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The disappointing results of some hypertensive therapies have caused doubts about traditional approaches to management of hypertension.36 Rates of successful blood pressure control remain low among treated patients.4 Only 47% of patients with hypertension achieve optimal blood pressures below 140/90 mmHg.37 Hypertension treatments that will help patients establish healthy lifestyle changes and have fewer and less severe side effects would probably lead to more optimum results and higher rates of patient compliance with treatment programs. In fact, the most common reason patients seek complementary alternative medicine (CAM) is dissatisfaction with the ability of conventional medicine to treat chronic diseases. Interestingly, those most likely to utilize CAM have higher educational levels, poorer health, and holistic philosophies.38

Herbs are used worldwide to treat a number of ailments alternatively. "Herbs have been used as medical treatments since the beginning of time."35 Gingko biloba is used to treat cerebral insufficiency and intermittent claudication, and St. John's wort (Hypericum perforatum) is an herbal remedy for depression. Hawthorne (Crataegus spp.) is a treatment for congestive heart failure, and horse chestnut (Aesculus hippocastanum) is used for chronic venous insufficiency. Saw palmetto (Serenoa repens) fruit is used as a remedy for benign prostatic hyperplasia.39

A number of herbs are recommended for the treatment of hypertension. Some have dangerous side effects and can be toxic. The list includes aconite (wolfsbane), American hellebore, bee pollen, cinnamon, coenzyme Q10, cucumber, dandelion, dong quai, garlic, gotu kola, hawthorne, kelp, mistletoe, nettle, parsley, peach, rauwolfia, and yerba maté.13

Resperpine is an alkaloid derivative of Rauwolfia serpentina. It is also known as snakeroot and has been used since ancient times as a Hindu Ayurvedic remedy for hypertension and psychoses.40 Resperpine was one of the first drugs used widely to treat systolic high blood pressure. It lowers blood pressure by decreasing cardiac output, heart rate, peripheral vascular resistance, and rennin secretion. It has the ability to block the uptake of biogenic amines,40 but adversely affects the nervous system and has uncomfortable side effects including nasal congestion, increased gastric secretion, and mild diarrhea.40

Tetradrine, an alkaloid extract of Stephania tetrandra, a Chinese herb, is a calcium ion channel antagonist. It blocks both T and L calcium channels and therefore stops the smooth muscle cells of the arteries from contracting. It also causes swelling of liver cells and has been deemed responsible for deaths caused by rapidly progressing renal failure (Chinese herb nephropathy) when used as part of a dieting regimen.35,40 Tetramethylpyrazine inhibits platelet aggregation and non-selectively antagonizes adrenergic receptors. Veratrum (hellebore) enhances nerve and muscle excitability, causing reflex hypotension, but also causes nausea and vomiting.35 Viscum album L is a semiparasitic plant that grows on various shrubs and trees, including apple trees, and has been used as an herbal remedy for hypertension and atherosclerosis.41

Some herbal remedies produce adverse and not necessarily publicized side effects on hypertension. Ephedrine, also known as ephedra or ma huang, stimulates adrenergic receptors, and can increase heart rate and peripheral vascular resistance, thus increasing high blood pressure even more.42 Interestingly, licorice extract is also known to cause increased blood pressure.25 Ruscus aculeatus (butcher's broom) was investigated as a potential treatment for hypotension, but probably would increase rather than lower blood pressure.43

Clinical research related to medicinal use of herbal products has grown.39 Patients are willing to spend their money on herbal and alternative medicines not covered by their insurance if they feel confident about getting a good product. This raises the issue that "the time has come to submit such products to the same rigorous, internationally accepted pharmacoeconomic approach as their synthetic competi-tors."39 Herbal remedies are totally unsupervised in the U.S. because of congressional interference with surveillance by the Food and Drug Administration (FDA).25 The development of patent medicines in the early part of the 20th century caused a decrease in the use of herbal medicines because scientists and physicians touted synthetic and patented medicines as more reliable and effective.40

