Nutriceuticals for cardiovascular health
1998; Elsevier BV; Volume: 82; Issue: 9 Linguagem: Inglês
10.1016/s0002-9149(98)00763-2
ISSN1879-1913
Autores Tópico(s)Free Radicals and Antioxidants
ResumoThe recently coined term "nutriceutical" is enjoying increasing popularity for describing a variety of nonprescription products that are used to enhance health. There are several interpretations (and variant spellings) of the term, but it is best reserved to describe products that are (1) naturally occurring substances (e.g., vitamins, amino acids, herbals) or formulations of these substances; (2) based on a strong scientific foundation; and (3) supported by clinical trials of their utility. Nutriceutical is a useful term for a physician to know because it is appearing more frequently in the lay press. However, this term has no legal standing. The US Food and Drug Administration (FDA) recognizes drugs, medical foods, dietary supplements, and food additives as distinct regulatory categories. Most "nutriceuticals" are dietary supplements, although a smaller percentage are medical foods and food additives. Cardiovascular nutriceuticals are agents in this category that have been shown to enhance cardiovascular health. For example, cardiovascular nutriceuticals may stimulate increased release of nitric oxide, block the production or enhance the degradation of superoxide anion, or have beneficial effects in preventing the oxidation of lipoproteins. The nutriceuticals to be discussed in this brief review include vitamin E, vitamin C, coenzyme Q10, carotenoids (beta carotene, lycopene), flavonoids, and l-arginine (Table I). A lipid-phase antioxidant, vitamin E (α-tocopherol) protects tissue lipids from attack by oxygen free radicals.1Sies H Stahl W Vitamins E and C, β-carotene, and other carotenoids as antioxidants.Am J Clin Nutr. 1995; 62: 1315S-1321SPubMed Google Scholar This extensively investigated antioxidant vitamin increases resistance to lipid peroxidation and reverses endothelial vasodilator dysfunction. Several major studies have demonstrated the cardioprotective benefits of supplemental intake of vitamin E: (1) Cholesterol Lowering Atherosclerosis Study (CLAS)2Hodis H.N Mack W.J LaBree L Cashin-Hemphill L Sevanian A Johnson R Azen S.P Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis.JAMA. 1995; 273: 1849-1854Crossref PubMed Scopus (314) Google Scholar—men who took ≥100 IU per day of supplementary vitamin E had less progression of coronary artery lesions than did men whose supplementary intake of vitamin E was 55 years old; and (3) Cambridge Heart Antioxidant Study (CHAOS)4Stephens N.G Parsons A Schofield P.M Kelly F Cheeseman K Mitchinson M.J Brown M.J Randomised controlled trial of vitamin E in patients with coronary disease Cambridge Heart Antioxidant Study (CHAOS).Lancet. 1996; 347: 781-786Abstract PubMed Scopus (1634) Google Scholar—doses of 400–800 IU of vitamin E decreased the relative risks of nonfatal myocardial infarction by 77% in patients with coronary atherosclerosis. The major aqueous-phase antioxidant, vitamin C (ascorbate) traps peroxyl radicals in the aqueous phase before they can initiate lipid peroxidation.1Sies H Stahl W Vitamins E and C, β-carotene, and other carotenoids as antioxidants.Am J Clin Nutr. 1995; 62: 1315S-1321SPubMed Google Scholar Vitamin C enhances the activity of vitamin E,1Sies H Stahl W Vitamins E and C, β-carotene, and other carotenoids as antioxidants.Am J Clin Nutr. 1995; 62: 1315S-1321SPubMed Google Scholar, 5Kwiterovich Jr, P.O The effect of dietary fat, antioxidants, and pro-oxidants on blood lipids, lipoproteins, and atherosclerosis.J Am Diet Assoc. 