As night would fall and while my parents gathered around the radio (not every home had a radio then), I would be watching Nature. I would wonder about things such as what caused the cooling breezes or what purpose those pesky mosquitoes served that nicer bugs couldn’t provide. Another persistent question was what purpose did the firefly lantern serve? What magic made it light? Why did the lanterns blink instead of just staying on? Several years later, about 1950, Dr. Bill McElroy at Johns Hopkins was paying a penny a firefly if you brought him a jar with a couple hundred or so. As a teenager, I was too old for catching lightening bugs, but if that deal had only been available when I was younger, I could have been rich as a child. However, I would have had to talk my older brother into driving down US Route 40 to Baltimore! Gas was only 15 cents a gallon then, but I doubt that our 16-year old family car could have survived the 70-mile trip. Dr. “Mac” McElroy became one of the most respected biochemists of all time. Now, why would this prestigious scientist pay a penny for a lightening bug? What was so important about the magic of the firefly glow? Life needs energy in order to exist. Most biochemical reactions require an external source of energy in order to proceed. The energy that drives the reactions of life must be released gradually and on demand. It must be stored in readily accessible forms and the rate of energy release must be finely controlled. In 1929 Fiske and Subbarow in Boston, discovered, characterized and identified ATP as the molecule involved in muscle contraction, though others, mostly Lohmann in Europe were unjustifiably credited with this discovery. In 1941, Lipmann identified ATP as the “high-energy” molecule in metabolism, and in 1947, Dr. McElroy determined that ATP was involved in the Firefly glow. However, ATP alone could not be the entire energy source for light emission since the energy released by ATP hydrolysis (7 kcal) is far less than the energy of a photon in the yellow region of the spectrum (50 kcal). In addition to my antioxidant research, I was developing and publishing research about fluorometric and other luminescence applications. I had moved to Silver Spring, MD to head a research applications laboratory for the American Instrument Company and to continue my research with antioxidants and luminescence. Bioluminescence was now a possible tool for
studying many biochemical pathways. We developed an instrument called the Aminco Chem-Glo which used measured ATP. Even today, I keep tabs with a close friend, Dr. David Miller, who continues to develop bioluminescence techniques and instrumentation. When I met Dr. Bill “Mac” McElroy in 1965, the research group at Johns Hopkins was still trying to solve the problem. Later, I would be introduced to other members of his group including Drs. Howard Seliger, Nathan Kaplan and E. H. White who had joined Dr. McElroy’s staff in the late 1950s. In 1965, Drs. McElroy and Seliger published a seminary paper linking the evolutionary origins of bioluminescence with the appearance of oxygen in geological time. Dr. McElroy was promoted Chair the Biology Department at Hopkins and later became the Chancellor at the University of California, San Diego. Dr. Kaplan moved with him. Now why am I telling you this long story about Johns Hopkins research with ATP and Dr. McElroy? Drs. Seliger and White continued the quest to solve the Firefly mystery. Now entering Dr. White’s laboratory at the department of chemistry is a bright young grad student by the name of Eliezer Rapaport. That’s right, the same Dr. Rapaport we will chat with now. Passwater: Is my recollection about Johns Hopkins and Fireflies fairly accurate? Rapaport: Yes. It is correct and vivid. I studied at The Johns Hopkins University Graduate School for a Ph.D. in Chemistry and during these years we established the mechanism of the firefly bioluminescence (J. Amer. Chem. Soc. 91:2178-2180, 1969). Passwater: And, that was the chemical basis for the Aminco Chem-Glo which I mentioned in the introduction. It lead to elucidating many, many enzymatic biochemical systems using your basic discovery. What got you interested in biochemistry in the first place? Rapaport: I was initially interested in synthetic and mechanistic organic chemistry. The firefly bioluminescence was a perfect problem for these
interests. Only later, after completing my studies at Hopkins, I moved to Harvard Medical School where I became interested in medical and physiological problems. Passwater: Why did you want to study Firefly bioluminescence at Hopkins? Rapaport: Hopkins was the place where bio- and chemiluminescence reactions were being studied. These type of chemical or biological (enzyme-catalyzed) reactions yield an electronically excited state product. The product emits light or photons in its return to an electronically ground state. Overall chemical energy is converted to light. Passwater: What did you see that led the team to solving the long sought after question? Rapaport: We had to identify the product of the firefly light reaction, the product being chemically unstable. The starting materials for the firefly bioluminescence were well established, firefly luciferin, ATP and the enzyme luciferase. Once we identified the reaction product, we established the reaction mechanism leading to the enzyme-bound product in an electronically excited state followed by the yellow-green light emission. Passwater: My first books were a 3-volume "The Fluorescence Guide to the Literature" by Plenum Press and I was the editor of Fluorescence News. It seemed to me that the most practical and sensitive tests in the world for countless biochemical analysis could use your luciferin/luciferase technique, so I became very interested in your research. Rapaport : Little did I know then that the light reaction of firefly luciferin, catalyzed by firefly luciferase and dependent on ATP would turn out to be the most sensitive and commonly used method for determining ATP levels as you mentioned. In the presence of excess luciferin, the enzyme luciferase
and in the presence of limiting concentrations of ATP, the rate of the overall firefly light reaction is dependent on its first step, the formation of luciferyl adenylate. Measurement of the light intensity directly correlates with the amount of ATP. Passwater: You extended this information into various directions. When did you move on to Harvard and what did you pursue there? Rapaport: In 1971, I moved to Harvard Medical School where I started looking at the mechanisms of intracellular ATP functions, especially in relation to tumor growth and in vivo cancer models. The thought then was that because of its metabolic lability (ability to change), ATP is not only the energy currency molecule, a substrate for biosynthetic reactions and an allosteric regulator of protein functions, but an intracellular signal, the levels of which could change quickly in response to extracellular events. Extracellular signals were thought to be stable molecules such as peptides or steroid hormones, since they had to survive the catabolic activities inside the vascular bed. Today we know that ATP and its catabolic product, adenosine, are overwhelmingly the two most "popular" extracellular signals, exactly because of their metabolic lability. Their metabolic lability enables them to act quickly only at sites and times as needed. ATP and adenosine interact extracellularly with families of receptors (P2X and P2Y for ATP and A for adenosine) and transmit signals, which are transduced into the inside of the cell. Through these mechanisms ATP and adenosine control virtually every physiological function. Passwater: That’s very important and we’ll certainly pick up on that point later. For right now, though, please give us an example. Rapaport: When one gets a cut in the skin and starts bleeding, the first event is the formation of a white plug or platelet aggregation. Such an event has to be induced by a labile molecule since one would not want a clot to be formed along the whole vessel, just at the site of the bleeding. The initial signal for recruiting platelets to aggregate, which is the first step in clot formation, is ADP (adenosine 5’-diphosphate), a molecule as labile as ATP and interacting with an ATP receptor on platelets. I will take a momentary leap here and describe how such receptors can be exploited in drug development. Since intravascular clotting, being a major cause of stroke and myocardial infarction, is highly undesirable, one way to block it is by
antagonizing ADP binding to its platelet ATP receptor. A popular anti-thrombotic drug called Plavix or Clopidogrel achieves that by binding to the P2Y12 receptor on platelets, blocking the binding of ADP and reducing the possibility of intravascular platelet aggregation. Extracellular ATP today is known to signal diverse functions such as the control of breathing, interacting with peripheral and central chemoreceptors as well as to signal the transmission of taste from the taste buds to the central nervous system, thus being the neurotransmitter linking taste receptors to taste nerves. Evolution captured the most popular intracellular molecule to fulfill the most diverse extracellular signaling, once multicellular organisms were formed. Passwater: So, ATP is more than the body’s energy currency. Its signaling function is also important. However, before we discuss more of the importance of ATP, let’s go back to the beginning and look at ATP basics. Rapaport: You are right, "It is all about ATP". Ironically, intracellular ATP is making a powerful comeback, as its inverse relationships to aging are being unraveled. The significant decline in skeletal muscle ATP synthesis is acknowledged today as being causal in aging. OK, let’s look at ATP 101 for our readers. Passwater: Let’s start with “What is ATP?” Rapaport: ATP is an organic molecule comprised of a purine (adenine) moiety attached through a 9-1’ glycosidic linkage to a D-ribose sugar and three phosphate units esterified to the 5’ hydroxyl of the ribose. (Please see Figure 1.) The high-energy bond of ATP is the terminal pyrophosphate bond of the beta to gamma phosphate groups. The chemical energy of the energy-rich phosphate bond of ATP can be transferred to other cellular materials or be converted to mechanical energy, as is the case during the process of muscle contraction.