Many dietary treatments have been suggested to slow or reverse the causes of hypertension. One popular program is the DASH (dietary approaches to stop hypertension) diet that calls for 27% calories from fat, 8 to 10 daily fruit and vegetable servings, and limited consumption of meat, including fish and poultry.9 The DASH diet also recommends that patients stop smoking, lose weight if overweight, reduce daily sodium intake to 2.4 g sodium (or 6 g table salt), maintain adequate dietary intake of potassium, calcium, and magnesium, and limit daily intake of alcohol to less than 1 oz of ethanol (equal to 24 oz beer, 8 oz wine, or 2 oz 100-proof liquor).25

The National Cholesterol Education Program (NCEP) recommends reducing total fat intake from the current 36 or 37% of daily caloric intake down to 30%.44 Another source adds reduction of stress and lower dairy, calcium, and potassium consumption to the list of lifestyle changes.45 The Third Joint National Committee report recommended nonpharmaceutical treatments that concentrate on weight control, sodium restriction, moderation of alcohol intake, cessation of cigarette smoking, and incorporation of a routine exercise program.15 A number of studies have shown that a body weight reduction as little as 10 lb is associated with significant reductions in systolic and diastolic arterial blood pressure, serum cholesterol, heart rate, and uric acid concentrations.15 Blood pressure increases as body weight increases, and excess weight can increase the risk of hypertension two to six times, especially for those with abdominal obesity.44 Regular aerobic exercise routinely lowers blood pressure. A 30-minute workout at 50% maximum oxygen uptake will lower blood pressure for the remainder of a 24-hour period.25 A publication of the Joint National Committee V noted a significant reduction in the number of hypertensive patients in the U.S. as a result of these nonpharmaceutical approaches.15

In 1999, the World Health Organization's International Society of Hypertension (WHO-ISH) set guidelines for the management of mild hypertension after noticing uncertainty among clinicians and policymakers concerning mild hypertension. The group suggested nonpharmacological lifestyle measures including smoking cessation, weight reduction, moderation of alcohol consumption, reduction of salt intake, dietary changes, increased physical activity, and use of coping skills to manage psychological factors and stress. WHO-ISH found that in controlled dietary trials, the blood pressure lowering effects of vegetarian diets were more dependent on the combined effects of increased consumption of fruits, vegetables, and fiber and the decreased intake of fats than whether meat was consumed.23 Actions to promote the risks associated with high dietary intake of sodium have met with resistance. Processed foods account for more than 75% of sodium intake in the U.S. diet.15 25 One source noted that those making and selling snack foods and sodas do not wish to see reductions in their profits and actively resist attempts to reduce dietary fat and salt levels.25

For many people, beneficial results can be achieved by reducing intakes of high sodium (Na)/low potassium (K) processed foods while increasing intakes of low Na/high K natural foods in their diets.25 An increase of fruits and vegetables in daily diet will increase K intake and that will reduce blood pressure15 and Na intake. The Framingham Heart Study noted that a dietary increase of three servings per day of K-rich fruits and vegetables was associated with a 22% decrease in the risk of stroke.25

Fresh fruits and vegetables are important sources of vitamin C, fiber,46 and magnesium (Mg).15 While calcium (Ca) supplements or increases of dietary Ca intake exert minimal effects on blood pressure, Mg supplements may cause a small drop in blood pressure. Dietary intake of fruits and vegetables is preferred as a source of Mg.15,25 Since the causes of hypertension produce long-term effects, a diet high in fruits and vegetables may be preventative.46 Studies show that a vegetarian diet is associated with low blood pressure47 and that vegetarians tend to have lower blood pressure overall.25 When hypertensives go on vegetarian diets, systolic blood pressure falls by an average of about 5 mmHg.25

In Norway, an increase of fruits and vegetables proved to decrease stroke mortality.48 In the Nurses' Health Study, a 12- to 14-year follow-up of the 75,000 female participants indicated a significant reduction in the risk of stroke with increased intake of fruits and vegetables25 and that a diet including more complex carbohydrates and less refined sugars tends to lower blood pressure.25 Short- and long-term consumption of black tea was found to regulate endothelial vasomotor abnormalities in coronary artery disease patients.49 No effect on atherosclerotic risks concerned with plaque on the arteries was discovered in treatments with tea.49 Other experiments proved that blood pressure in laboratory animals can be lowered by the addition of green tea to water for ingestion.50,51 The decreases are caused by antioxidants residing in fruits, vegetables, and tea.46,52 Lowering oxidation levels in spontaneously hypertensive rats has shown physical evidence that antioxidants are antihypertensive.107