1997; 97: S31-S41Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar and it improves and normalizes endothelial vasodilator function in patients with chronic heart failure by increasing the availability of the potent vasodilator nitric oxide.6Hornig B Arakawa N Kohler C Drexler H Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure.Circulation. 1998; 97: 363-368Crossref PubMed Scopus (340) Google Scholar, 7Solzbach U Just H Jeserich M Hornig B Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients.Circulation. 1997; 96: 1513-1519Crossref PubMed Scopus (275) Google Scholar Improved endothelial function with vitamin C has also been observed in patients with hypertension, hypercholesterolemia, and diabetes mellitus.6Hornig B Arakawa N Kohler C Drexler H Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure.Circulation. 1998; 97: 363-368Crossref PubMed Scopus (340) Google Scholar, 7Solzbach U Just H Jeserich M Hornig B Vitamin C improves endothelial dysfunction of epicardial coronary arteries in hypertensive patients.Circulation. 1997; 96: 1513-1519Crossref PubMed Scopus (275) Google Scholar, 8Ting H.H Creager M.A Ganz P Roddy M.A Haley E.A Timimi F.K Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia.Circulation. 1997; 95: 2617-2622Crossref PubMed Scopus (335) Google Scholar As was the case with vitamin E, the ARIC study found that vitamin C slowed the progression of atherosclerosis in men and women >55 years old.3Kritchevsky S.B Shimakawa T Tell G.S Dennis B Carpenter M Eckfeldt J.H Peacher-Ryan H Heiss G Dietary antioxidants and carotid artery wall thickness the ARIC Study.Circulation. 1995; 92: 2142-2150Crossref PubMed Scopus (159) Google Scholar However, the CLAS study did not show any cardiovascular benefit with high intake of supplementary vitamin C.2Hodis H.N Mack W.J LaBree L Cashin-Hemphill L Sevanian A Johnson R Azen S.P Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis.JAMA. 1995; 273: 1849-1854Crossref PubMed Scopus (314) Google Scholar The lipid-phase antioxidant coenzyme Q10 is a free radical scavenger that regenerates vitamin E.1Sies H Stahl W Vitamins E and C, β-carotene, and other carotenoids as antioxidants.Am J Clin Nutr. 1995; 62: 1315S-1321SPubMed Google Scholar It inhibits the oxidation of low-density lipoprotein. In both animal and human models, coenzyme Q10 protects left ventricular function from ischemia reperfusion injury,9Yokoyama H Lingle D.M Crestanello J.A Kamelgard J Kott B.R Momeni R Millili J Mortensen S.A Whitman G.J Coenzyme Q10 protects coronary endothelial function from ischemia reperfusion injury via an antioxidant effect.Surgery. 1996; 120: 189-196Abstract Full Text PDF PubMed Scopus (49) Google Scholar apparently through its antioxidant properties.9Yokoyama H Lingle D.M Crestanello J.A Kamelgard J Kott B.R Momeni R Millili J Mortensen S.A Whitman G.J Coenzyme Q10 protects coronary endothelial function from ischemia reperfusion injury via an antioxidant effect.Surgery. 1996; 120: 189-196Abstract Full Text PDF PubMed Scopus (49) Google Scholar The synthesis of coenzyme Q10 is inhibited by 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors ("statins"). At the present time, although it is a fairly popular (yet expensive) dietary supplement, there are insufficient clinical data to recommend the use of coenzyme Q10 as a cardiovascular agent. Table IPotential Cardiovascular Benefits of NutriceuticalslegendARIC = Atherosclerosis Risk in Communities study; ATBC = Alpha-Tocopherol, Beta-Carotene cancer prevention study; CAD = coronary artery disease;CARET = Carotene and Retinol Efficacy Trial; CHAOS = Cambridge Heart Antioxidant Study; CLAS = Cholesterol Lowering Atherosclerosis Study; EURAMIC = European Community Multicenter Study on Antioxidants, Myocardial Infarction and Breast Cancer; HMG-CoA = 3-hydroxy-methylglutaryl coenzyme A; HPFS = Health Professionals Follow-up Study; HPS = Health Professionals Study; LDL = low-density lipoprotein; LV = left ventricular; M = men; MI = myocardial infarction; NHS = Nurses' Health Study; SHHS = Scottish Heart Health Study; W = women; ZES = Zutphen Elderly Study.NutriceuticalPotential BenefitCautionsVitamin E↓ progression of CAD in M (CLAS)↓ progression of atherosclerosis, M/W >55 yr (ARIC)↓ risk of nonfatal MI (CHAOS)Vitamin C↓ progression of atherosclerosis, M/W >55 yr (ARIC)Coenzyme Q10Protects LV function from ischemic perfusion injurySynthesis inhibited by HMG-CoA reductase inhibitorsBeta carotene↓ risk of CAD (SHHS; NHS; HPFS)↑ risk of lung cancer among smokers (CARET; ATBC) ↑ ischemic heart disease mortality (ATBC)Lycopene↓ risk of MI (EURAMIC)Flavonoids↓ CAD mortality (ZES)↓ CAD mortality in men with previous CAD (HPS)Soybean productsGenistein inhibits thrombus formationRed wineQuercetin may contribute to cardioprotective effectBlueberriesPotential cardioprotective effect on LDLLicorice rootPotent antioxidantHigh intake can cause hypokalemia and hypermineralcorticoidisml-Arginine↑ Coronary and peripheral blood flow27Boger R.H Bode-Boger S.M Thiele W Junker W Alexander K Frolich J.C Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease.Circulation. 1997; 95: 2068-2074Crossref PubMed Scopus (477) Google Scholar, 28Drexler H Fischell T.A Pinto F.J Chenzbraun A Botas J Cooke J.P Alderman E.L Effect of l-arginine on coronary endothelial function in cardiac transplant recipients relation to vessel wall morphology.Circulation. 1994; 89: 1615-1623Crossref PubMed Scopus (125) Google Scholar, 29Lerman A Burnett Jr, J.C Higano S.T McKinley L.J Holmes Jr, D.R Long-term l-arginine supplementation improves small-vessel coronary endothelial function in humans.Circulation. 1998; 97: 2123-2128Crossref PubMed Scopus (380) Google ScholarNo convenient capsule formulation available↓ Angina and intermittent claudication24Cooke J.P Dzau V.J Nitric oxide synthase role in the genesis of vascular disease.Annu Rev Med. 1997; 48: 489-509Crossref PubMed Scopus (652) Google Scholar, 25Cooke J.P Tsao P.S Endothelial alterations in atherosclerosis the role of nitric oxide.in: Webb D Vallance P Endothelial Function in Hypertension. Springer-Verlag, Heidelberg1997: 29-38Crossref Google ScholarMild antiplatelet effectlegend ARIC = Atherosclerosis Risk in Communities study; ATBC = Alpha-Tocopherol, Beta-Carotene cancer prevention study; CAD = coronary artery disease;CARET = Carotene and Retinol Efficacy Trial; CHAOS = Cambridge Heart Antioxidant Study; CLAS = Cholesterol Lowering Atherosclerosis Study; EURAMIC = European Community Multicenter Study on Antioxidants, Myocardial Infarction and Breast Cancer; HMG-CoA = 3-hydroxy-methylglutaryl coenzyme A; HPFS = Health Professionals Follow-up Study; HPS = Health Professionals Study; LDL = low-density lipoprotein; LV = left ventricular; M = men; MI = myocardial infarction; NHS = Nurses' Health Study; SHHS = Scottish Heart Health Study; W = women; ZES = Zutphen Elderly Study. Open table in a new tab There have been >600 naturally occurring carotenoids that have been identified. These substances are fat-soluble plant pigments that provide the bright color of various fruits and vegetables.10Stahl W Sies H Lycopene a biologically important carotenoid for humans?.Arch Biochem Biophys. 