Figure 1. Chemical structure of Adenosine triphosphate (ATP) Passwater: What does ATP do? Rapaport: Intracellularly, ATP is:· the major cellular and organ energy source· a phosphate and adenylyl groups donor· an intermediate in numerous cellular biosynthetic reactions· a regulator of the activity of a variety of cellular proteins. Extracellularly, ATP and its in vivo catabolic product, adenosine, regulate intracellular reactions in every organ and tissue by interacting with their specific families of receptors.
Passwater: How does ATP do this? Rapaport: ATP as the energy currency acts by releasing the energy locked in the hydrolysis of the beta-gamma phosphodiester bond, yielding adenosine 5’-diphosphate (ADP). As a phosphate donor ATP transfers the gamma phosphate group to hydroxyl groups of the amino acids serine or tyrosine on proteins in a class of reactions catalyzed by enzymes called kinases. The phosphorylation of proteins is a major regulatory step inside the cell. ATP acts as a phosphate donor to a great variety of low molecular weight molecules containing hydroxyl, sulfhydryl and amino groups in reactions catalyzed by specific kinases. ATP transfers adenylyl (AMP) group in the activation of substrates such as amino acids in the first step of protein synthesis, which is the formation of aminoacyl adenylate. This is one of the ways in which ATP can act as intermediate in biochemical reactions. ATP also acts intracellularly in the regulation of the activities of proteins by binding to their regulatory subunit and acting as an allosteric effector. Extracellularly, by interacting with their specific receptors, ATP and adenosine initiate either a metabolic signal or an ion channel signal, which then bring about initiation of specific cellular activities. Passwater: How is ATP made in the body? Rapaport: Intracellular ATP is present at high concentrations, from 2.2 millimolar in red blood cells to 3 millimolar in liver cells to 2-10 millimolar in skeletal muscle cells. There are three main processes for extracting energy from the food we eat and storing this energy in ATP. The lesser pathway if called glycolysis, which is the first group of reactions in converting carbohydrates into cellular ATP. It is carried out in the cytosol and does not require oxygen presence. It is the breakdown of the sugar glucose, either from molecular glucose itself or from glycogen, which is a cellular storage form for glucose, to two three-
carbon units, producing ATP molecules from ADP in an inefficient process that proceeds anaerobically. Thus the breakdown of glucose, which is termed glycolysis (Figure 2), although energetically inefficient, is highly desirable since it is not dependent on oxygen presence and can therefore take place under poor blood flow conditions. Hence the old adage “sugar is good for the heart”.
Figure 2: Production of ATP by glycolysis. Passwater: So the net production of ATP from glycolysis is only two molecules of ATP for each molecule of glucose. There are four molecules of ATP produced but two molecules are used in the reactions which leaves a net production for two molecules of ATP after ten enzymatic reactions involved in glycolysis. What is the second way ATP is produced in the body from metabolism? Rapaport: A second mode of ATP synthesis is from pyruvate in the citric acid cycle (Figure 3). Pyruvate is a major three carbon unit product of glucose catabolism and by the catalytic action of pyruvate dehydrogenase yields acetyl coenzyme A. Acetyl coenzyme A is then utilized for ATP synthesis in the mitochondria in a sequence that is also dependent on oxygen presence but to a lesser extent than the oxidation of fatty acids.
Figure 3: The production of ATP by the citric acid cycle. The reduced forms of NAD+ (NADP+) and FAD (NADH and FADH2 respectively) are reoxidized by the electron transport system in the step producing ATP from ADP.
Passwater: Well this is more productive than glycolysis as 36 molecules of ATP are produced from a molecule of glucose via the citric acid cycle and oxidative phosphorylation. What’s the most efficient way of producing ATP? Rapaport: However, the most effective mode of ATP synthesis by phosphorylation of ADP, is by beta oxidation of fatty acids in the mitochondria, which is a cellular organelle where aerobic metabolism takes place. Beta oxidation of fatty acids is energetically a very effective pathway, however, it is totally dependent on oxygen presence and therefore extremely sensitive to blood flow. Passwater: For our non-chemist readers, beta oxidation is simply the snipping off of a two-carbon unit from the backbone of a fatty acid at the second carbon called the “beta” carbon in from the carbonyl end group. This is a four-step process. Each cleavage of two carbons results in the production of one molecule each of NADH, FADH2 and Acetyl-CoA. Each molecule of NADH leads to producing three molecules of ATP. Each molecule of FADH2 produces two molecules of ATP and each molecule of Acetyl-CoA eventually produces 12 molecules of ATP. So when a molecule of a fat such as the 16-carbon Palmitate is oxidized it leads to the formation of 129 molecules of ATP. [(7x3) + (7x2) + (8x12) = 131 – 2] Thus a typical fatty acid such as palmitate yields 129 molecules of ATP, whereas the sugar glucose yields only 38 molecules of ATP, 2 from glycolysis and 36 from the citric acid cycle and oxidative phosphorylation. Do we make enough ATP for our needs? Rapaport: Only when we are young and do not suffer from stress or ailments. Reactive oxygen species (ROS), generated constantly near the mitochondrial membrane act in producing mutations in mitochondrial proteins and within time, significantly decrease mitochondrial function (aerobic ATP synthesis, respiration or oxidative phosphorylation). This is what happens upon aging whereby skeletal muscle mitochondrial ATP synthesis drops to half of what it is in adults. Other organs are also similarly affected leading to a drop of 50% in total blood (red blood cell) ATP levels. Hence the efficacy of antioxidants that Dr. Passwater has been touting for so long. By capturing the reactive oxygen species or intermediates, antioxidants support cellular energetics.
