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Optimizing blood pressure with nutritional support.

Hypertension affects about one in three persons in the U.S, and the estimate by the Center for Disease Control (CDC) is that approximately 68 million U.S. adults have high blood pressure (HBP). (1) As a leading risk factor for mortality, HBP accounts for 13.5% of all deaths, (2), (3) and frighteningly, there are often no warning signs or symptoms associated with HBP. Consequently, this disease often goes unrecognized, making it a potentially deadly syndrome. Additionally, according to the CDC, having HBP also raises the risks for other conditions such as heart disease and stroke, (4) which account for the leading causes of death in, the United States.

In addition to pharmacological means, vitamins, minerals and botanicals can also be a beneficial adjunct in the management of hypertension. As well as these, other 'alternative approaches' proven beneficial in supporting the normalization of BP include lifestyle changes, meditation, yoga, and biofeedback. (5)

Vitamins, minerals and other natural products possess properties that beneficially impact blood pressure (BP). Although numerous natural products can beneficially impact BP, this discussion will focus on a combination of the following: Vitamins C, D, and [B.sub.6], magnesium, taurine, biotin, and grape seed extract (CSE), all of which offer beneficial attributes in impacting BP.

Vitamin C functions as a powerful water-soluble antioxidant and it aids in protecting other naturally occurring non water-soluble antioxidants, such as vitamin E, from oxidation. It also serves to maintain the unsaturation/saturation ratio of fatty acids, and is required for the biosynthesis of collagen, L-carnitine, and certain new-otransmitters. (6), (7) Humans, along with certain other animals, lack the enzyme L-gulonolactone oxidase, and consequently are unable to synthesize Vitamin C (ascorbic acid). (8)

In various human controlled clinical trials (epidemiologic, observational, cross sectional and controlled prospective), an inverse correlation between vitamin C intake and plasma ascorbate level, and systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate has been demonstrated. (9) In a review and meta-analysis of clinical trials juraschek, S, et al. noted that short term vitamin C supplementation resulted in reduced levels of both SBP and DBP. (10) Likewise, Kupari M. et al. recognized pulmonary arterial hypertension resulting from scurvy, which they postulated arose as a consequence of the impaired availability of endothelial nitric oxide, and an inappropriate activation of the hypoxia-inducible family (HIF) of transcription factors. (11) HIF coordinates the body's responses to hypoxia, and its activity is regulated by the oxygen-dependent prolyl hydroxylases, which require vitamin C and iron as cofactors. Prolyl-4-hydroxylation is required for oxygen-dependent protein stability of HIFs, and is a necessary component in the structural assembly of collagens. (12) Deficiency of these cofactors may result in uncontrolled HIF activity and pulmonary vasoconstriction, both of which are responsive to vitamin C and iron administration. (11) Furthermore, the synthesis and availability of endothelial nitric oxide is increased by vitamin C.

Even in the absence of deficiency, Vitamin C has a vasodilatory capacity. (13) As noted above, vitamin C and iron are essential cofactors for the prolyl hydroxylase domain enzymes. These enzymes act as oxygen sensors regulating the activity of the hypoxia-inducible family (HIF) of transcription factors. (14) Other studies suggest that vitamin C may help keep arteries flexible. (15)

Vitamin C lowers BP and improves vascular function, thus lowering the risk of heart attack and stroke. Vitamin C can also be beneficial in nervous irritability, and has been demonstrated to improve the production of endothelium-dependent nitric oxide, and reduce monocyte adherence to the endothelium. (13) Moreover, vitamin C has been shown to play a role in vasodilation, and reduce vascular smooth-muscle-cell apoptosis, which prevents plaque instability in atherosclerosis. (16), (17) According to the 2001-2002 National Health and Nutrition Examination Survey (NHANES) study, the mean intake of vitamin C is 105.2 mg/day for adult males and 83.6 mg/day for adult females. (18) In a study by Hajar, I, et al, utilizing 500, 1000 and 2000 mg, they noted no additional benefit in lowering BP with a dose higher than 500 mg of vitamin C per day in mildly hypertensive patients. (19)