1996; 336: 1-9Crossref PubMed Scopus (607) Google Scholar, 11Kohlmeier L Kark J.D Gomez-Garcia E Martin B.C Steck S.E Kardinaal A.F.M Ringstad J Thamm M Masaev V Riemersma R Martin-Moreno J.M Huttunen J.K Kok F.J Lycopene and myocardial infarction risk in the EURAMIC Study.Am J Epidemiol. 1997; 146: 618-626Crossref PubMed Scopus (341) Google Scholar They are transported in the body via lipoprotein.11Kohlmeier L Kark J.D Gomez-Garcia E Martin B.C Steck S.E Kardinaal A.F.M Ringstad J Thamm M Masaev V Riemersma R Martin-Moreno J.M Huttunen J.K Kok F.J Lycopene and myocardial infarction risk in the EURAMIC Study.Am J Epidemiol. 1997; 146: 618-626Crossref PubMed Scopus (341) Google Scholar The singlet oxygen-quenching properties of carotenoids contribute to the prevention of lipid peroxidation.10Stahl W Sies H Lycopene a biologically important carotenoid for humans?.Arch Biochem Biophys. 1996; 336: 1-9Crossref PubMed Scopus (607) Google Scholar The most ubiquitous and thoroughly studied carotenoid is β carotene.1Sies H Stahl W Vitamins E and C, β-carotene, and other carotenoids as antioxidants.Am J Clin Nutr. 1995; 62: 1315S-1321SPubMed Google Scholar The major precursor of vitamin A, β carotene is found in many yellow, orange, and dark green leafy vegetables and in some yellow fruits.12Albanes D Heinonen O.P Taylor P.R Virtamo J Edwards B.K Rautalahti M Hartman A.M Palmgren J Freedman L.S Haapakoski J Barrett M.J Pietinen P Malila N Tala E Liippo K Salomaa E.R Tangrea J.A Teppo L Askin F.B Taskinen E Erozan Y Greenwald P Huttunen J.K Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study effects of base-line characteristics and study compliance.J Natl Cancer Inst. 1996; 88: 1560-1570Crossref PubMed Scopus (752) Google Scholar In the Health Professionals Follow-up Study,5Kwiterovich Jr, P.O The effect of dietary fat, antioxidants, and pro-oxidants on blood lipids, lipoproteins, and atherosclerosis.J Am Diet Assoc. 1997; 97: S31-S41Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar men in the highest quintile of β carotene intake had a significantly lower risk of coronary artery disease than did those in the lowest quintile of intake. In the Nurses' Health Study,13Stampfer M.J Hennekens C.H Manson J.E et al.Vitamin E consumption and the risk of coronary disease in women.N Engl J Med. 1993; 328: 1450-1456Crossref PubMed Scopus (1924) Google Scholar women in the highest quintile of intake had a 22% reduction in risk of coronary artery disease compared with those in the lowest quintile. However, in studies among patients at high risk for lung cancer—Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) and Carotene and Retinol Efficacy Trial (CARET)—high doses of β carotene correlated with an increased risk of lung cancer.12Albanes D Heinonen O.P Taylor P.R Virtamo J Edwards B.K Rautalahti M Hartman A.M Palmgren J Freedman L.S Haapakoski J Barrett M.J Pietinen P Malila N Tala E Liippo K Salomaa E.R Tangrea J.A Teppo L Askin F.B Taskinen E Erozan Y Greenwald P Huttunen J.K Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study effects of base-line characteristics and study compliance.J Natl Cancer Inst. 1996; 88: 1560-1570Crossref PubMed Scopus (752) Google Scholar, 14Omenn G.S Goodman G.E Thornquist M.D Balmes J Cullen M.R Glass A Keogh J.P Meyskens Jr, F.L Valanis B Williams Jr, J.H Barnhart S Cherniack M.G Brodkin C.A Hammar S Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.J Natl Cancer Inst. 1996; 88: 1550-1559Crossref PubMed Scopus (1060) Google Scholar Neither of these studies, nor the Physicians' Health Study, showed a protective effect of β carotene on cardiovascular disease.11Kohlmeier L Kark J.D Gomez-Garcia E Martin B.C Steck S.E Kardinaal A.F.M Ringstad J Thamm M Masaev V Riemersma R Martin-Moreno J.M Huttunen J.K Kok F.J Lycopene and myocardial infarction risk in the EURAMIC Study.Am J Epidemiol. 