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)
What we have learned from Dr. Rapaport’s research is that ATP also has extremely important roles outside of cells (extracellular) as well. Extracellularly, ATP and its in vivo degradation product, adenosine, activate specific ATP and adenosine receptors on cells such as in the artery linings, nerve endings and various organs to produce beneficial health effects. As a result, extracellular ATP and adenosine are regulators of many physiological responses including vascular, heart and skeletal muscle functions. Oral ATP supplements directly increase extracellular blood plasma ATP pools to improve blood vessel tone, increase vasodilation and enhance blood flow. Not only is extracellular ATP cardioprotective and organ protective, it enhances delivery of nutrients and oxygen to the brain, heart and all tissues and organs of the body as well as stimulates removal of waste products such as lactic acid. Furthermore, extracellular ATP can increase needed intracellular ATP as it is used up; it accomplishes this by stimulating oxygen and glucose disposal that are needed for intracellular ATP synthesis.Let’s resume our chat with Dr. Rapaport about his research. As you may remember, Dr. Rapaport received his Ph.D. from Johns Hopkins University in 1971. He serves on the faculties of Harvard Medical School at the Massachusetts General Hospital, Boston University School of Medicine and the Worcester Foundation for Experimental Biology. Passwater: When you first developed ATP supplements, were you attempting to directly raise intracellular ATP? Rapaport: No, I understood that intracellular levels of ATP are too high to be affected directly. The total amount of ATP in liver is 3 millimolar or about 3.7 grams and the total amount of ATP in blood is 0.9 millimolar or 2.3 grams, considering a blood volume of 5.5 liters in an adult. These types of ATP levels could not be affected by acute administration of oral ATP.However, I discovered that blood plasma levels of ATP were in the submicromolar range totaling less than 1 mg. These levels could definitely be elevated by the acute administration of oral ATP, and later I found out that they easily were.I also knew however, that mitochondrial ATP synthesis was strictly dependent on oxygen and that oxygen could be metabolically expensive since its availability is dependent on blood flow. Glycolysis, which proceeds anaerobically does not require oxygen presence but is dependent on glucose or its storage form, glycogen. In addition, I knew that contracting skeletal muscle releases ATP and adenosine and that the release of ATP and adenosine by the exercising muscle is a biological mechanism for answering the metabolic demands of the ATP-depleted muscle.
Thus, it became clear that extracellular (blood plasma) ATP, which is the master regulator of blood flow and acts in very low levels, can achieve enhancement of cellular ATP synthesis by stimulating the intracellular pathways of ATP synthesis.When I found that blood plasma pools of ATP are extremely low, one ten thousandth the pool of red blood cell, and can be easily increased by administration of ATP in animals, I began studying the route of ATP from the point of its administration to its appearance in the blood plasma. I used radioactively double-labeled ATP, labeled by radioactive phosphates as well as tritium on the adenine ring. The mechanisms that yield increases in blood plasma ATP pools were established by following the radioactive labels.As previously mentioned, it was found that oral ATP, which has a first passage liver effect, can easily increase blood plasma ATP pools. I then demonstrated that the pathway of red blood cell ATP synthesis originates from adenosine, which is supplied to the red blood cell by the turnover of the hepatic ATP pools and that red blood cells release their expanded ATP pools into the blood plasma in a non-hemolytic process. That was the first known example of ATP released from a cell, any cell, into the extracellular environment also termed interstitial fluid in tissues. Passwater: What led you to observe that your ATP supplements produced health benefits by acting intracellularly or extracellularly? Rapaport: I was fascinated by the work of Dr. Tom Forrester in the 1970s. He was trying to justify the Roman aphorism “mens sana in corpore sano” or a healthy mind in a healthy body. He was attempting to identify the metabolic communication between exercising muscles and increased oxygen consumption in the brain, which translates into improved brain function. The system he studied dealt with the release of purines, ATP and adenosine from skeletal muscle during exercise, and their effect on the subsequent improvement in blood flow. Since I was interested in cancer and the inverse relationship between exercise and tumor development in experimental animals, which was established, I looked further into this phenomenon.What I found in the literature was that in exercising rats, experimental tumor volumes were inversely related to the levels of exercise (and therefore to the level of blood plasma ATP). Epidemiological studies in humans also indicated inverse relationship between incidence of cancer and regular exercise. Epidemiological studies showed then and still demonstrate today that regular exercise in humans has a long list of favorable effects. These effects range from maintaining insulin sensitivity and glycemic control to regulating normal blood pressure. Furthermore, it was known that tumor metastases, the spread of secondary tumor growth, in striated muscle were clinically rare.
This sequence of events led me to my early studies of ATP administration into tumor-bearing mice whereby I began to establish the mechanism of extracellular ATP formation from exogenously supplied ATP in general and the effects of ATP infusions in advanced cancer in particular. The early studies in experimental animals showed improvements in a variety of organ functions, especially liver, in tumor-bearing animals.These studies provided the first indications that increases in liver, blood and blood plasma ATP pools produced survival advantages in tumor-bearing mice and that these survival advantages were directly related to the increases in hepatic ATP pools. Animals with advanced disease died not from the effects of the tumor but from liver failure. Elevated liver ATP pools shifted liver protein synthesis from acute phase protein synthesis to a normal spectrum of liver protein synthesis. It meant increase in albumin synthesis and decreases in C-reactive protein and lactate dehydrogenase (LDH) synthesis as well as decreases in blood liver enzymes.I also noticed that stressed animals or tumor-bearing animals had lower than normal liver, red blood cell and blood plasma ATP pools. Stress was introduced in mice by shifting the light-dark cycle in the animal room once every few days depending on the desired level of stress. Passwater: Previously, we have discussed that specific ATP receptors are activated and you described P2X and P2Y ATP receptors, as well as adenosine receptors A. Please review briefly and as non-technically as possible, what an ATP or adenosine receptor is and what it does. Rapaport: Receptors are proteins that are imbedded in the cell membrane and contain extracellular loops to which the ligand (ATP or adenosine in our case) binds. The receptor contains intracellular loops as well and upon binding of the ligand to the receptor outside the cell, the intracellular loops undergo changes in shape (conformation) that in turn promote changes in cellular function (originating by the binding of the ligand to the receptor outside the cell).ATP receptors are either P2X, ionotropic receptors, or P2Y metabotropic receptors. Adenosine receptors are A1, A2-alpha, A2-beta and A3, all metabotropic receptors. The ionotropic P2X receptors are non-specific ion channels whereby the binding of extracellular ATP results in inflow of Ca++ and Na+ ions into the cell and outflow of K+ to the outside of the cell. Once this happens, the cell membrane is depolarized and a signal of action potential is fired. The metabotropic P2Y receptors bring about stimulation and /or inhibition of intracellular synthesis of certain signals (produced inside the cell by activation of the enzyme phospholipase C or stimulation or inhibition of the enzyme adenylyl cyclase) upon the binding of extracellular ATP to the receptor outside the cell.
