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Blood Pressure Drug Aids In Fat Loss

April 7th, 2009 · No Comments

In the aerial battles that take place during times of war, fighter pilots who shoot down five enemy fighter planes earn the title of ACE; card sharks who do suspiciously well at poker are said to have an ACE up their sleeve; a student who answers every question correctly on a test is said to ACE the exam. Clearly, the word ACE describes a trait of power. Yet, in the medical vernacular, the acronym (abbreviation) ACE stands for angiotensin-converting enzyme.
ACE, in the medical context, is an enzyme that plays a role in maintaining blood pressure. Everyone who has had a physical for sports or even been seen at a clinic gets his blood pressure checked, as it is considered a “vital sign.” The vital signs are indicators of a person’s health that can be rapidly measured, including: body temperature, heart rate, blood pressure and respiratory rate (breathing). If any or all of these measures are abnormal, it indicates the body is facing a health challenge. A person’s blood pressure is measured by using a sphygmomanometer (cuff) and a stethoscope. The cuff is filled with air, much like the old-style Reebok Pump basketball shoes, to a point that occludes (collapses) the brachial artery by tightening about the arm. The valve is then opened slowly until the pulse is heard at a point further down the arm; hearing the pulse through the stethoscope indicates that the blood behind the cuff has enough pressure to push past the occlusive pressure of the cuff. The point at which the pulse is first heard marks the systolic pressure, or top number. Once the cuff has deflated (like a car tire) to the point it no longer occludes the artery, the pulse can no longer be heard, as it is flowing through the cuff point unimpeded. The point at which the pulse can no longer be heard is the diastolic pressure, or bottom number. A normal blood pressure reading is at or below 120/70.
Blood pressure is dynamic, as most people do not exist in a sensory deprivation chamber. When a person is scared or excited, blood pressure escalates rapidly to meet the “fight or flight” needs for survival. Conversely, some people suffer from very low blood pressure when becoming overheated or emotionally overwhelmed, even fainting from “shock.” These rapid changes in blood pressure are due to two opposing branches of the autonomic nervous system called the sympathetic and parasympathetic. The sympathetic nervous system’s effects are mediated primarily through the neurotransmitter norepinephrine and the hormone adrenalin (think of an adrenalin rush). The parasympathetic effects are primarily mediated via the vagus nerve.
Not every moment in life is a roller-coaster event; long-term control of the blood pressure is established through a number of interrelated systems. There are many “detectors” of blood pressure, which makes sense considering it is a “vital sign.” It may help to think of the body as a machine; just like any mission critical system, redundancy is built-in to assure that standard operating conditions are maintained. The numerous systems involved in monitoring and adjusting blood pressure reduce the likelihood of a physiological problem in a healthy person, but also make it very difficult to correct high blood pressure when hypertension develops. Physicians used to attempt to correct hypertension with escalating doses of one medication, but contemporary practices are evolving into multiple drugs at lower doses to improve efficacy with lower risks of side effects.

Among the blood pressure-related adjusters is the renin-angiotensin-aldosterone system that maintains blood pressure by regulating sodium concentration and vascular constriction. Pressure is affected by several factors, including: the diameter of blood vessels, the length of blood vessels (essentially unchanging) and viscosity. [These factors are used in calculations following Poiseuille’s Equation.] Sodium pulls water into the bloodstream, increasing pressure by pulling more fluid into the bloodstream. However, increasing the fluid component of blood (the solid component is made of red blood cells, white blood cells and platelets) also “thins” the blood or makes it more watery. This is important, as a “thick” blood (viscose) is more likely to clot, which is related to heart attacks and strokes.1 Vascular constriction refers to the ability of arteries to narrow (constrict) or open up (dilate). A narrow tube of any kind increases pressure significantly when compared to a wider tube. As an example, use a drinking straw to blow a napkin across a table; then use the cardboard tube from a paper towel roll or toilet paper that is the same length as the straw to do the same. You will see the drinking straw generates much more force and is harder to blow through; this is due to the smaller bore (inside diameter or hole size) of the straw compared to the paper towel roll. By affecting sodium and vasoconstriction, the renin-angiotensin-aldosterone system can increase blood pressure by increasing sodium content (and thus the volume of blood by increasing the “water” component) and narrowing the arteries.
ACE-Inhibitors
Given the central role these effects have on blood pressure, it is clear why ACE-inhibitors, which decrease the activity of the renin-angiotensin-aldosterone system, are effective drugs used in the treatment of hypertension. Common ACE-inhibitors include: captopril, enalapril, quinapril, lisinopril and benazapril; these drugs are sold under a variety of brand names. ACE-inhibitors are effective, but not without risk; the classic ACE-inhibitor, captoptil, appears to be slightly more prone to adverse side effects.2