Vitamin D regulates calcium absorption and metabolism, and also functions as a prohormone. In this capacity, vitamin D plays an important role in the function of both the vascular system and the kidneys. (20) Atherosclerosis, or hardening of the arteries, is classified as a chronic inflammation of the arterial wall, resulting from the accumulation of white blood cells (macrophages) and lipids (LDL) in the arterial wall. Higher vitamin D levels help direct calcium to the bones and teeth rather than the soft tissues such as the arteries, thus diminishing the potential for atherosclerosis. A deficiency in vitamin D, a largely unacknowledged epidemic, (21) is associated with a risk of cardiovascular disease (CVD), combined with its associated mortality risk. (22), (23), (24) In patients with hypertension, a deficiency in 25(OH)D (37 nmol/L) has been independently associated with cardiovascular events. (25) Vitamin D deficiency has also been indicated as an "independent risk factor for incident arterial hypertension." (26)

One of the major risk factors for hypertension and cardiovascular disease is speculated to be an inappropriate activation of the renin-angiotensin system, (27) which plays a role in the regulation of BP. Renin converts the inactive forms of angiotensin into angiotensin I, which is subsequently converted into angiotension II. Angiotension II acts via AT, and AT, receptors, resulting in constriction of the blood vessels. This action elevates BP, and in turn mediates the generation of free radicals, potentially resulting in tissue injury. (28) It has been demonstrated that 1,25(OH)2D3 suppresses the transcription of the renin gene, in part due to blocking the formation of the cyclic AMP within the enhancer region of the gene promoter. (29) Consequently, vitamin D may function as a potential agent in altering renin production, and subsequently positively impacting BP and cardiovascular health.

Pulse wave velocity (PWV) and left ventricular mass index (LVMI) are two parameters assessed as markers for arterial disease. PWV is considered the "gold standard for non-invasive evaluation of aortic stiffness," (30) while left ventricular hypertrophy, defined by an increase in left ventricular mass index (> 95 g/[m.sup.2] in women and > 115 g/[m.sup.2] in men) is independently associated with an increase in sudden or arrhythmic death, as well as an increase in all-cause mortality. (31) Furthermore, left ventricular hypertrophy (LVH) predisposes patients to organ damage. (32) Kuloglu 0, et al. illustrated that vitamin D levels are independently associated with PWV ([beta] = -0.432, P < 0.001), and LVMI ([beta] = -0.235, P = 0.002). (33) In this study, higher PWV and LVMI values were reported in the low vitamin D group (serum vitamin D <20 ng/mL), compared to the high vitamin D group (serum vitamin D greater [greater than or equal to]20 ng/mL). Vitamin D level in this study was also independently associated with high-sensitivity C reactive protein (hs-CRP) levels, which were higher in patients with vitamin D deficiency, compared to vitamin D sufficient patients ([beta] = -0.143, P = 0.047). hs-CRP is a marker of inflammation, and elevated levels are viewed as a marker of cardiovascular disease.

A higher Vitamin D status has also been correlated to a reduction in arterial calcification, by virtue of its action on processes that are useful for intimal and medial artery calcification. (34) Zittermann A, et al. noted that the involved processes include the release of both pro-inflammatory cytokines and adhesion molecules, as well as the "proliferation and migration of vascular smooth muscle cells (VSMCs)." (34) Like endothelial cells, VSMCs possess an enzymatically active 25-hydroxyvitamin D3-1a-hydroxylase system, (35) which allows for the local synthesis of active vitamin D metabolites.36 Moreover, it has been stated that "cardiovascular functions are impaired in vitamin D deficient states." (36) Both low and high levels of vitamin D are associated with vascular calcification, thus a delicate balance between optimal vitamin D status and excess vitamin D exists. (37) However, it is probable that a beneficial impact can be obtained with supplemental vitamin D, as a high percentage of the population is vitamin D deficient.

Metabolic syndrome is a collection of at least three of the factors that include abdominal obesity, elevated triglycerides ([greater than or equal to]150 mg/dL), low HDL cholesterol ([greater than or equal to]40 mg/dL in men or <50 mg/dL in women), elevated SBP ([greater than or equal to]130 mm Hg), elevated DBP ([greater than or equal to]85 mm ), and elevated fasting glucose ([greater than or equal to]100 mg/dL). It has been demonstrated that a positive correlation exists between these factors and the level of 25(OH)D. (38) A low 25 (OH)D concentration has also been correlated to insulin sensitivity. Specifically, a negative effect on the function of pancreatic 13-cells was demonstrated in conjunction with hypovitaminosis D. (39) In this study, which assessed insulin sensitivity and 3-cell function, with respect to 25(OH)D status, it was noted that 37.3% (47 out of 126) of the participants had low 25 (OH)D concentrations (<20 ng/mL), which was correlated to a "decompensated [beta] cell function," and elevated plasma glucose levels, as compared to those subjects with higher vitamin D levels. This discrepancy was observed regardless of race; Asian American, 47%; African Americans, 54%; White 26%; and Mexican American, 41%, and was highly significant. In this study, an "independent and positive correlation between 25(OH)D and insulin sensitivity index" was also demonstrated. Interestingly, a conservative value of 20 ng/mL was chosen in this study to denote hypovitaminosis D, which is well below the 50 mon indicated by authorities as the level for determining hypovitaminosis D. (40) Thus it is highly likely that the correlation between vitamin D deficiency and metabolic syndrome is much greater. Also, the 60% improvement in insulin sensitivity observed with vitamin D therapy was also a more potent reduction than either metformin (13%) or troglitazone (54%). (41)