To date, seven different P2X receptors subtypes, eight different P2Y receptors subtypes and four adenosine (A) receptors subtypes have been identified. Once the intracellular signal is delivered, the cell performs a function that is therefore initiated by the binding of ATP or adenosine to the specific receptors outside the cell. These functions are numerous and vary from vasodilation of blood vessels to detection of particular tastes or serving in detection of low blood oxygen levels. Passwater: Although, oral supplementation of ATP doesn’t directly raise intracellular ATP, isn’t intracellular ATP indirectly increased by oral ATP supplementation, as well as its promoted increases in extracellular ATP? Rapaport: Absolutely, by enhancing blood flow, extracellular, blood plasma pools of ATP, stimulate the disposal of oxygen and nutrients, mostly glucose, at peripheral sites such as skeletal and cardiac muscle as well as support the removal of waste products such as lactic acid and ammonia. In addition and as importantly, blood plasma pools of ATP stimulate blood flow, oxygen and glucose consumption by the brain.The importance of this activity is that in the brain improved blood flow equals improved metabolism, which yields benefits to brain functions. By improving blood flow and thus answering cellular metabolic demands, extracellular ATP indirectly enhances cellular ATP synthesis. Adenosine and ATP were also shown to potentiate the insulin-stimulated glucose transport by increasing the levels of GLUT 4, the glucose transporter, on the membrane of skeletal muscle. Cellular ATP synthesis by glycolysis, the breakdown of glucose to three carbon units is the preferred mode of cellular ATP synthesis since it can proceed in the absence of oxygen. Passwater: This is important new information for a lot of people, including cardiologists and scientists. Can you give me a couple of references for their benefit? Rapaport: Well, off the top of my head I can quickly give you three key references, but there are more. The article by Susanne Leij-Halfwerk et al. demonstrates that extracellular ATP expands liver ATP pools in humans in a direct manner. (Leij-Halfwerk S., Hendrik J. Agteresch, P. E. Sijens, and Dagnelie P.C. Hepatology 2002;35:421-424)A second article that comes to mind discusses the significance of stimulating glycolysis in the diseased heart for the purpose of generating “glycolytic” ATP, which also expands indirectly the heart’s ATP pools. (Opie, LH, The Lancet Vol 364 November 13, 2004)
A third paper shows that adenosine stimulates glucose disposal (uptake by GLUT 4) in skeletal muscle and provides the references for the well-established adenosine-induced stimulation of glucose uptake by cardiac muscle as well as in adipose tissue. (Han, D-H; Hansen, P. A.; Nolte, L. A. and Holloszy, J. O. Diabetes 47:1671–1675, 1998) There are many more publications related to the indirect stimulation of ATP synthesis in humans, and I have published animal studies about this myself. Passwater: How do extracellular ATP and adenosine affect skeletal muscle function by stimulating glucose disposal? Rapaport: The main glucose transporter is a protein GLUT 4, which is synthesized inside cells and upon the action of insulin at the insulin receptor membrane site, GLUT 4 is translocated to the cell membrane and becomes active in transporting glucose from the blood into the cell. Skeletal muscle is the most important peripheral target (separate from the central target, the brain) for insulin action and glucose uptake. The regulation of skeletal muscle glucose uptake is a primary factor in maintaining proper health since skeletal muscle contains about 80% of the body carbohydrate stores in the form of glycogen.As discussed previously, glycolysis, the breakdown of glucose from glycogen or from transported glucose, is the preferred mode of intracellular ATP synthesis because it is not dependent on oxygen presence and can proceed under poor blood flow conditions. Such conditions may exist during endurance exercise whereby skeletal muscles are hypoxic (in an oxygen poor environment).There is increasing data that adenosine is an important regulator of insulin’s actions in skeletal muscle cells. Adenosine was reported to increase the sensitivity of insulin receptors to the action of insulin and thus stimulate disposal of blood glucose into skeletal muscle cells. This activity of adenosine is mediated by the adenosine A1 receptor, which has been linked to insulin signaling by augmenting the activity of insulin at its receptor.Therefore adenosine, which is the in vivo degradation product of ATP, has a significant role in maintaining and improving insulin sensitivity. Once insulin sensitivity is impaired, insulin resistance gradually develops followed by Type 2 diabetes and its clinical complications. Passwater: You have been involved in the development of intravenous administration of ATP in the treatment of non-resectable, advanced refractory cancer in patients who have failed surgery, chemo-and/or radiation therapy. Could you review these clinical trials.
Rapaport: Since the 1960s it has been observed that patients suffering from a variety of cancers have lower levels of erythrocyte ATP pools as compared to healthy controls. These findings were in agreement with various studies that have recognized a strong relationship between aging and the development of cancer. The decline in erythrocyte ATP pools was also observed in patients with a variety of other advanced life-threatening diseases.In the early 1980s I demonstrated in several published studies that the administration of ATP to tumor-bearing animals yielded significant inhibition of tumor growth and in cachectic-weight losing animal tumor models, both inhibition of tumor growth and host weight loss. These two activities of ATP were not interrelated but were in direct relationship to the expansions of liver, red blood cell and blood plasma ATP pools. Passwater: What is the biological significance of extracellular ATP in the control of tumor development? Rapaport: Cancer cachexia in humans suffering from advanced cancers is associated with host weight loss, with anorexia, hormonal aberrations and depletion and redistribution of host metabolic factors. It is the decline in vital host functions and organ failure, which leads to subsequent death. In advanced cancer patients, gluconeogenesis, which is the synthesis of glucose from three carbon unit catabolic products such as lactic acid, alanine or glycerol, takes place in the liver at a large energy (ATP) cost. Glucose is then taken up by the tumor and is broken down by glycolysis yielding a much smaller amount of energy. This type of host-tumor interplay and the liver-tumor futile cycle are responsible for the depletion of visceral energy stores, skeletal muscle function and blood ATP pools in patients suffering from advanced cancer.My studies of the early 1980s demonstrated that the liver has a central role in controlling the progression of cancer in the advanced-disease patient, and, as importantly, intracellular pools of ATP in the hepatic parenchymal cells were the major factor in affecting liver function. When liver ATP pools were low, liver protein synthesis shifted to the synthesis of acute phase proteins leading to inflammation and overall decline in bodily functions. The hallmarks of these activities were low albumin, low pre-albumin, high liver enzyme levels in the blood, high C-reactive protein levels, high tumor necrosis factor-alpha and high lactic acid dehydrogenase (LDH) levels in the blood.Increasing liver ATP levels to normal or above normal levels by administration of exogenous ATP initiated a reversal in the spectrum of protein synthesis by the liver along with inhibition of gluconeogenesis, thus stopping the drainage of visceral energy stores. Along with the changes
promoted by administration of ATP, survival advantages and the slowdown in disease progression became noticeable. Passwater: What do clinical trials with ATP on cancer patients indicate? Rapaport: The utilization of continuous intravenous infusions of ATP at levels below 100 mcg/kg of body weight per minute, levels which do not affect heart rate or arterial blood pressure, were shown in four different human clinical trials in the United States and The Netherlands to have a variety of measurable positive effects in advanced cancer patients, mostly patients suffering from non-resectable, advanced, refractory, stage IIIB/IV non-small-cell lung cancer (NSCLC) with life expectancy of about six months.In a phase II trial and a small phase III trial, which included a control arm of best supportive care without ATP infusion, of stage IIIB/IV NSCLC patients, statistically significant survival advantages compared to best supportive care controls and historical controls were recorded. Passwater: In advanced cancer, terminal stage disease and death are due to hepatic and multiple organ failure rather then the tumor itself. Quality of life declines rapidly. Did the studies examine this? Rapaport: Yes, this point that you make is the key to the treatment of advanced, refractory cancer as well as other advanced diseases. In addition to inhibition of progression and stabilization of the disease, a variety of quality of life end points were obtained by the use of validated advanced cancer questionnaires. These included, in particular, improvements in appetite and reduction in fatigue, two of the most problematic aspects of advanced cancers. Improved liver function by ATP infusions affected the synthesis of proteins, which are positive prognostic factors in advanced cancer. Continuous intravenous infusions of ATP improved skeletal muscle strength as measured by several methods in two separate clinical trials.Finally, Karnofsky performance status, which is determined by the clinical investigator, contrary to the validated questionnaires answered by the patients and which is a surrogate quality of life parameter, was stabilized in patients receiving ATP infusions. The current experimental protocols utilize once-weekly continuous intravenous infusions of ATP for eight hours at levels up to 50 mcg/kg per minute on an outpatient basis either in an outpatient clinic or in home care. This particular protocol is administered in clinical trials involving patients suffering from a variety of non-resectable cancers who have failed surgery, chemo-and/or radiation therapy and who have life expectancy of less than six months.