At this point, most athletes may be wondering what all this discussion about ACE-inhibition has to do with fat loss. Granted, some bodybuilders, powerlifters and athletes have hypertension (it affects about 27 percent of the United States adult population and fully 67 percent of adult men have either hypertension or pre-hypertension).3 Yet, it is not the blood pressure-lowering effects of ACE-inhibitors that have caught the attention of bodybuilders and obesity researchers, but the fat-reducing and insulin-sensitizing effects, as noted in several published studies. A recent report coming out of the Howard Florey Institute in Melbourne, Australia, published in the Proceedings of the National Academy of Science described the potential (for mice) of controlling ACE in treating/preventing obesity.4 Michael Mathai and his colleagues studied a strain of mice that were genetically altered such that they did not produce the enzyme ACE. Compared to normal mice, the ACE-less mice weighed 20 percent less despite eating the same amount of food as the control mice, had 50 percent to 60 percent less fat, but the same fat-free mass, deposited less fat intra-abdominally (the metabolically bad fat) and regulated blood sugar better. In trying to determine how these effects were mediated (how they happened), the researchers discovered the ACE-less mice had a higher resting metabolism, burned more total calories per day and had more gene activation of processes involved in the breakdown and release of stored fat.

Surely, this cutting-edge research should take the bodybuilding and obesity communities by storm! Gene research! Lab mice! Australia! Throw in Mel Gibson, some flamethrowers, plus poorly maintained cars sporting superchargers and it has all the makings of a post-apocalyptic, sci-fi classic. Sadly, for any aspiring screenwriter already penning a sequel-laden script, this is likely to prove as another example of where humans are more complex than mice or someday we will all bow down before our white-furred, pink-eyed overlords when genetically altered lab mice establish their place as the dominant species. The use of ACE-inhibitors (e.g., captopril) has been mentioned in literature and gym circles for years. Numerous studies have reported conflicting results on the effect of ACE-inhibition on fat cell metabolism, as well as insulin sensitivity.5
Bill Llewellyn, author of an annual reference text on anabolic steroids (as ergogenic aids), has included commentary on captopril for years.6 He notes that the first reference to ACE-inhibition as a potential fat-reducing drug was printed in (the late) Dan DuChaine’s newsletter Dirty Dieting.7 Llewellyn discusses some interesting and relevant aspects of captopril’s actions that might account for some of the fat-reducing potential.6 As mentioned by a writer in Duchaine’s Dirty Dieting who penned under the name Dharkam, captopril seems to reduce the number of a2-adrenoreceptors in fat cells.8 Fat cells contain receptors for adrenalin-like hormones and neurotransmitters that interact with a class of receptors called adrenoreceptors. The ß-class (beta) of adrenoreceptors increase the breakdown and release of stored fat in a fat cell. The a2-receptors (alpha 2) effectively decrease the fat-reducing (and appetite-suppressing) effect of adrenalin-like drugs; the drug/supplement yohimbine is touted as a fat-reducing and appetite-suppressing agent because it blocks stimulation of the a2-adrenoreceptor.9
By blocking the ACE enzyme, captopril also holds potential in acting as a mild diuretic, as it would reduce the amount of aldosterone produced.10 Aldosterone is a steroid hormone produced in the adrenal cortex (a small gland that is located just above the kidneys); its effects include promoting sodium retention. As most people are aware, higher levels of sodium lead to increased water retention. For a hypertensive, this can contribute to higher blood pressure, which is why most are on a sodium-controlled diet; for a bodybuilder/athlete, this may lead to increased subcutaneous water, which would blur muscle definition.