The effects of grains served as the topic of another study. A total of 88 men and women were divided among 2 groups: 23 males and 22 females consumed an oat cereal over a 12-week period; the remaining 22 males and 21 females were left as a control group. It was noted that 73% of the group given an oat-based diet opposed to 42% of the control group showed decreased blood pressure, took half their recommended doses of hypertension drugs, or even stopped medications com-pletely.53 Cholesterol levels in the oat group were lowered by 24.2 mg/dl in comparison to the control group, while LDL cholesterol levels decreased by 16.2 mg/dl in the oat group.53

In a study conducted with 59 healthy omnivorous subjects at Royal Perth Hospital, the influence of a vegetarian diet on blood pressure was investigated. The 30 women and 29 men, aged 25 to 63 years, and all professional, clerical, or technical employees of the hospital, were divided into 3 groups. The control group ate an omnivorous diet for the entire 14-week period. One experimental group ate an omnivorous diet for 2 weeks, followed by a lacto-ovo-vegetarian diet for 6 weeks, and then resumed the omnivore diet for the final 6 weeks. The second experimental group ate an omnivorous diet for the first 8 weeks, followed by a lacto-ovo-vegetarian diet for the final 6 weeks. On Mondays through Fridays, both groups ate 2 meals per day in the hospital dining room. The participants received instructions about meals eaten outside the hospital.47

The systolic, diastolic, and mean blood pressure measurements showed no change in the control group (mean BP = DBP + [(SBP - DBP)/3]).854 All three blood pressure measurements fell significantly in each of the control groups during the time they were on the vegetarian diet. The blood pressure levels of the experimental group that reverted to the omnivorous diet rose significantly at that time. The diet-related decrease measured 5 to 6 mmHg in systolic pressure and 2 to 3 mmHg in diastolic pressure. No correlation was indicated between intakes of Na or K and high blood pressure because the diets were similar in that regard. Furthermore, 52%

of the participants had higher education background, 25% smoked, and 71% ingested moderate amounts of alcohol, so these factors were not indicated as causes for the increase in blood pressure. The blood pressure changes in the experimental groups were most evident during the final week on the vegetarian diet, with the blood pressure returning to previous levels within 5 to 6 weeks of return to the omnivorous diet.47 Another source indicated that vegetarians tend to have lower blood pressure and that omnivores placed on a vegetarian diet show an average drop of 5 mmHg in systolic blood pressure.15

Perhaps the drop in blood pressure was due to increased dietary fiber, polyun-saturated fats, and magnesium; a reduction of dietary saturated fat, cholesterol, and total fat;47 or ingestion of flavonoids. Another early study concluded "that average flavonoid intake may contribute to differences in mortality from CHD (coronary heart disease) across populations."55 A study that used a 131-item questionnaire on 34,789 male health professionals aged 40 to 75 years "found a modest but nonsignificant inverse association between intake of flavonols and flavones and subsequent coronary mortality rates." In the conclusion, the researchers admitted the data did "not exclude the possibility that flavonoids have a protective effect in men with established coronary heart disease."56

10.5 FLAVONOIDS: TYPES, SOURCES, AND STUDIES

Flavonoids, also called bioflavonoids, are members of a larger group called polyphenols56,57 and are secondary metabolites extracted from plants and found in numerous foods such as red wine, black tea, onions, and apples.58 Universally present in vascular plants,59 they color flowers and fruits to attract pollinators and repel predators.59 The blue anthocyanins are colored in part by magnesium metal.60 Fla-vonoids differ from one plant species to another.57