Passwater: I assume that you used continuous intravenous infusions of ATP because it was easier to elevate ATP levels and easier to control in a clinical trial. Once the research is completed, would you foresee being able to raise extracellular ATP levels sufficiently via oral supplementation to obtain significant results? Rapaport: You are correct; the utilization of continuous intravenous infusions was designed to achieve controlled elevation of ATP pools in a short period of time. I do foresee the use of oral ATP since we know now that oral ATP formulations can promote elevations of bodily ATP pools. Passwater: Is reduction in fatigue in advanced cancer patients treated with ATP administration related to improvements observed in measurements of skeletal muscle function, and would these effects apply to other groups? Rapaport: Attempting to improve skeletal muscle strength has not been limited to patients suffering from advanced disease. The desire to slow the aging process by improving skeletal muscle strength (function) has attracted a considerable degree of interest over time and has been the Holy Grail of aging research. Hormone treatments of elderly men with human growth hormone (GH) and testosterone and hormone treatment of elderly women with GH 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 importantly, the risk of adverse effects especially in the form of Type 2 diabetes associated with the use of these hormonal regimens was substantial. The improvements in hepatic, blood flow and muscle functions that were observed in advanced cancer patients after ATP administration, raise hopes that these parameters can be positively affected by different modes of ATP administration in other populations. The primary independent negative prognostic factors of survival that significantly benefited from ATP administration were serum albumin and serum bilirubin levels, serum lactate dehydrogenase (LDH) levels, blood levels of tumor necrosis factor-alpha (TNF-alpha), skeletal muscle strength and Karnofsky performance status, all of which are also known to be significant quality of life determinants. These prognostic factors however, are not limited to advanced cancer and exist in most if not all advanced diseases as well as in aging itself.
Passwater: We will discuss the individual indications for oral ATP in the next interview, but right now, let’s discuss ATP supplements and what structure/functions claims are allowed for oral ATP? Rapaport: I will confine my remarks to PEAK ATP , which is a trademarked dietary supplement prepared according to my issued patents and shown to increase circulatory ATP pools in blood plasma (extracellular).The structure/function claims for PEAK ATP formulations are:1. Improves vascular health, circulatory functions and blood flow to peripheral sites.2. Increases overall energy levels and reduces fatigue.3. Benefits skeletal muscle function, strength, and recovery.4. Boosts mental acuity and may lessen the perception of fatigue and/or exercise-associated pain.5. Protects heart and liver functions.6. Promotes glycemic regulation.7. Supports joints health.The structure/function claims for PEAK ATP (oral ATP-disodium formulations) are based on claimed benefits of supplementation, of a classical human metabolite deficiency, with the exact same metabolite.1. Severe declines (50%) in human physiological ATP pools have been demonstrated in skeletal muscles and red blood cells during aging (Short KR, Bigelow ML, Kahl J, Singh R, Coenen-Schimke J, Raghavakaaimal S, Nair KS: Decline in skeletal muscle mitochondrial function with aging in humans. Proc. Natl. Acad. Sci. USA 2005; 102:5618-5623. Conley KE, Jubrias SA, Esselman PC: Oxidative capacity and ageing in human muscle. J. Physiol. 2000; 526:203-210. Rabini RA, Petruzzi E, Stafolani R, Tesei M, Fumelli P, Pazzagli M, Mazzanti L: Diabetes mellitus and subjects’ ageing: a study on the ATP content and ATP-related enzyme activities in human erythrocytes. Eur. J. Clin. Invest. 1997; 27:327-332).Muscle contraction, exercise and physical endurance result in loss of skeletal muscle ATP pools (Steiner MC, Evans R, Deacon SJ, Singh SJ, Patel J, Fox J, Greenhaff PL, Morgan MDL: Adenine nucleotide loss in the skeletal muscles during exercise in chronic obstructive pulmonary disease. Thorax 2005; 60:932-936. Jianhua L, King NC, Sinoway LI: Interstitial ATP and norepinephrine concentrations in active muscle. Circulation 2005; 111:2748-2751).Adverse physical conditions resulting from physiological stress or disease produce significant losses in muscle, blood and organ ATP pools (Weiss RG, Gerstenblith G, Bottomley PA: ATP flux through creatine
The Science of ATP: Part 4 An interview with Eliezer Rapaport, Ph.D., exploring the connection between ATP and aging. By Richard A. Passwater, Ph.D. We have been chatting with adenosine triphosphate (ATP) research pioneer Dr. Eli Rapaport for the past three months, discussing the basic chemistry of ATP and Dr. Rapaport’s research that has led to important health findings for ATP supplements.
We have discussed how ATP is used within cells (intracellular) to produce and store the energy that drives the countless thousands of biochemical reactions that produce “life.” The energy contained within the phosphate bonds of ATP is converted to both chemical and mechanical energies. ATP’s high energy bond can be transferred to other compounds to drive the biochemical reactions that move nutrients into cells, remove waste products, propel nerve signals, make proteins and other body compounds, move skeletal muscles, regulate blood flow, contract the heart muscle and virtually everything that involves life.What we have learned from Dr. Rapaport’s research is that ATP also has extremely important roles outside of cells (extracellular) as well. Extracellularly, ATP and its in vivo degradation product, adenosine, activate specific ATP and adenosine receptors on cells such as in the artery linings, nerve endings and various organs, to produce beneficial health effects. As a result, extracellular ATP and adenosine are regulators of many physiological responses including vascular, heart and skeletal muscle functions. Oral ATP supplements directly increase extracellular blood plasma ATP pools to improve blood vessel tone, increase vasodilation and enhance blood flow. Not only is extracellular ATP cardioprotective and organ protective, it enhances delivery of nutrients and oxygen to the brain, heart and all tissues and organs of the body as well as stimulates removal of waste products such as lactic acid. Furthermore, extracellular ATP can increase needed intracellular ATP as it is used up and achieves it by stimulating oxygen and glucose disposal that are needed for intracellular ATP synthesis.In this installment, as we resume—and conclude—our chat with Dr. Rapaport about his research and the many ways in which ATP supplements provide health benefits, we will consider the potential of ATP in benefiting conditions that are directly related to aging. Specifically, we will look at cardiac protection, peripheral arterial disease (PAD), arthritic diseases, type 2 diabetes and its clinical complications, cerebral circulation and mental acuity.As you may remember, Dr. Eliezer Rapaport received his Ph.D. from the Johns Hopkins University in 1971. He 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. Passwater: Would you remind our readers about the basic relationships between physiological ATP pools and aging? Rapaport: For the convenience of our readers, I am going to include references, which are keyed by numbers in parentheses. A list of these references is available on request. During aging (e.g. 65-75 years old), initial levels of red blood cell ATP pools drop to about half of what they are in
young individuals (1). Older humans (mean age of 68.8 years) retain only 50% of muscle mitochondrial ATP synthesis as compared with adults (mean age of 38.8 years) (2). Purine (ATP and adenosine) losses, adversely affecting organ and skeletal muscle functions, were also reported in diseases and other stressful conditions (3). The reduced blood and skeletal muscle pools of ATP in the aged, lead to a variety of adverse conditions, which are primarily the result of decreased blood flow. Passwater: Yes, but what can we do about it? Does oral ATP help? Rapaport: Yes. Let me start at the beginning with earlier studies. Animal studies showed that low levels of ATP administered directly into the duodenum, the proximal part of the small intestine, yielded significant positive cardiovascular and pulmonary responses (4). The duodenum is the area of the small intestines where enteric or uncoated ATP pills are absorbed, followed by the incorporation of the adenosine and inorganic phosphate moieties into the liver ATP pools. The expanded liver ATP pools are the source of elevated blood plasma ATP pools, as was described in detail in our previous interviews.To go back to the effects of ATP administered directly into the duodenum in rabbits, they included reductions in pulmonary vascular resistance, reductions in peripheral vascular resistance followed by increases in blood flow. No effects on arterial blood pressure or heart rate were observed.An increase in left ventricular work index, which is an indication of improved cardiac output was found. Cardiac output 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 observed after the administration of ATP. 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. Passwater: To what degree can blood flow be improved? Rapaport: Low physiological levels of blood plasma ATP (less than 1 microolar), induced an 8% increase in vascular diameter, corresponding to a minimum of 17% increase in blood flow (5). Vasodilation induced by physiological levels of ATP is mediated primarily by 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 diffuses into and acts in neighboring perivascular smooth muscle cells, which control