Additionally, the insulin-sensitizing effect of ACE-inhibition may be due in part to increasing preferential uptake of glucose (sugar) into the muscle cell, at least in the mouse. One study has shown an increase in GLUT-4 transporters (doorways that shuttle sugar from the blood to the inside of a muscle cell) in captopril-treated mice.11 This would increase the efficiency of disposing of sugar consumed in a meal, reducing the insulin load and restoring glycogen after a workout more effectively. Relative to body fat, this would reduce the fat-storing effect of insulin and prevent insulin from impairing the breakdown and release of stored fat.

All of these effects are positives insofar as supporting the potential use of an ACE-inhibitor for treating/preventing fat loss. Yet, more recent research, such as Mathai’s study, expand on the possible mechanisms for ACE-inhibitors to work as fat-reducing drugs. As Mathai noted, the ACE-less mice had higher resting metabolisms and daily energy expenditure, which means they burned more calories than normal mice, even while resting. Further, specific genes (the functional parts of DNA that determine how a cell functions) that promote the breakdown and release of stored fat were more active, suggesting ACE might turn on fat-storing pathways or turned down fat-burning pathways in normal mice (and hopefully humans). In the fat cell, ACE is involved in the formation of angiotensin II. This protein appears to act directly and indirectly, as it interacts with receptors as well as generating other messenger signals.

Questions About Rodent Studies
Some interesting observations have been made regarding the ACE-related pathway in adipocyte (fat cell) physiology. Early rodent studies suggest that production of angiotensin II (the protein product of the ACE-related patway) is beneficial. It was proposed that angiotensis II increased the differentiation of preadipocytes to adipocytes by promoting the production of PGI2.12 What this means is that the body created more fat cells to handle the “fat load.” Though this sounds bad, it is actually good in that having too few fat cells (by number) results in the fat cells becoming “overstuffed” or hypertrophic. Large or hypertrophic fat cells are directly related to insulin resistance and a host of metabolic disorders.13 However, as with many other examples, it appears that rodents are not the best model to study when trying to understand ACE inhibition in man.14
Angiotensin II interacts with two classes of the AT receptor, AT1 and AT2. AT1 receptors are related to the development of hypertension in the vascular system; in the fat cell, AT1 activation is related to inhibited lipolysis (stored fat breakdown) and increased fatty acid synthase (fat production).15 AT2 appears to have opposing effects, including promoting the breakdown and release of stored fat.16-18 In the 1994 study using rodents, it was shown that the beneficial effects of angiotensin II were blocked by aspirin (which inhibits PGI2 production) and an AT2 antagonist (a drug that blocks the AT2 receptor from being stimulated by angiotensin); blocking the AT1 receptor did not prevent the metabolically positive effects of angiotensin.12 As rodents experience a net benefit from angiotensin II, it is possible those species (mice and rats, possibly even sheep which are not rodents) have fewer AT1 receptors in the fat cell than AT2.

In humans, or at least obese or obese-prone humans, this is likely not the case. Human fat cells do react to angiotensin II, though it appears to require a concentration that is equal to or greater than that required to induce hypertension.19 When angiotensin II is injected directly into the area of subcutaneous fat, stored fat is prevented from being broken down or released.20
Is this usable information yet? As Llewellyn notes, the bodybuilders who have used captopril to aid in fat loss have mixed opinions; some believed it helped while others felt there was no effect. Is it possible that ACE-inhibition is not the way to go to take advantage of this relatively unknown pathway? Looking back on the studies, rodent and human, it appears that AT1 blockade may be more potent and selective than ACE-inhibition. The ACE-less mice that were leaner and burned more calories had 85 percent to 97 percent less ACE-activity in tissues than normal mice. To reach that level of inhibition in the fat cell holds the potential for serious side effects, particularly in someone who is not hypertensive or being monitored by a physician.