Citrus flavonoids were discovered (and named vitamin P) in 1936 by Rusznyak and Szent-Gyorgyi, who proposed that their intake strengthens blood vessel walls and decreases capillary fragility seen in scurvy.57 61 62 The vitamin status was discontinued in 1950 upon recommendation of the Federation of American Societies for Experimental Biology.61 For the most part, the biologic actions of flavonoids are specific toward activated cells; they exert little or no effect on normal cells.61 Therefore, "it might be possible to identify a range of flavonoids that could be employed selectively in pharmaceutical use depending on the endpoint desired."63 Flavonoids are currently under study for potential value in treating allergic reactions, cancer, diabetes, and inflammatory and viral infections.59 Flavonoids prevent oxidation, chelate or bind metals, stimulate the immune system, prevent the formation of carcinogens, and protect against bacteria and viruses.64

More than 4000 flavonoids and many sources have been identified.5765 Howard M. Merken and Gary R. Beecher of Agricultural Research, a magazine published by the U.S. Department of Agriculture, are reportedly preparing a database of all fla-vonoids. They previously launched a database of isoflavones in soy foods in 1999.64 Flavonoids also have a few nonplant sources. They have been found in the wings and bodies of butterflies in the Satyridae, Lycaenidae, and Papilionidae families.66 The only reported mammalian source of flavonoids is 4'-methoxyflavan from the scent glands of the Canadian beaver, Caster fiber.66 Flavonoids cannot be synthesized by humans.65

Flavonoids have many subclasses including isoflavones, catechins, anthocyani-dins, flavonols, flavones, flavanones found in citrus fruits,56,62,67 biflavone,68 and biflavonoids.69 Anthocyanins are found in edible cereals, green and root vegetables, and fruits.67 Biflavone is also called amentoflavone and is a selective inhibitor of COX.68 Similarly, bioflavonoids are associated with amentoflavone, bilobetin, morel-loflavane, and ginkgetin, and prevent phospholipase A2.69 Flavones include chrysin, apigenin, tangeritin, luteolin,58 and nobiletin. The apigenin flavone is found in parsley and thyme56 and has been used to treat inflammation.61 Some common flavonols are kampferol or kaempferol, quercetin which is found in many Western foods and stops oxidation and cytotoxicity definition of LDLs,70 myricetin,58 and rutin. The quercetin and kaempferol flavonols are found predominantly in onions, kale, broccoli, apples, cherries, berries, tea, and red wine.56 The astilbin (dihydroquercetin 3-rhamnoside) and engeltin (dihydrokaempferol 3- rhamnoside) dihydroflavonols are found in char-donnay grapes and white wines.67 Flavonones include naringenin, naringin, eriod-ictyl, hesperetin, and hesperidin. The subclass of dihydroflavonols includes taxifolin or dihydroquercetin. Catechin, gallocatchin, and gallate are flavanes. Isoflavones or phytoestrogens include coumestrol, equol,58 daidzein, glycitein, and genistein. Coumestrol is one of the coumestanes. Caffeic A (CAFA) is a cinnamate. Alpha-tocopherol (a-TOC) and gamma-tocopherol (g-TOC) are in the subclass of tocopherols. Another subclass is 3-methyl-cholanthrene.71

Flavonoids are composed of benzene rings with multiple hydroxyl groups and as a result are also called polyphenols62 (see Figure 10.2). Many are also combined molecularly with sugar and called glycosides. Examples are hesperidin, found in oranges, lemons, limes, and tangerines; naringin and narirtin, found in grapefruits; and eriocitrin, found in lemons and limes.61 It has been suggested that grapefruit juice increases the absorption of several calcium channel blockers.61 The extreme bitterness of citrus peels is due to naringin.67 In 1981, Wollenweber and Dietz showed "flavones and flavonols of leaf works and plant extrudes nearly always occur in the free state, without glycosylation, and often in methylated form."60

Flavonoids in plants are unaffected by heat, oxygen, dryness, or limited acidity, but they can change in the presence of light.72 For example, high exposure to light leads to high oxidation.4 Ultraviolet B rays can encourage accumulation of fla-

Flavan Nucleus A I C

Flavan Nucleus A I C

FIGURE 10.2 Chemical structure of nucleus.