vascular tone and produce relaxation and vasodilation of the blood vessel in response to NO. Passwater: That’s significant and certainly important. Is extracellular ATP involved in mechanisms of vasodilation other than NO synthesis? Rapaport: Yes. 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 (5). Passwater: Is there a relationship between extracellular ATP and aging involving muscle mass? Rapaport: The direct correlation between aging and the decline mostly in skeletal muscle mitochondrial ATP synthesis (2,6) as well as the significant decreases in blood ATP parameters upon aging in humans (1) and experimental animals (7,8) have been established. Recently however, decreases in ATP levels caused by intentionally introduced mutation into mitochondrial DNA in animals (9) and declines in skeletal muscle mitochondrial function in humans (10) were demonstrated to be a direct cause of aging. Thus, a direct relationship between significant declines in skeletal muscle and blood levels of ATP and the aging process has now been established (9,10). Passwater: Can this relationship be utilized to slow aging? Rapaport: 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 (GH) and testosterone and hormone treatment of elderly women with GH
and hormone replacement therapy (HRT), was the subject of a recent large clinical trial (11). 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 (11). However, the results clearly demonstrated that lean body mass did not translate into improved skeletal muscle function and as importantly, the risk of adverse effects associated with the use of these hormonal regimens was substantial (12). Passwater: Let’s move to the roles of ATP and adenosine in cardiac protection. What are the basic mechanisms thought to be responsible? Rapaport: Gram for gram, the heart consumes more energy than any other organ of the body. It’s no wonder, then, that recent research ties the failing heart with massive losses in cardiac ATP. For the first time ever, researchers at Johns Hopkins University used magnetic resonance spectroscopy to examine beating hearts. They discovered that people with a history of heart failure have a significant reduction in myocardial ATP (13). Passwater: This is an important point that Dr. Stephen Sinatra made with us when he emphasized that “it’s all about ATP.” Most cardiologists still do not understand the concept of ATP leakage. Rapaport: The creatine kinase reaction, which utilizes the phosphorylation of ADP by creatine phosphate, catalyzed by creatine kinase, to buffer against the severe losses of ATP, fails in the diseased heart. Two basic mechanisms serve in the protection of the heart by ATP and adenosine. One is the well-established role of ATP in maintaining normal blood pressure. It has been demonstrated that the increase in blood pressure upon aging is related to lower levels of blood plasma (extracellular) purines (ATP and adenosine) in the aged (7,8).Several research groups claimed that the blood pressure lowering effects of omega-3 polyunsaturated fatty acids, such as DHA and EPA, are the result of these acids inducing the release of ATP from vascular endothelial cells (14,15). Passwater: It’s interesting how the heart nutrients are entwined with ATP production: gPLC is used to carry fats into the heart cells for ATP production; coenzyme Q-10 is critical for ATP production; ribose provides a basic building block for ATP synthesis; and fish oil omega-3 fatty acids are involved with releasing ATP into the vascular network.
Rapaport: There is also a second mechanism in which adenosine acts as a major cardiac protector through its interaction with adenosine receptors: 1. by interacting with adenosine A1 receptors, adenosine attenuates the release of catecholamines, which by interacting with beta-adrenoceptors produce myocardial hyper-contraction and 2. by interacting with adenosine A2 receptors, adenosine stimulates coronary blood flow and inhibition of platelet and leukocyte activation. The release of catecholamines as a result of the low cardiac output in heart failure leads to a compensatory hyperadrenergic state. The increased catecholamines levels also lead to elevations in blood plasma free fatty acids, which increase the dependency of the failing heart’s energy production on beta oxidation of fatty acids, a process heavily dependent on blood flow for the delivery of oxygen. Under the poor flow conditions, a futile cycle is formed.The stimulation of coronary blood flow in the diseased heart by ATP and adenosine operate by mechanisms of reduction in systemic vascular resistance through vasodilation as outlined earlier in this interview. These activities of adenosine described under 1 and 2, tend to synergistically inhibit the effects of ischemic (oxygen-poor) heart disease.In addition, the most powerful cardioprotective effect of adenosine is in ischemic preconditioning. When brief periods of ischemia precede sustained ischemia, the resulting infarct size is dramatically reduced. Ischemic preconditioning operates via adenosine A1 receptor activation (16,17).Administration of ATP, the biological precursor of adenosine, produces conditions that mimic the brief periods of ischemia without actually having ischemic conditions. These cardioprotective effects then act in significantly benefiting heart function during chronic heart failure and acute myocardial infarction (16). Passwater: How do ATP and adenosine act in relief of progression and symptoms of peripheral arterial disease (PAD), which is prevalent among older members of the population. Rapaport: Peripheral arterial disease (PAD) is the result of systemic atherosclerosis, which produces atherosclerotic plaques, initially in the arterial lumen of the lower extremities resulting in a progressive decline in blood flow to the lower extremities. Because of its under-diagnosis, it is often called a “silent killer.” The prevalence of PAD was found to be 4.5% in a population of American men and women over the age of 40 and is more common in people over 55.All the symptoms of the variety of peripheral vascular diseases are caused by the narrowing of blood vessels in the legs and are therefore benefited by
treatment with ATP and its physiological vasodilatory activities. The currently used drugs for the treatment of PAD are all vasodilators of one type or another; recently, these have been used along with statins. Peripheral arterial disease greatly increases the risks of heart attack or stroke and of dying within a decade.The reason for the considerable underestimation of PAD is because only symptomatic patients (those suffering from intermittent claudication, a condition that causes pain during walking) are taken into account. Two-thirds of those afflicted with peripheral arterial disease do not know they have it because of lack of symptoms, except for a steady decline in their ability to walk intermediate distances.As mentioned, the cause of the disease is atherosclerosis, the buildup of fatty deposits on the arterial wall. There are other common warning signs besides pain (intermittent claudication), which indicate the existence of peripheral arterial disease. These include discoloration of the legs or feet, foot ulcers that fail to heal or legs that swell easily, become numb or cold or feel tingly. However, relying only on symptoms for diagnosing PAD causes a majority of cases to go undetected.The ratio between systolic arterial pressure in the ankle and in the brachial artery (Ankle Brachial Index, ABI) is now considered a gold standard for identifying patients with peripheral arterial disease. This ratio is decreased considerably with the progression of peripheral arterial disease. The drugs used to treat intermittent claudication are pentoxifylline (Trental) and cilostazol (Pletal). Statins, which are drugs used to lower LDL cholesterol (such as Simvastatin), in addition to antiplatelet/anticlotting agents such as low dose aspirin or clopidogrel (Plavix), which inhibit artery-blocking clots, are commonly used in the management of peripheral arterial disease. Passwater: However, thanks to your research, we know that ATP can be very beneficial to PAD patients. Rapaport: Well, there is research in this area even preceding mine. Since the early 1950s, adenine nucleotides such as AMP (adenosine 5’-monophosphate) and ATP have been successfully used for the treatment of symptoms of peripheral vascular diseases (18-20). AMP acts by the same mechanism as ATP, both agents undergoing degradation to adenosine and inorganic phosphate in the systemic circulation, followed by absorption and incorporation into liver ATP pools and resulting in significant stimulation of peripheral blood flow via mechanisms described earlier. At that time, ATP was used in Europe whereas AMP was used mostly in the United States.Today, ATP is the preferred treatment for the expansion of blood plasma ATP pools because it is more effective and can commonly be produced in a purer