1997; 146: 618-626Crossref PubMed Scopus (341) Google Scholar Indeed, in ATBC, participants who received β carotene had higher mortality due to ischemic heart disease than did participants who did not receive β carotene.15The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study GroupThe effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers.N Engl J Med. 1994; 330: 1029-1036Crossref PubMed Scopus (4433) Google Scholar The carotenoid lycopene gives tomatoes their red color. Lycopene appears to be a more potent antioxidant than β carotene and may be responsible for many of the cardiovascular attributes originally claimed for β carotene.11Kohlmeier L Kark J.D Gomez-Garcia E Martin B.C Steck S.E Kardinaal A.F.M Ringstad J Thamm M Masaev V Riemersma R Martin-Moreno J.M Huttunen J.K Kok F.J Lycopene and myocardial infarction risk in the EURAMIC Study.Am J Epidemiol. 1997; 146: 618-626Crossref PubMed Scopus (341) Google Scholar In the European Community Multicenter Study of Antioxidants, Myocardial Infarction, and Cancer of the Breast (EURAMIC),11Kohlmeier L Kark J.D Gomez-Garcia E Martin B.C Steck S.E Kardinaal A.F.M Ringstad J Thamm M Masaev V Riemersma R Martin-Moreno J.M Huttunen J.K Kok F.J Lycopene and myocardial infarction risk in the EURAMIC Study.Am J Epidemiol. 1997; 146: 618-626Crossref PubMed Scopus (341) Google Scholar high tissue levels of lycopene were associated with a low risk of myocardial infarction. Lycopene also appears to have protective effects against prostatic and gastrointestinal tract cancer.10Stahl W Sies H Lycopene a biologically important carotenoid for humans?.Arch Biochem Biophys. 1996; 336: 1-9Crossref PubMed Scopus (607) Google Scholar, 11Kohlmeier L Kark J.D Gomez-Garcia E Martin B.C Steck S.E Kardinaal A.F.M Ringstad J Thamm M Masaev V Riemersma R Martin-Moreno J.M Huttunen J.K Kok F.J Lycopene and myocardial infarction risk in the EURAMIC Study.Am J Epidemiol. 1997; 146: 618-626Crossref PubMed Scopus (341) Google Scholar In contrast, low intake of lycopene is associated with macular degeneration.10Stahl W Sies H Lycopene a biologically important carotenoid for humans?.Arch Biochem Biophys. 1996; 336: 1-9Crossref PubMed Scopus (607) Google Scholar There are >4,000 naturally occurring flavonoids found in fruits, vegetables, red wine, and tea, for which they provide color, texture, and taste.5Kwiterovich Jr, P.O The effect of dietary fat, antioxidants, and pro-oxidants on blood lipids, lipoproteins, and atherosclerosis.J Am Diet Assoc. 1997; 97: S31-S41Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 16Formica J.V Regelson W Review of the biology of quercetin and related bioflavonoids.Food Chem Toxicol. 1995; 33: 1061-1080Crossref PubMed Scopus (1545) Google Scholar As free radical scavengers, flavonoids inhibit lipid peroxidation, promote vascular relaxation, and help prevent atherosclerosis.16Formica J.V Regelson W Review of the biology of quercetin and related bioflavonoids.Food Chem Toxicol. 1995; 33: 1061-1080Crossref PubMed Scopus (1545) Google Scholar, 17Hollman P.C.H Katan M.B Absorption, metabolism, and health effects of dietary flavonoids in man.Biomed Pharmacother. 1997; 51: 305-310Crossref PubMed Scopus (516) Google Scholar Various flavonoids have antihypertensive, antiarrhythmic, anti-inflammatory, and antiallergenic properties.16Formica J.V Regelson W Review of the biology of quercetin and related bioflavonoids.Food Chem Toxicol. 