4-Oxo-Flavonoid Nucleus O

4-Oxo-Flavonoid Nucleus O

FIGURE 10.2 Chemical structure of nucleus.

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FIGURE 10.3 Nucleus structures of flavonoid classes.

vonoids.73 Photostability of these molecules is a result of glycosylation or detachment of the hydroxyl group from the C-3 of ring C.74 Glycosylation causes an increase in the polarity of the flavonoid molecules, which is important for cell vacuole storage in plants.4

Most classes of flavonoids, such as flavones and flavanones, are found as gly-cosides in nearly all plants72 (see Figure 10.3). Because light can stimulate biosynthesis of 4-oxo-flavonoid, its concentration is greater near the surface of the plant.4 Vast amounts of quercetin glycosides are found in the skins of red grapes,75 Spanish cherry tomatoes,73 and apples.76 Thus, plants with high skin-to-volume ratios are said to have high flavonol contents.4 Quercetin content in fruit and vegetables can range from less than 1 mg/100 g (endive) to 147 mg/100 g (cranberries).77

Cultivation, preparation, and storage are influential variables as well. Many leafy vegetables including lettuces, endives, and leeks show flavonoid level variations from season to season, whereas red cabbage and pears do not.77 Grapes grown in warm sunny areas produce wines high in flavonol content compared to grapes grown in colder climates.75 Boiling can decrease the quercetin content of vegetables and fruits more than microwaving or frying.78 Storage effects on flavonoid accumulation are not as precisely determined. One study noted that quercetin levels of bilberries and strawberries stored for 9 months at -20°C decreased by 40% and increased by 32%, respectively.79

At the Plant Flavonoids in Biology and Medicine meeting held in Buffalo, NY, in 1985, Tony Swain of the Department of Biology at Boston University noted that some of the 6- and 8-hydroxy-substituted flavonoids found in angiosperms did not appear in lower plants. He stated that flavonoids, first, are typical phenolic compounds and thus act as potent antioxidants and metal chelators. It is advantageous to plants to be able to isolate and reduce the activities of oxidant-inducing metals such as iron and copper taken from the soil. Those that include a 4-carbonyl and a 5- (or 3-) hydroxy group are very good metal chelators. Second, flavonoids are conjugated aromatic compounds that screen out ultraviolet light and attenuate visible light. Third, they interfere with the feeding, reproduction, germination, and growth of seedlings, as well as the growth and development of animals, bacteria, fungi, and viruses. Isoflavones particularly simulate steroidal and other growth controllers in predators. Pranthocyanidins, ligans, and biflavonoids (polymeric forms) can bind proteins, enzymes, polysaccharides, nucleic acids, and other polymers. Fourth, flavonoids play a role in strengthening the structures of plant cell walls, especially ligins.59

Other sources of flavonoids used to treat a variety of health issues are citrus, extracts of bilberry, hawthorne, horse chestnut (Aesculus hippocastanum), gotu kola (Centella asciatica), butcher's broom (Ruscus aculeatus), and Ginkgo biloba. Potentially useful citrus flavonoids were discovered in the peels and leaves of Dancy tangerines.80 Achillea wilhelmsii is an herb that grows wild in Iran and is a rich source of flavonoids.58 Procyanidins are found in cocoa, red wine, apples, and cranberries.81 Flavonoids in pomegranates have been associated with anti-aging properties in Israel.82 Additionally, pycnogenols, complexes of flavonoids or polyphenols found in extracts of grape seeds and the bark of the Landes pine, have been used in the treatment of varicose veins at doses of 150 to 300 mg/day.13 Grape seeds, pulp, and skins have been used in the treatment of circulatory disorders, as have other proanthocyanidins.57 Flavonoids have been found in cabbage, beans, radishes, and rhubarb stalks.67 Flavonoids from pome and stone fruits tend to be concentrated in the peels. Those found in the skins and flesh of soft fruits tend to increase as the fruit ripens. Some raspberries contain hundreds of milligrams of flavonoids per 100 grams of fresh fruit. Blood oranges are colored by glycosides of cyanidin and delphinidin.67 Flavonoids are also found in grains, legumes, soy, beer, and bourbon.58