form. AMP was approved as a drug in the United States in 1967, in a form of intramuscular injections of 25 mg once or twice daily followed by three times weekly for the treatment of stasis dermatitis or skin ulcers, which are the results of varicose or phlebitic veins. An oral formulation of 250 mg of ATP administered daily can easily achieve the intravascular levels of ATP produced by the AMP injections, which are in the milligram levels. The successful treatment of a variety of conditions resulting from venous insufficiency and chronic or acute thrombophlebitis with AMP or ATP has been documented (18-20). Passwater: As I understand, the beneficial treatment of arthritic diseases and especially inflammatory arthritic conditions with AMP and ATP also dates back to the early 1950s. What caused the abandonment of the successful utilization of these natural agents? Rapaport: There were two main reasons for the loss of interest in utilizing ATP or AMP in the effective treatments of peripheral vascular diseases and arthritic diseases. One reason was that adenosine did not show any efficacy in improving these dysfunctions. Yet it was known that ATP or AMP is rapidly degraded to adenosine and inorganic phosphate inside the vascular bed.This issue has now been resolved since I demonstrated that adenosine and inorganic phosphate, but not adenosine alone, incorporate into the liver ATP pools supplying the adenosine precursor for expanded red blood cell ATP synthesis and release of ATP into the blood plasma compartment.The second reason was lack of patent protection, which was also resolved by my issued broad patents applicable to administration of ATP or AMP for expansion of blood plasma ATP pools, rather than for specific utilities.Osteoarthritis, a degenerative disorder where a specific joint function deteriorates rapidly, along with bursitis, tendonitis and rheumatoid arthritis, which is a systemic disease affecting all joints, all become prominent in the subpopulation over 50 years old. Osteoarthritis, a condition affecting more than 20 million Americans, was thought earlier to be a disease involving only deterioration of a joint’s cartilage but is now acknowledged to encompass tissues surrounding the ailing joint as well. Namely, muscles, bones, tendons, ligaments and bursa, which are sac-like cavities filled with synovial fluid and located at sites where joint friction occurs, all contribute to the painful inflammatory disease, the symptoms of which are treated with several types of medication along with surgical procedures.The drugs and supplements used to treat the symptoms of osteoarthritis are over-the-counter pain-killers, nonsteroidal anti-inflammatory agents (indomethacin, ibuprofen or naproxen), cox-2 inhibitors Vioxx and Celebrex, tetracycline, hyaluronic acid, corticosteroids, and glucosamine and
chondroitin sulfate. The most common surgical procedures available for relief of pressure on joints are arthroscopic surgery and joint replacement. Rheumatoid arthritis, a crippling systemic autoimmune disease of the joints, is more debilitating than the other joint diseases and afflicts 2.5 million people in the United States. Drugs that are commonly prescribed for rheumatoid arthritis include methotrexate along with the recently developed biologics ethanercept (Enbrel), infliximab (Remicade) and anakinra (Kineret), all three are designed to block the activities of inflammatory cytokines.The etiology of osteoarthritis is unknown but is considered to be the result of interacting mechanical and biological causes. All forms of arthritic diseases involve decreases in blood flow to the afflicted joints, accumulation of undesirable agents in the vicinity of the afflicted joints such as bacteria, environmental toxins, along with waste and tissue breakdown products that contribute to the inflammatory reaction around the degenerating joints. Thus, treatments that produce increases in blood flow to and from the afflicted joints provide substantial benefits to the joints’ health. Both AMP and ATP have been used since the 1950s as effective treatments for the relief of symptoms of debilitating arthritic diseases such as osteoarthritis, bursitis and tendonitis (21-24).An effective oral formulation of ATP, can easily repeat the early successes of intramuscular injections of AMP and ATP in the alleviation of symptoms of arthritic diseases. A mechanical breakdown of the joint’s cartilage was thought to be the overriding cause of osteoarthritis. Let me re-emphasize: It is now accepted that all the tissues surrounding the afflicted joint, which were mentioned earlier as contributors to the inflammatory disease are also important in the prevention of this disease. Muscles, bones, ligaments, tendons and bursa, all benefit from enhanced circulation, which tend to strengthen the tissues by increasing the supply of oxygen and nutrients and the removal of waste products. This process is particularly relevant to muscles (25-27), which by supporting the joint, prevent tears in tendons and ligaments. A weakness or tear in tendons or ligaments forces the joint’s cartilage to bear more weight, hastening its degradation. Passwater: What are the biochemical mechanisms whereby ATP and adenosine act in benefiting the regulation of blood sugar levels? Rapaport: In our last interview we discussed the increasing data demonstrating that adenosine is an important regulator of insulin’s actions in skeletal muscle cells. Adenosine was reported to increase the sensitivity of insulin receptors to the action of insulin and thus stimulate disposal of blood glucose into skeletal muscle cells. This activity of adenosine is mediated by the adenosine A1 receptor, which was shown to be linked to insulin signaling by augmenting the activity of insulin at its receptor. Therefore adenosine,
which is the in vivo degradation product of ATP, has a significant role in maintaining and improving insulin sensitivity.Once insulin sensitivity is impaired, insulin resistance gradually develops followed by Type 2 diabetes and its clinical complications. Type 2 diabetes, or non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disease resulting primarily from a variety of pancreatic beta cell disorders and insulin resistance. Beta cell dysfunction in regulating insulin secretion yields the chronic hyperglycemia with all its associated clinical complications. Blood plasma glucose levels are responsible for the stimulation of insulin secretion by beta cells.The transport of glucose into pancreatic beta cells is followed by its glycolytic metabolism resulting in increases in beta cells’ ATP pools (28,29). A slight increase in beta cell ATP levels is sufficient to close its ATP-sensitive potassium channels, thus depolarizing beta cell membrane and opening its calcium channels. The resulting influx of extracellular calcium and an increase in recruitment of calcium from intracellular stores yield an increase in total cellular calcium levels, which then activate the granular insulin secretory machinery. Thus, intracellular beta cell ATP pools have a key role in transducing the signals of the stimulus-secretion coupling pathway.Toxins such as alloxan or streptozotocin, which produce experimental diabetes in animals, act by interfering with mitochondrial oxidative phosphorylation, producing small decreases in cellular ATP pools. Due to the sensitivity of beta cells to ATP pools function, only beta cells, among all the animal cells, are affected by these toxins, which significantly reduce insulin secretion in response to glucose stimulation resulting in a form of diabetes.In addition to beta cell intracellular ATP pools, a powerful effect of extracellular ATP was demonstrated more than 30 years ago on the physiological secretion of insulin by acting as insulin secretagogue. This effect of extracellular ATP is a result of its interaction with P2 receptors on beta cell membrane coupled to increases in extracellular calcium influx and recruitment of calcium from intracellular stores leading to insulin release from beta cell granules.Detailed animal studies identified the regulation of insulin secretion and improvement in glucose tolerance by the action of ATP or its agonists on the P2Y receptors that are present on beta cells (28,29). These roles of intracellular ATP inside beta cells and extracellular ATP in blood plasma in the physiological regulation of insulin secretion, are now well-established (28,29). The aged, who suffer from chronic decline of red blood cell and blood plasma ATP pools (extracellular) and reductions in mitochondrial ATP synthesis (intracellular), are therefore particularly susceptible to defects in the stimulus-secretion coupling pathway of insulin secretion.In addition, it has been demonstrated that low levels of ATP, similar to those present under normal physiological conditions, stimulate the expression of