1995; 33: 1061-1080Crossref PubMed Scopus (1545) Google Scholar A study in the Netherlands, the Zutphen Elderly Study,18Herrog M.G.L Feskens E.J.M Hollman P.C.H Katman M.B Krombout D Dietary antioxidant flavonoids and risk of coronary heart disease the Zutphen elderly study.Lancet. 1993; 342: 1007-1011Abstract PubMed Scopus (3974) Google Scholar found a strong inverse association between the intake of various flavonoids and coronary artery disease, with a >50% reduction in mortality risk. Similar results were reported in a Finnish study in which participants were followed for 2 years. In the United States, the Health Professionals Study19Knekt P Reunanen A Järvinen R Seppänen R Heliövaara M Aromaa A Antioxidant vitamin intake and coronary mortality in a longitudinal population study.Am J Epidemiol. 1994; 139: 1180-1189Crossref PubMed Scopus (539) Google Scholar found a modest, but not insignificant, inverse association between flavonoid intake and coronary mortality in men with previous coronary heart disease.17Hollman P.C.H Katan M.B Absorption, metabolism, and health effects of dietary flavonoids in man.Biomed Pharmacother. 1997; 51: 305-310Crossref PubMed Scopus (516) Google Scholar Following is a brief discussion of 4 flavonoid-rich food products that may provide cardioprotective benefits. Soy beans are rich in flavonoids, the most prevalent of which, genistein, inhibits thrombus formation.20Potter S.M Soy protein and serum lipids.Curr Opin Lipidol. 1996; 7: 260-264Crossref PubMed Scopus (65) Google Scholar Substitution of soy protein for animal protein in human diets decreases the levels of both total cholesterol and low-density lipoprotein cholesterol. The precise contribution of flavonoids to this effect, however, has not been elucidated.20Potter S.M Soy protein and serum lipids.Curr Opin Lipidol. 1996; 7: 260-264Crossref PubMed Scopus (65) Google Scholar Quercetin, the most common food flavonoid, is found in abundance in red wine.16Formica J.V Regelson W Review of the biology of quercetin and related bioflavonoids.Food Chem Toxicol. 1995; 33: 1061-1080Crossref PubMed Scopus (1545) Google Scholar It has been suggested that quercetin is responsible for the cardioprotective effect of moderate intake of red wine, although ethanol itself may have cardioprotective attributes.16Formica J.V Regelson W Review of the biology of quercetin and related bioflavonoids.Food Chem Toxicol. 1995; 33: 1061-1080Crossref PubMed Scopus (1545) Google Scholar The beneficial effects of quercetin that affect the cardiovascular system include inhibition of platelet aggregation and prevention of oxidative modification of low-density lipoprotein, both of which processes are involved in the development of atherosclerotic lesions. The aqueous extract of Vaccinium myrtillus (blueberry) is rich in antioxidants and exerts a potent protective action in preventing the oxidation of low-density lipoprotein. On a molar basis, Vaccinium myrtillus appears to be a more potent antioxidant than vitamin C.21Laplaud P.M Lelubre A Chapman M.J Antioxidant action of Vaccinium myrtillus extract on human low density lipoproteins in vitro initial observations.Fundam Clin Pharmacol. 1997; 11: 35-40Crossref PubMed Scopus (44) Google Scholar Chinese licorice (Glycyrrhiza glabra) has been used for medicinal purposes for 6,000 years. It has antioxidant, antiplatelet, anti-inflammatory, and antiviral properties. However, high intake of glycyrrhizic acid, the predominant flavonoid-containing component of licorice, can cause hypokalemia and hypermineralocorticoidism, which leads to sodium retention and potassium loss, edema, and increased blood pressure.22Strömer F.C Reistad R Alexander J Glycyrrhizic acid in liquorice evaluation of health hazard.Food Chem Toxicol. 