Vitamin B6 is required as a component for growth and maintenance of virtually every bodily function. Functionally, it participates in the production of neurotransmitters, fatty acid and hormone metabolism, and in the form of pyridoxal-5-phosphate (P5P), as an important component in the activity of enzymes. In fact, more than one hundred forty enzyme activities are dependent upon P5P. (42) As a dietary component, it is readily available as one of three interconvertible forms; aldehyde (pyridoxal), alcohol (pyridoxine), or amine (pyridoxamie), with the active coenzymes being pyridoxal phosphate and pyridoxamine phosphate. (43)

With respect to the cardiovascular system, vitamin B6 functions in cardiovascular health directly as a consequence of its effects on vascular tissue, (44) and indirectly via its role in the conversion of homocysteine to methionine. (45), (46) Low levels of vitamin B6 have been correlated to increased cardiovascular risk, including the development of atherosclerosis and coronary artery disease. (47) Additional benefits independent of homocysteine metabolism have also been suggested, (48) including the role of P5P-related compounds in redirecting the ischemic myocardium towards glucose oxidation rather than fatty acid oxidation, (49) thereby exerting a cardioprotective role. It has also been speculated that P5P may act in reducing ischemia-reperfusion (I/R) injury, thus resulting in a reduced amount of cardiovascular damage. (50), (51)

Lal KJ and Dakshinamurti K, demonstrated that low levels of vitamin B6, coupled with low levels of calcium, are associated with a significant increase in systolic blood pressure (SBP) in animals. (52) By increasing the dietary level of B6, they demonstrated reduced SBP, as well as an attenuation of the increased SBP induced by a low-calcium diet. In a second animal study utilizing obese animals, the inclusion of a five fold increase in vitamin B6 was demonstrated to completely attenuate hypertension. Similar changes were also observed in the lean control model. (53) Lin PT, et al. reported that in human subjects with low P5P levels (<30 nmol/L) the risk of coronary artery disease was significantly increased, and was further increased with altered lipid profiles. (54) Low plasma levels of P5P were also demonstrated to be "inversely related to major markers of inflammation, and independently associated with increased coronary artery disease (CAD)." (48) Likewise, low plasma levels of P5P have been inversely correlated to the levels of C-reactive protein. (55)

B6 loss can also be accelerated by particular drugs including amphetamines, oral contraceptives, chlorpromazine (a drug used in the treatment of schizophrenia), and resperine (a drug used to treat high blood pressure). An abnormal [B.sub.6] status has been implicated in certain diseases, such as rheumatoid arthritis, perceived to result as a consequence of the inflammatory process. (56)

Biotin is readily available in foods, and is manufactured in vivo by the intestinal microflora. Functionally, biotin participates in the metabolism and utilization of fats, carbohydrates and amino acids. It is also a factor in gene expression by virtue of its role in the expression of nitric oxide. Biotin-dependent cell signaling mechanisms have also been identified. In addition, biotin also has advantageous attributes in normalizing hyperglycemia, and controlling blood glucose, (57), (58) as well as in hypertension.

In studies utilizing the spontaneously hypertensive rat strain, the long-term administration of biotin (3.3 mg/ L) was demonstrated to decrease SBP. (59) A single dose of biotin (0.5 or 5 mg) was also noted to decrease SBP. In addition, biotin also delayed the onset of stroke in this animal strain, and reduced by approximately one-half the percentage of coronary arterial thickening, as compared to the control.