the glucose transporters GLUT1 and GLUT4 in the plasma membrane of skeletal muscle cells. Elevated levels of extracellular ATP increase the expression of these glucose transporters, thus promoting enhanced uptake of glucose from the blood plasma (30). The physiological regulation of glycemic levels by ATP is especially significant in view of the problems existing with the pharmacological management of type 2 diabetes. Insulin is the mainstay treatment of diabetic patients. The overwhelming adverse reaction to insulin is hypoglycemia. Hypoglycemia (excessively low blood glucose levels) is a major risk and should be weighed against the benefits of insulin treatment, especially in patients who respond to milder hypoglycemic drugs. The sulphonylureas act by stimulating insulin release from pancreatic beta cells by binding to and closing the ATP-sensitive potassium channels leading to insulin release by mechanisms described earlier.The meglitinides are not sulphonylureas but are capable of binding to the same target on the beta cells and acting by the same mechanism. Glibenclamide, gliclazide, glipizide and glimepiride are the sulphonylureas most commonly used in treatment of type 2 diabetes. The major adverse effect of sulphonyluraes is hypoglycemia, which can lead to a coma. Metformin and thiazolidinediones affect insulin sensitivity by independent mechanisms and disaccharidase inhibitors reduce rapid carbohydrate absorption.It is acknowledged that no single agent is capable of achieving target glucose levels in type 2 diabetes patients without major risk factors. Proper diet and nutritional supplements have a beneficial role when properly used in combinations with mild hypoglycemic agents. A major problem with the use of the synthetic non-physiological hypoglycemic drugs is that in aged diabetic patients, hepatic and renal functions are impaired, resulting in longer and sustained effects of these drugs due to their improper clearance from the circulation.The major clinical complications prevalent in aged diabetic patients include peripheral vascular disease, diabetic neuropathy, diabetic nephropathy and eye disorders such as cataracts, glaucoma and diabetic retinopathy. The established vasoreactivity of ATP in stimulating blood flow especially to the lower extremities makes oral ATP especially attractive in providing benefits in chronic hyperglycemic induced peripheral vascular disease and diabetic neuropathy. The use of oral ATP by the aged, would provide physiological regulation of glycemic levels along with improvements in some of the major clinical complications especially prevalent in the aged patients. Passwater: How do oral ATP supplements play a role in improving the cerebral circulation and benefiting mental acuity?
Rapaport: More than 20 years ago, Forrester et al., (31) demonstrated that ATP at physiological levels, plays a major role in the local control of cerebral blood flow in baboons. Intracarotid injections of very low levels of ATP, readily achievable by oral ATP formulations, showed a threshold vasodilatory response at 0.004 micromolar in the baboon. Starting at this level, ATP increased oxygen consumption in the baboon brain parenchyma through an increase in regional cerebral blood flow, which in turn was the result of the cerebral vessels’ pronounced vasodilation by ATP. In the central nervous system (CNS) increased flow equals improvements in metabolism, which yields enhanced function. Since skeletal muscles have been known to release ATP during exercise, the well-known aphorism mens sana in corpore sano, or a healthy mind in a healthy body seems validated.In cerebral arteries and arterioles, ATP is the major regulator of blood flow inducing the synthesis of NO at low concentrations of ATP and EDHF (endothelium-derived hyperpolarization factor) at higher concentrations of ATP. Both NO and EDHF stimulate blood flow in the cerebral vasculature and are synthesized in response to ATP interactions with P2Y receptors. Since ATP is released from red blood cells, pathological conditions that result in the loss of red blood cells, such as cerebral hemorrhage, are expected to result in reduced vasomotor responses.In an animal model of cerebral hemorrhage, the loss of red blood cells was shown to be crucial to the physiological regulation of the cerebral circulation. It was demonstrated that the loss of ATP and oxyhemoglobin, both of which released in large amounts during red blood cell lysis, is responsible in producing an attenuated vasoactive response during cerebral hemorrhage. Endothelial cells in both cerebral macro- and microvessels contain a substantial distribution of P2Y receptors, which suggests that under normal flow conditions, ATP released from red blood cells regulates vasodilation and enhancement of cerebral blood flow in response to metabolic demand.The size of the cerebral arteries or arterioles determined whether the ATP-induced vasodilation was produced by NO or endothelium-derived hyperpolarizing factor (EDHF) with the role of NO declining as the vessel size is decreased and the role of EDHF becoming more prominent (32).Because of its mechanism and the prominence of ATP in stimulating regional cerebral blood flow, oral ATP consumed in the absence of specific cerebral metabolic demand is likely to produce a significant enhancement of flow, metabolism and function in the brain. The result would be improved mental acuity in response to oral ATP formulations. There is no currently available agent that is known to improve mental acuity in the aged. Passwater: How does oral ATP-Induced stimulation of the peripheral microcirculation benefit skin aging and removal of superfluous fat deposits?
Rapaport: A variety of conditions related to impaired peripheral microcirculation and chronic venous deficiency, are common in the elderly. These include skin aging, Raynaud’s disease, acrocyanosis, cold-induced vasospasm and unesthetism related to deposits of superfluous fat such as cellulite. The quest for agents that improve the microcirculation by acting as topical vasodilators, has been the holy grail of the cosmetic industry. Esculoside (U.S. Patent No. 5,679,358) or ginkgo biloba (European Patent No. 275,005) are examples of primary ingredients in cosmetic preparations of topical vasodilators utilized in these conditions.The clinical indications of Raynaud’s disease and acrocyanosis are usually treated with pharmacological oral vasodilators such as prazosin and the Ca-channel blocker nifedipine. These vasodilators while showing some activity in Raynaud’s disease are acknowledged to be ineffective in the treatment of acrocyanosis.It is however the conditions of cellulite and unesthetism related to the deposits of superfluous fat, mostly in females thighs, face and neck areas, that constitute a particularly large market. These conditions are thought to be the result of poor arterial and arteriolar blood flow and lack of perfused capillaries, which make these fat deposits metabolically isolated. Therefore, in cases where lipolysis is achieved due to diet or topical treatment, free fatty acids cannot be removed from the interstitial environment of the white adipose tissue and are reconstituted as fat by lipogenesis. For the reduction in aging of the skin, topically active cosmetic preparations that improve peripheral microcirculation and increase vasoactivity of the arteries and precapillary arterioles have been sought.Oral ATP formulations are an established physiological peripheral vasodilator that has been discussed earlier in this interview as acting in the treatment of skin ulcers and stasis dermatitis due to varicose or phlebitic veins. In addition, conditions such as pruritus and pain, attributed to venous insufficiency, were resolved by AMP or ATP treatment (18-20). Oral ATP formulations have considerable potential in the treatment of skin aging and deposits of superfluous fat. Passwater: Well, Dr. Rapaport, this has been a very enlightening chat. The health benefits to our readers are enormous. We thank you very much for taking the time to discuss your research with us. It has been a long journey since my childhood days of watching “lightning bugs” with amazement. Little did I realize then that what I was watching was the energy of a chemical bond converted to the form of light emission, in a biological reaction initiated by one of the most fascinating molecules in living organisms-ATP." WF
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