1993; 31: 303-312Crossref PubMed Scopus (179) Google Scholar, 23Vaya J Belinky P.A Aviram M Antioxidant constituents from licorice roots isolation, structure elucidation and antioxidative capacity toward LDL oxidation.Free Radic Biol Med. 1997; 23: 302-313Crossref PubMed Scopus (498) Google Scholar Accumulating clinical evidence indicates that this semi-essential amino acid may be useful in patients with cardiovascular disease. l-Arginine appears to exert its beneficial effect via its metabolism to nitric oxide (NO) and citrulline by the enzyme NO synthase.24Cooke J.P Dzau V.J Nitric oxide synthase role in the genesis of vascular disease.Annu Rev Med. 1997; 48: 489-509Crossref PubMed Scopus (652) Google Scholar NO is the most potent endogenous vasodilator. NO also inhibits key processes involved in atherogenesis, including platelet aggregation, monocyte adherence and infiltration, vascular smooth muscle cell proliferation, and oxidative enzyme activity.25Cooke J.P Tsao P.S Endothelial alterations in atherosclerosis the role of nitric oxide.in: Webb D Vallance P Endothelial Function in Hypertension. Springer-Verlag, Heidelberg1997: 29-38Crossref Google Scholar The NO synthase pathway is impaired in persons with atherosclerotic arterial disease. This appears to be due in part to increased circulating levels of the endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA).26Vallance P Leone A Calver A Collier J Moncada S Endogenous dimethylarginine as an inhibitor of nitric oxide synthesis.J Cardiovasc Pharmacol. 1992; 20: S60-S62Crossref PubMed Scopus (426) Google Scholar ADMA is a competitive antagonist of NO synthase, and its adverse impact can be overcome by the administration of supplemental l-arginine. Administration of l-arginine can improve coronary and peripheral blood flow in humans.27Boger R.H Bode-Boger S.M Thiele W Junker W Alexander K Frolich J.C Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease.Circulation. 1997; 95: 2068-2074Crossref PubMed Scopus (477) Google Scholar, 28Drexler H Fischell T.A Pinto F.J Chenzbraun A Botas J Cooke J.P Alderman E.L Effect of l-arginine on coronary endothelial function in cardiac transplant recipients relation to vessel wall morphology.Circulation. 1994; 89: 1615-1623Crossref PubMed Scopus (125) Google Scholar A recent Mayo Clinic trial29Lerman A Burnett Jr, J.C Higano S.T McKinley L.J Holmes Jr, D.R Long-term l-arginine supplementation improves small-vessel coronary endothelial function in humans.Circulation. 1998; 97: 2123-2128Crossref PubMed Scopus (380) Google Scholar revealed that oral supplementation with l-arginine (9 g/day) improved coronary blood flow response to acetylcholine by 150% and significantly decreased angina in patients with coronary artery disease. Because the dosage of l-arginine required to have a beneficial effect is not convenient to take in the form of capsules (e.g., eighteen 500-mg capsules per day were used in the Mayo Clinic study), we have recently developed an l-arginine–enriched nutrient bar (the HeartBar) that may be a palatable way for patients to incorporate this supplement into their diets. Available evidence suggests that we cannot dismiss the potential value of nutriceuticals in the treatment of cardiovascular disease. To meet the rigorous definition of a nutriceutical as proposed in this article, a candidate agent must be tested in clinical trials, particularly among high-risk groups, under the same rigorous standards applied to more conventional pharmaceuticals before it can be recommended routinely to patients.
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