory activities, chronic oral administration of ATP provides purine precursors (adenosine) for salvage synthesis of ATP in peripheral tissues.

The most important aspect of the vasodilatory activities of blood plasma ATP and adenosine is the stimulation of blood flow, without affecting heart rate or arterial blood pressure. I am reminded of your theme in several of your recent columns—“It is all about ATP”—in stating that “The most important effect of oral ATP is about its ability to stimulate blood flow, where and when it is needed, without affecting heart rate or arterial blood pressure.” All of these effects are the direct result of the expansions of liver, red blood cell and blood plasma ATP pools after administration of ATP. Circulatory, blood plasma ATP is now widely acknowledged to be the master regulator of intravascular events.


Passwater: What is the mechanism of vasodilation by blood plasma ATP and adenosine?


Rapaport: Animal studies showed that chronic administration of oral ATP, at levels similar to the dose recommended for human use, yielded significant positive cardiovascular and pulmonary responses. These included significant reductions in pulmonary vascular resistance and significant reductions in peripheral vascular resistance followed by increases in blood flow. No effect on arterial blood pressure or heart rate was observed.

An increase in left ventricular work index, which is an indication of improved cardiac index was also observed. Cardiac index is a value that expresses the efficiency of the heart in circulating the blood throughout the vascular bed and is expressed in units of L/min/sq m. In addition, an increase in arterial oxygen pressure (PaO2) was established. Intraluminal ATP, at physiological concentrations, was shown to produce not only local vasodilation, but also vasodilation at sites upstream from the site of its application.

Adenosine on the other hand, induced only local vasodilation. Low physiological levels of blood plasma ATP (about one micromolar), induced 8% increase in vascular diameter, corresponding to a minimum of 17% increase in blood flow. Vasodilation induced by physiological levels of ATP is mediated primarily through nitric oxide (NO), which is synthesized by the enzyme NO synthetase in vascular endothelial cells in response to the interaction of ATP with P2Y receptors. The NO then acts in neighboring perivascular smooth muscle cells, which control vascular tone and produce relaxation and vasodilation of the blood vessel in response to NO.

At higher levels of ATP, corresponding to ATP released from red blood cells containing expanded ATP pools, other mechanisms of vasodilation operate besides NO synthesis. These mechanisms include induction of vasodilatory prostaglandins synthesis, mostly prostacyclin (PGI2) as well as non-NO, non-prostacyclin induced vasodilation that is mediated by the direct interactions of ATP and adenosine with their corresponding receptors. As importantly, endothelium-derived hyperpolarization factor (EDHF) is synthesized and released in response to intraluminal ATP. In the cerebral arteriols elevated ATP stimulates blood flow in response to metabolic demand by inducing EDHF synthesis. Thus, circulatory ATP regulates and controls blood flow to the central nervous system as well as to peripheral sites.


Passwater: What is the importance of the stimulation of blood flow? Does it have practical health consequences?


Rapaport: The stimulation of blood flow by exogenously administered ATP is extremely important not only from a physiological mechanistic point of view but also from a practical point of view. Stimulation of blood flow in answering the metabolic demands of peripheral tissue—such as cardiac or skeletal muscle, lung or liver—supports oxygen delivery and nutrient disposal at these sites. It also improves the removal of waste products such as lactic acid from skeletal muscle environment. Stimulation of blood flow to the brain improves oxygen consumption, which leads to improved brain metabolism and function. One can state that improvements in blood flow, slow aging at cellular and organ levels.


Passwater: Could you point to a specific clinical indication where orally consumed, ATP-induced stimulation of blood flow leads to a practical result?


Rapaport: Yes. An example is the treatment of low back pain by ATP capsules consumed orally, at a total of 90 mg per day. Oral ATP for the treatment of sub-acute low back pain is approved as a drug in France. It has been established that the administration of ATP elevates levels of extracellular ATP, the “master regulator” of blood flow. Providing the body with supplemental ATP activates ATP receptors on vascular endothelial cells, the layer of cells lining the blood vessels. This improves the tone of the blood vessels and relaxes the vessel walls so that more oxygen-rich blood can get through to the heart, lungs, liver, brain and skeletal muscles. All of this happens without adversely affecting blood pressure or heart rate. (Please see Figure 1)



Several published in vitro, in vivo and human studies have demonstrated the enhancement of skeletal muscle function by circulatory ATP. In addition, both ATP and adenosine are known to have anti-nociceptive (pain-inhibiting) effects in acute and chronic pain. The two human clinical trials undertaken in order to assess efficacy and safety of oral ATP in sub-acute low back pain (LBP) were an experimental drug efficacy placebo-controlled, double blinded trial (trial one) and a drug-guidelines effectiveness trial (trial two).

Patients in both trials were screened on day 0, day 7, day 30 and day 90 using a series of assessments. The primary outcome measure was the Roland-Morris Disability Questionnaire (RDQ). Secondary measures included visual analog scale (VAS) pain, overall efficacy assessments by patients and investigator, and number of rescue analgesics consumed. Oral ATP was well tolerated. No severe drug-related adverse events were recorded in either trial, and only two patients complained of indigestion. Both trials indicated that oral ATP had a significant positive effect on LBP: in the first trial, versus placebo, in the second trial, versus advice to stay active. In both trials, statistically significant reductions in the use of rescue analgesics by the ATP groups, compared to the placebo group, were observed. Throughout the course of both trials, participants were allowed to take “rescue analgesic” tablets consisting of dextropropoxyphene (30 mg) and acetaminophen (400 mg) for the first 30 days with daily consumption being recorded.