The low rate of heart disease in France, a high consumer of red wine which is high in flavonoid content, is named the French Paradox. In comparison to Americans, the French have similar levels of serum cholesterol, saturated fat intake, and prevalence of smoking — all considered contributory factors for heart disease.61

Flavonols and flavones are subgroups of flavonoids that have antioxidant properties and are most often found in vegetables, fruits, tea, and red wine.56 The antioxidant properties of flavonols and catechins suggest that they may prevent atherosclerosis. They also inhibit lipoxygenase (LOX).83 The LOX and cyclooxyge-nase (COX) enzymes affect blood pressure by increasing aggregation platelets that regulate blood clotting.84 Individually, LOX mediates pharmacology, while COX increases the production of prostaglandin, a hormone that mediates blood pressure.20 In general, flavonoids are powerful inhibitors of COX,83 antioxidants, and tyrosine and kinase blockers.57 Most attack lipid bilayers85 and inhibit LDLs58 and platelets.86

Antiplatelet/antioxidant therapy has been accomplished through the actions of flavonoids in red wine and purple grape juice. It is now thought that nitric oxide (NO) is the relaxing factor in coronary and other arteries. NO is secreted by endothelial cells when increased blood flow passes over them.87 The endothelial cells can be damaged or become dysfunctional through hypertension, increased LDL cholesterol, diabetes, cigarette smoking, free radicals, or elevated plasma homocysteine.88 This damage would decrease the production of NO. Decreased NO allows platelets and other cells to adhere to arterial walls.87 This action increases blood pressure as the inner diameters of the arteries decrease. In a dog study, purple grape juice proved better than aspirin as an antiplatelet medication. The dogs were given amounts equal to about 20 oz of purple grape juice for an adult human. The purple grape juice treatment showed no renewed platelet activity, while about 60% renewed activity occurred with aspirin treatment.87

Antioxidants include dietary substances and some vitamins that quench free radical reactions and thus lessen oxidation of some cell constituents.44 An increase in LDL increases the chance of cardiovascular disease (CVD). When LDL is oxidized, "it is more easily taken up by the macrophages, causing foam cell formation in the intima of the arteries, triggering the atherogenic process."44 Vitamins C and E and beta-carotene appear to play a role in decreasing lipid peroxidation and the oxidization of LDL.44

Flavonoids such as quercetin, kaempferol, myristin, epigenin, and luteolin are polyphenolic antioxidants found in fruits, vegetables, and red wines.4449 They inhibit oxidation of LDL cholesterol and reduce thrombotic tendencies.44 Some soy isofla-vones are effective in lowering serum cholesterol. Other sources of antioxidant-acting flavonoids revealed in a Japanese study are pine bark — touted as 50 times more powerful than vitamin E — green tea, and persimmons.57 Persimmon juice has been used as a traditional medicine to treat hypertension and prevent stroke in Japan. Persimmon juice contains various condensed tannins.89 The mix of proantho-cyanidin flavonoids in pine bark varies, and the same is believed true of other flavonoid sources. Researchers studied 6 but only found 1 that was 50 times more powerful than vitamin E. Proanthocyanidins are water-soluble and vitamin E is oil-soluble. Humans require both water- and oil-soluble antioxidants, so pine bark is not a viable replacement for vitamin E.57 Other sources warn that although antiox-idants are popular, their use in the prevention of cardiovascular disease has not yet been proven in trials.11

A study was done in Japan to investigate the possible relation between low coronary artery disease and intake of green tea, which is high in flavonoid content, but concluded more study was necessary.90

The Caerphilly Study investigating flavonols and ischemic heart disease in Welsh men found that quercetin can inhibit LDL oxidation and therefore prohibit platelet aggregation in vitro.90 The major sources of the flavonols were black and green teas, red wines, and onions.90