By blocking the ACE enzyme, captopril also holds potential in acting as a mild diuretic, as it would reduce the amount of aldosterone produced.10 Aldosterone is a steroid hormone produced in the adrenal cortex (a small gland that is located just above the kidneys); its effects include promoting sodium retention. As most people are aware, higher levels of sodium lead to increased water retention. For a hypertensive, this can contribute to higher blood pressure, which is why most are on a sodium-controlled diet; for a bodybuilder/athlete, this may lead to increased subcutaneous water, which would blur muscle definition.

Additionally, the insulin-sensitizing effect of ACE-inhibition may be due in part to increasing preferential uptake of glucose (sugar) into the muscle cell, at least in the mouse. One study has shown an increase in GLUT-4 transporters (doorways that shuttle sugar from the blood to the inside of a muscle cell) in captopril-treated mice.11 This would increase the efficiency of disposing of sugar consumed in a meal, reducing the insulin load and restoring glycogen after a workout more effectively. Relative to body fat, this would reduce the fat-storing effect of insulin and prevent insulin from impairing the breakdown and release of stored fat.

All of these effects are positives insofar as supporting the potential use of an ACE-inhibitor for treating/preventing fat loss. Yet, more recent research, such as Mathai’s study, expand on the possible mechanisms for ACE-inhibitors to work as fat-reducing drugs. As Mathai noted, the ACE-less mice had higher resting metabolisms and daily energy expenditure, which means they burned more calories than normal mice, even while resting. Further, specific genes (the functional parts of DNA that determine how a cell functions) that promote the breakdown and release of stored fat were more active, suggesting ACE might turn on fat-storing pathways or turned down fat-burning pathways in normal mice (and hopefully humans). In the fat cell, ACE is involved in the formation of angiotensin II. This protein appears to act directly and indirectly, as it interacts with receptors as well as generating other messenger signals.

Questions About Rodent Studies
Some interesting observations have been made regarding the ACE-related pathway in adipocyte (fat cell) physiology. Early rodent studies suggest that production of angiotensin II (the protein product of the ACE-related patway) is beneficial. It was proposed that angiotensis II increased the differentiation of preadipocytes to adipocytes by promoting the production of PGI2.12 What this means is that the body created more fat cells to handle the “fat load.” Though this sounds bad, it is actually good in that having too few fat cells (by number) results in the fat cells becoming “overstuffed” or hypertrophic. Large or hypertrophic fat cells are directly related to insulin resistance and a host of metabolic disorders.13 However, as with many other examples, it appears that rodents are not the best model to study when trying to understand ACE inhibition in man.14
Angiotensin II interacts with two classes of the AT receptor, AT1 and AT2. AT1 receptors are related to the development of hypertension in the vascular system; in the fat cell, AT1 activation is related to inhibited lipolysis (stored fat breakdown) and increased fatty acid synthase (fat production).15 AT2 appears to have opposing effects, including promoting the breakdown and release of stored fat.16-18 In the 1994 study using rodents, it was shown that the beneficial effects of angiotensin II were blocked by aspirin (which inhibits PGI2 production) and an AT2 antagonist (a drug that blocks the AT2 receptor from being stimulated by angiotensin); blocking the AT1 receptor did not prevent the metabolically positive effects of angiotensin.12 As rodents experience a net benefit from angiotensin II, it is possible those species (mice and rats, possibly even sheep which are not rodents) have fewer AT1 receptors in the fat cell than AT2.

In humans, or at least obese or obese-prone humans, this is likely not the case. Human fat cells do react to angiotensin II, though it appears to require a concentration that is equal to or greater than that required to induce hypertension.19 When angiotensin II is injected directly into the area of subcutaneous fat, stored fat is prevented from being broken down or released.20
Is this usable information yet? As Llewellyn notes, the bodybuilders who have used captopril to aid in fat loss have mixed opinions; some believed it helped while others felt there was no effect. Is it possible that ACE-inhibition is not the way to go to take advantage of this relatively unknown pathway? Looking back on the studies, rodent and human, it appears that AT1 blockade may be more potent and selective than ACE-inhibition. The ACE-less mice that were leaner and burned more calories had 85 percent to 97 percent less ACE-activity in tissues than normal mice. To reach that level of inhibition in the fat cell holds the potential for serious side effects, particularly in someone who is not hypertensive or being monitored by a physician.

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