Biotin also plays an important role in the synthesis and generation of nitric oxide (NO), which is a key regulator in many biological processes, including vasodilation, and immune defenses. (60) NO reacts with a vast array of target molecules, which in turn function as mediators in vasodilator actions, smooth muscle relaxation, and pro- and anti-inflammatory reactions. (61) Biotin, in a dose-dependant manner, has been demonstrated to increase the concentration of NO, mediated in part by the biotin-dependent expression of endothelial nitric oxide synthetase (eNOS) and neuronal nitric oxide synthase (nNOS).6I Specific therapeutic regimens, such as the use of anticonvulsants or lipoic acid, may increase the need for biotin. (62)

Although Magnesium (Mg) is widely available in the food supply, deficiencies are very prevalent in the general population. In vivo, greater than three hundred metabolic reactions require Mg as a cofactor. As examples, Mg is required for energy production, oxidative phosphorylation, and glycolysis. (63) An additional action of Mg is the role it plays in the active transport of both calcium and potassium ions across the cell membrane. This process plays an important role in nerve impulse conduction, muscle contraction, normal heart rhythm, (64) and chronic inflammation. (65) In relation to BP, a dose dependent reduction in BP has been observed with Mg supplementation. (66)

In animal studies, Mg deficiency results in an elevation of blood lipids and proliferation of the smooth muscles. (37) A separate study noted a significantly higher SBP, DBP, and mean BP in Mg-deficient rats, assessed at nineteen weeks on a Mg-deficient diet, as compared to control (P<0.05). The increase in BP in this study was also associated with an increase in arterial stiffness and an accelerated age-dependent decrease in arterial distensibility. (68) Musso CG noted that an altered Mg balance is correlated with "diabetes mellitus, chronic renal failure, nephrolithiasis, osteoporosis, aplastic osteopathy, and heart and vascular disease." (69) Added to this Joffres, MR, et al. noted that Mg users had lower SBP and DBP; an average of 4rninHg lower for SBP and 1.2mmHg lower for DBP (p=0.03 and p-0.04, respectively). (70) In this same study, total Mg intake was also noted as the "nutrient with the strongest inverse association with BP."

Users of supplemental Mg typically have higher levels of Mg as compared to food alone, noted in one study as 1.31 times greater in men and 1.14 times greater in women (71) (350 mg in men, 267 mg in women in the supplemental group; 268 mg in men, 234 mg in women in the non-supplemented group). A consumption of Mg lower than the estimated average requirement (EAR), estimated in approximately 60% of the adult population, has also been associated with a "signif-icantly higher BMI and plasma C-reactive protein concentration." (72) The association of low Mg status with an increased level of "chronic inflam-matory stress" has also been suggested. (65) This association could be improved with increased Mg intake. A negative effect on Mg status has been observed with the use of thiazide diuretics, (73), (74) demonstrated to correlate with premature ventricular contractions. When combined with other synergistic nutritional components, a dose of 87 mg, as Mg ascorbate, was observed to have a significant effect in normalizing BP. (75)

Grape Seed Extract (GSE) is a complex mixture of highly concentrated polyphenols, (76) including trans-resveratrol, oligomeric proanthocyanidins (OPCs), and flavonoid compounds. Extensive antioxidant activity has been demonstrated in human studies with grape or grape constituents. These antioxidant activities include an increase in total antioxidant capacity, reduced levels of oxidation products, and increased levels of erythrocyte glutathione reductase and plasma ascorbate. (77) it is primarily due to these antioxidant properties that products containing these extracts are candidate therapies for a wide range of human diseases. Although the medicinal value of grapes has been recognized since the days of the ancient Egyptians, renewed interest in these compounds has recently occurred, principally due to the health-promoting benefits of resveratrol. (78) Consequentially, GSE is recognized as being therapeutically beneficial for a broad range of human conditions, but particularly for cardiovascular health.

Late in the 20th Century, an inconsistency termed the "French Paradox," was recognized in French men. This paradox noted the apparent cardioprotective effects of red wine in this population, even with the consumption of a high fat diet, thus spurring an interest in the possible association of wine and grape constituents, and the reduction in cardiovascular health complications. A number of studies have demonstrated the numerous benefits of these grape-derived coin, pounds, including reduced oxidative stress and inflame-mation, inhibition of platelet aggregation, resultant blood vessel dilation and improvement in endo-thelial dysfunction. (79), (80), (81) In a meta-analysis of nine randomized, controlled trials (N=390), Feringa HH, et al. noted a significant lowering of SBP, and heart rate with grape seed extract (150-2,000 mg). (82)

Grapes have been demonstrated to possess antioxidant and lipid-lowering benefits, both in vivo and in vitro. Grape seed also possesses anticoagulant (83), (84) and antiplatelet (85), (86) properties. Of the polyphenolic compounds in grapes, greater than 70% is concentrated in the seed. (87) Grape seed extract (GSE) has been used by integrative practitioners in Europe to treat venous insufficiency, promote wound healing, to alleviate inflammatory conditions, and as a "cardioprotective" therapy. In Ayurvedic medicine, grape is the primary ingredient in the herbal preparation "Darakhasava", which is typically used as a cardiotonic. (88) Overall, grape OPCs appear to be well tolerated, with few side effects reported in the literature.