A separate 6-year study that used a 131-item questionnaire on 34,789 male health professionals aged 40 to 75 years "found a modest but nonsignificant inverse association between the intake of flavonols and flavones and subsequent coronary mortality rates." The biennial follow-up questionnaires were completed and returned via mail by 94% of the original participants in 1988, 1990, and 1992. The participants were questioned about foods and frequencies of intake to determine their intakes of three flavonols and two flavones. The primary food sources of the flavonoids were tea (25%), onions (25%), apples (10%), and broccoli (7%). The study also found that the men with higher intakes of flavonols and flavones were slightly older, drank less alcohol, smoked less, and ate more dietary fiber. These men were also more likely to take vitamin E supplements. In the conclusion, the researchers admitted that the data "do not exclude the possibility that flavonoids have a protective effect in men with established coronary heart disease."56

In a Finnish study, an inverse association between flavonols from dietary intake of apples and onions and cardiovascular mortality was reported.90 Hertog et al. reported an inverse association between the intake of quercetin and coronary mortality of elderly men in Zutphen, the Netherlands.44,62,99 The major dietary sources of quercetin and related flavonols were tea and onions. However, the study showed heart disease mortality increased with tea and decreased with onion intake. This may be due to the fact that the tea drinkers were more likely to be manual laborers who ate more fat, smoked more, and had lower alcohol intakes. Additionally, metabolic studies indicated that quercetin compounds found in onions had higher bio-availabilities than those from tea.62 A similar study concluded that although data did not support a strong inverse relationship between flavonoid intake and CHD, it is possible that flavonoids exert a protective effect in men with established CHD.56

Rat studies suggest that green tea extract has the ability to lower blood pressure.92 In humans, blood pressure lowering effects of green tea were noticed in a study comparing the effects of black tea, green tea, and caffeine in water. The subjects consumed equal amounts of one of the liquids, and the caffeinated water was included in order to verify that the blood pressure lowering effects were not results of the caffeine in the teas.92 Thirty percent of the flavonoids in green tea is epigallocatechin gallate.57

Some caution is necessary in regard to isoflavonoids. Unlike other flavonoids, isoflavonoids are plant chemicals whose biosynthesis is dependent on the presence of plant stressors, and therefore may not be consistent in quantity or strength.93 While flavonoid composition is generally consistent within a plant species, isofla-vonoid biosynthesis is particularly dependent on plant pathogens.93

Data on the absorption of flavonoids by humans are scarce and sometimes contradictory.94 One report stated that humans absorb about 52% of the quercetin in onions.56 Cooking and food preparation account for some loss of flavonoid content. About 20% or less of flavonoid content is believed to be lost through cooking.94 Flavonoids are more predominant in the peels of pome and stone fruits and in the rinds of citrus fruits rather than in the flesh. They are found in proportion to greenness of the leaves in lettuce, parsley, rosemary, and thyme. The "green tips of asparagus contain enough rutin to react with soluble iron during storage in cans to become discolored."67

There is a suggestion that flavonoids may become carcinogenic at high doses. A press release from the School of Public Health of the University of California at Berkeley states that some chemical components from fruits and vegetables that are concentrated and sold in high doses as flavonoid supplements in health food stores can make people sick. Some of these substances are ginkgo pills, quercetin tablets, grape seed extract, and flax seeds. According to a professor of toxicology at Berkeley, these supplements are not regulated by any government agency. They can bind with and damage chromosomes and DNA in cell cultures at high levels, alter the activities of various enzymes, and interfere with hormone metabolism, especially estrogen and thyroid hormones. However, dietary intake could never produce such high levels of flavonoids. For example, people normally ingest 5 to 68 mg of quercetin through food intake daily, whereas one supplement recommends taking 1000 mg daily.95

Essential hypertension is usually associated with increased blood viscosity due to erthyrocyte deformability or aggregation. In a study of 20 individuals with moderate hypertension, decreases in blood pressure levels and plasma viscosities were noted following administration of 3 daily doses totaling 3000 mg troxerutin for 4 weeks. Participants' levels of sodium, potassium, glycamia, creatinine, uric acid, cholesterol, triglycerides, and immunoglobulins remained unchanged both over time and compared to the control group of 20 individuals matched for age and sex.54

When spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto rats were given oral daily doses of quercetin for 5 weeks, the results were reduced blood pressure, plasma, and hepatic malondialdehyde levels and increased glu-tathione peroxidase activity. Systolic pressure fell by -18%, diastolic by -23%, and mean by 21% in SHRs.96 None of these effects were noted in the normotensive rats.97 Similar studies were done using flavonoids extracted from Spergularia purpurea. Systolic blood pressure dropped by -17% and diastolic by -24% in SHRs. With the flavonoid substance, the normotensive rats showed decreases of -11% in systolic blood pressure and -16% in diastolic pressure.98

The flavonoid compounds responsible for antihypertensive activity are rare, mostly ephedrannins and mahuannis A and B.99 Four flavonones (5-hydroxy-6,7,3',4'-tetramethoxyflavone, eupatorin, tetramethylscutellarein, and sinensetin) have been found in the kumis kucing (Orthosophon aristatus) leaves used in traditional Javanese medicine to treat hypertension.100 In tests, these flavones suppressed contractions induced by K ions in endothelium-denuded rat thoracic aorta.100

Flavonoids are already used in medical treatments. Daflon® 500 mg is a registered brand name for the purified flavonoid fraction MPFF, and it is used in the treatment of hemorrhoidal and chronic venous insufficiency diseases. It contains 90% diosmin and 10% hesperidine, both derived from flavones.101 Daflon has been used in cases of venular occlusion associated with elevation in capillary blood pressure and primary venous insufficiency characterized by venous wall dilation and valve dysfunction.101 It acts favorably by inhibiting the synthesis of prostaglandins and free radicals.6 Daflon is also known as Ardium, ArVenum 500, Detralex, and Venitol; it is manufactured by Laboratoires Servier in France.101

The beta-adrenergic blocking effects of some benzopyrone derivatives, propra-nolol-type chromone, and flavone derivatives noted in 1986 led to the development of flavodilol as an antihypertensive drug.102 Flavodilol is a (±) 7-2-hydroxy-3-(pro-pylamino)2-hydroxypropoxy flavone maleate.102 The flavodilol maleate known as PR 877-530L was synthesized by the organic chemistry department of the Pennwalt Pharmaceutical Division in Rochester, NY, for use in a rat study. SHRs showed about a 26% reduction in systolic blood pressure for 2 to 24 hours after dosing. According to Watkins et al. (1985), flavodilol produced dose-related decreases up to 30% in arterial pressure in SHRs.103 Interestingly, the same dose did not lower blood pressure or cause hypotension in normotensive Sprague-Dawley rats.103 Fla-vodilol was undergoing early phase II clinical trials in 1985.103 The synthesis and antihypertensive activity of (3-phenyl flavoxy) propanolamines were described by Wu et al (1987). "These active compounds represent a unique series of effective antihypertensive agents that, despite possessing structural characteristics typical of b-blockers, do not have b-adrenergic receptor blocking activity."102

Pycnogenol, a mixture of flavonoids in the bark extract from the French maritime pine (Pinus pinaster) and used as a dietary supplement, was administered to nonsmoking, mildly hypertensive patients. The results showed decreases in systolic blood pressure, but no discernible decreases in diastolic blood pressure.104 Another study concentrated on pycnogenol's effects on asthma and concluded it could be useful.105 In a cardiovascular-related study, pycnogenol significantly inhibited platelet aggravation in tobacco smokers without causing increases in bleeding following aspirin use to achieve the same goal.106

With so many flavonoids from diverse sources, it is not likely many will appear in tablet form soon. Flavonoids may work better in conjunction with other flavonoids. An added concern is that using isolated flavonoids may be similar to the act of taking beta-carotene and ignoring all the other "mixed" carotenoids.57 Various laboratory studies are underway to test the effectiveness of flavonoid substances in the treatment of hypertension and other diseases. Research is funded in part by organizations including the National Heart, Lung, and Blood Institute; the Produce for Better Health Foundation;64 and the Department of Citrus.71 While we do not yet have any conclusive evidence of success in this area, the hope is for more natural-based remedies with fewer adverse side effects.

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    Can diosmin be taken permanently?
    2 years ago

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