Passwater: Before we continue with individual indications for oral ATP, what are the new data that tie the significant declines in bodily ATP during aging to the decreases in the rate of mitochondrial ATP synthesis being causal in aging?


Rapaport: During aging (65-75 years old), initial levels of red blood cell ATP pools drop to about half of what they are in young individuals. Older subjects (mean age of 68.8 years) retain only 50% of skeletal muscle mitochondrial ATP synthesis as compared to adults (mean age of 38.8 years). Purine (ATP and adenosine) losses, adversely affecting organ and muscle function, were also reported in diseases and other stressful conditions. The reduced blood and tissue pools of ATP in the aged, produce a variety of adverse conditions originating in decreased blood flow, which in turn is the result of significantly diminished vasodilation. Thus, the existence of strong impetus for using oral ATP formulations to improve vasoreactivity in the prevention and treatment of conditions that affect the aged population.

As to causality, recent experiments have shown that it is the decline in mitochondrial ATP synthesis in skeletal muscle that initiates aging in experimental animals. The decline in mitochondrial ATP synthesis is a direct result of mutations in mitochondrial DNA caused by reactive oxygen intermediates produced near the mitochondrial membrane. Transgenic mice, in which the generation of reactive oxygen intermediates was slowed down by increased mitochondrial expression of the enzyme catalase, had a significantly longer life span than control animals. Transgenic mice that were altered genetically to introduce errors into mitochondrial DNA at an increased rate, resulting in a faster than usual decline in the rate of mitochondrial ATP synthesis, exhibited early signs of aging culminating in shorter life spans.


Passwater: How do oral ATP formulations interfere with the process of aging?


Rapaport: Improvement of skeletal muscle function has long been the Holy Grail of anti-aging research. The desire to slow the aging process by improving skeletal muscle strength and function has attracted a considerable degree of interest. Hormone treatments of elderly men with human growth hormone (HGH) and testosterone and hormone treatment of elderly women with HGH and hormone replacement therapy (HRT), was the subject of a recent large clinical trial. The results confirmed the apparent positive effects of growth hormone and sex steroid combinations on body composition, namely, increasing lean body mass and decreasing fat mass. However, the results clearly demonstrated that lean body mass did not translate into improved skeletal muscle function and, as important, the risk of adverse effects associated with the use of these hormonal regimens was substantial (Blackman MR, et al.: Growth hormone and sex steroid administration in healthy aged women and men. A randomized controlled trial. JAMA 2002; 288:2282-2292. Cassel CK: Use it or lose it. Activity may be the best treatment for aging. JAMA 2002; 288:2333-2335). The failure of these recent trials resulted in increased interest in oral ATP formulations. Rigorous scientific, pre-clinical and human clinical studies have demonstrated that reversal of the loss of ATP upon aging or disease by oral supplementation of ATP distinctly benefited:

* Vascular health, circulatory functions and blood flow to peripheral sites.

* Peripheral vascular diseases and joint ailments such as osteoarthritis, bursitis and tendonitis.

* Skeletal muscle functions, physical performance, energy levels and reduction in fatigue.

* Cardiovascular function and endurance.

* Physiological regulation of glycemic (blood sugar) levels).

* Cerebral circulation, improved brain oxygen consumption and function leading to improved mental acuity and reduction in the perception of fatigue.


Passwater: That’s a significant list of ways ATP supplements can impact aging. Let’s let our readers reflect on this and pick up again next month with some additional ways that oral ATP supplementation produces important health benefits. WF


Figure 1: (Top) Model of red blood cell oxygen delivery to exercising skeletal muscle fiber. The erythrocyte acts in sensing oxygen demand and releases an oxygen molecule of the four oxygen molecules bound to hemoglobin to support mitochondrial ATP synthesis in the muscle fiber. At the same time, ATP released from the erythrocyte and its degradation product adenosine, act by binding to specific receptors to answer the metabolic demands of the muscle fiber by stimulating blood flow to the muscle. The enhanced blood flow stimulates further oxygen disposal and nutrient (glucose) delivery to the muscle along with increased rate of waste product (lactic acid) removal. (Bottom left) ATP and adenosine control vascular tone by binding to specific receptors on vascular endothelial cells. Vasoactive agents such as nitric acid (NO), endothelium-derived hyperpolarization factor (EDHF) and prostacyclin (PGI2) are synthesized in response and by acting inside neighboring perivascular smooth muscle cells produce vessel relaxation. (Bottom right) The three modes of ATP synthesis inside skeletal muscle fiber: In the mitochondria by oxidative phosphorylation from fatty acids or pyruvate and by the oxidative breakdown of glucose in the cytosol. (Reproduced with permission of Tom Fowner)


© 2006 Whole Foods Magazine and Richard A. Passwater, Ph.D.

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