Another beneficial property of GSE is its function in the regulation of nitric oxide release. Nitric oxide plays a physiological role in cardiovascular function as a "modulator of vascular relaxation". (89) Shao ZR, et al. demonstrated that grape seed proanthocyanidin extract (GSPE), attenuated ischemia/reperfusion-induced cell death (p<0.001), increased the release of nitric oxide, and restored cardiac contractility in an animal model. Specifically, GSE protected cardiomyocytes from ischemia/reperfusion (1/R) injury, via an increased production of NO during reperfusion. (90) NO also functions to modulate an excess generation of reactive oxygen species (ROS). GSE has also been demonstrated to exhibit radical-scavenging activity, to prevent oxidative damage, and to increase both erythrocyte glutathione reductase and antioxidant enzymes. (91), (92), (93)

Taurine is an inhibitory neurotransmitter, and a conditionally essential amino acid that participates in various metabolic processes, including bile acid conjugation, xenobiotic detoxification, membrane stabilization, osmoregulation, neuromodulation, and in the modulation of cellular calcium levels. (94) Taurine has also been demonstrated to have protective benefits in hypertension, (95) and metabolic syndrome, (96) as well as provide benefits for stroke, and atherosclerotic diseases. (97), (98), (99) In fact, in animal studies utilizing the stroke-prone spontaneously hypertensive rat (SHRSP), taurine intake was demonstrated to decrease the incidence of stroke from eighty percent (80%) to ten percent (10%). (100), (101) In data evaluated from the Cardiovascular Disease and Alimentary Comparison Study (CARDIAC), taurine and magnesium were demonstrated to be negatively associated with mortality from ischemic heart disease in a Japanese population. (102) Taurine was also demonstrated to reduce cardiovascular disease (CVD) risks, and contribute to longevity.

Myeloperoxidase (MPO) is a highly prevalent phagocytic enzyme, which has been implicated in the pathogenesis of various inflammatory diseases including atherosclerosis. As a result of its phagocytic action, MPO produces the oxidant product hypo-chlorous acid (HOCI). As an oxidant, HOC] has the ability to modify a great variety of biomolecules via the process of chlorination and/or oxidation. (103) Taurine was demonstrated to offer cellular protection against HOCI by readily reacting with this molecule and forming taurine chloramine, which in turn participates in neutralizing the radical's adverse affect. (104) Consequently, taurine is speculated to aide in vascular cell survival, or in the regeneration to repair the vascular wan. (105), (106) By controlling inflammation, taurine is speculated to be an important factor in stroke prevention.

Taurine functions as a major osmolyte in the renal medulla, (107), (108), (109) which was evident in a study utilizing the salt-sensitive hypertensive rat strain. In this study taurine was associated with the suppression of elevated levels of plasma epinephrine and norepinephrine, presumed to be linked with its anti-hypertensive action. Taurine was also demonstrated to influence renal vascular resistance. (111), (112), (113)

In addition to the functions noted above, taurine also participates in the activity of NO synthase, (114) and is involved in the generation of nitric oxide, as evidenced by an increase in serum nitric oxide (NO) levels with supplementation. In hypertensive-prone Kyoto rats taurine administration was demonstrated to ameliorate hypertension. (115) Additionally, taurine has an influence on blood flow within capillaries, vesicles, and arterioles, via multiple mechanisms, including the NO synthase activity, the renin-angiotensin system, and vascular tone. It also plays a role in the rheology (flow) of erythrocytes. (116), (117), (118)

The tailored combination of vitamins, minerals and botanicals, as discussed above, offers a comprehensive and beneficial approach in the management of hypertension. Since the vascular epithelium is considered a metabolically active organ, possessing endocrine, paracrine, autocrine and intracrine functions, (119) optimizing these functions can assist in optimizing blood pressure. The synergistic effect of these nutrients assists in improving both prehypertension and hypertension, thus aids in improving overall health.


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by: Rachel Olivier, MS, ND, PhD
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