Natural Plant-derived Ingredients for Hypertension
Plant-based bioactive peptides, such as from peas and flax seed, offer the potential to reduce hypertension. Kelley Fitzpatrick, NutraSolutions content editor, provides an overview of research and mechanisms behind why these compounds work.
January 2012/NutraSolutions -- Coined the “silent killer,” hypertension, or high blood pressure, is a serious risk factor for cardiovascular diseases—but, without any symptoms. Many people are not even aware they have hypertension and the accompanying health risks.
The “Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure,” defines hypertension as systolic blood pressure above 140mmHg and diastolic blood pressure above 90mmHg. Normal blood pressure is below 120mmHg/80 mmHg1.
The disease is responsible for about 13% of deaths in the world, according to the World Health Organization (WHO). In 2008, almost one quarter of all deaths globally, about 13.4 million people, were due to heart disease, stroke or other vascular diseases that may be related to high blood pressure2.
Approximately 19% of adults aged 20-79 in Canada3 and 33% in the U.S. are at risk for hypertension or  high blood pressure with the risk increasing with age4. Over 53% of those between 60-79 years have elevated blood pressure. And, 14% take anti-hypertensive medications, yet their blood pressures are not under control. Even with today’s diagnostic procedures, about 16% of Americans with hypertension are unaware of their condition.
In the WHO report5, “WHO/ISH Hypertension Guidelines,” it was stressed: “Hypertension is a growing cardiovascular risk factor globally, due to the increase in life­span and contributing conditions, such as obesity. Treatments for hypertension are effective in preventing cardiovascular disease and improving quality of life, but hypertension still exists as a significant unmanaged condition.”
In treating hypertension, alternatives to pharmaceutical drugs (that may have toxic or significant side effects) are being investigated. Researchers are exploring a class of compounds called bioactive peptides, which, although they may have less therapeutic effect, would not have the same serious side effects as drugs. An intriguing focus is the beneficial blood pressure lowering properties of peptide fractions contained in flax seed and peas.
These plant products have also been shown to have significant antioxidant, anti-inflammatory and immune system modulating effects.  In addition, flax seed is high in fiber, lignans and the omega-3 fatty acid, alpha-linolenic acid; peas are rich in fiber, minerals and protein7, 8.
Both flax seed and peas contain high-quality essential amino acid profiles and an abundance of branched chain amino acids8, 9. Their bioactive properties lie within the hydrolysate fraction of the protein component.
A number of food-grade techniques, including solubilization, precipitation, enzymatic digestion and ultra-filtration have been developed to produce protein precipitates, which are then converted into hydrolysates8, 9. Hydrolysates are of interest, because they are small enough to bypass digestion in the gastrointestinal tract and, therefore, can be tested for hypotensive and other properties.
Specific hydrolysates derived from flax seed have antioxidant properties in their ability to “quench” damaging free radicals and provide protection against lipid peroxidation9. In particular, sulphur-containing, acidic and hydrophobic amino acids show potent free radical scavenging properties against DPPH and hydroxyl radicals. Hydrolysates rich in the amino acids lysine and leucine appear to be effective scavengers of superoxide radicals9. In subsequent research, flax seed hydrolysate was further purified to contain a high branched chain amino acid content, which yielded potent protection of linoleic acid by scavenging free radicals including superoxide, hydroxyls and 2,2-diphenyl-1-picrylhydrazyl. This hydrolysate blend could be an ideal candidate treatment for individuals with pro-inflammatory conditions13.
With regard to hypertension, work has been conducted with peptides from both flax seed and peas. Blood pressure is controlled through a series of enzyme reactions known as the renin-angiotensin cascade, the most important of which is the Angiotensin Converting Enzyme (ACE). This enzyme converts Angiotensin I to Angiotensin II, which increases blood pressure. It does so by causing constriction of the arteries and stimulating the release of aldosterone from the adrenal cortex; this acts to enhance the kidneys’ salt and water retention. Angiotensin II can also degrade bradykinin, a vasodilator. The ultimate result of these actions is an increase in blood volume and, hence, pressure11, 12. Flax seed protein hydrolysates have been shown to inhibit ACE activity and, therefore, reduce the production of Angiotensin II9.
Flax seed hydrolysates may also positively influence the activity of nitric oxide (NO), an important molecule that regulates vascular tone, neurotransmission and the immune system. Underproduction of NO can cause vasoconstriction and an increase in blood pressure. And, an overproduction of NO can cause oxidative damage and an inflammatory response.
NO is produced by the enzyme nitric oxide synthase (NOS), which is dependent upon the protein calmodulin.  Flax seed hydrolysate fractions have been reported to reduce NOS activity by modifying the structure of calmodulin14. Thus, these hydrolysates may help re-balance an overproduction of NO and reduce the onset of oxidative stress and inflammation.
The physiological benefits of hydrolysates from the protein component of field peas have also been investigated8,17. Pea protein hydrolysates (PPH) were found to reduce the production of several pro-inflammatory molecules, including tumor necrosis factor—alpha (TNF-a) (-35%) and interleukin-6 (IL-6) (-80%). In a mouse model, ingestion of PPH resulted in an increase in the immune regulators immunoglobulin A+, IL-6, IL-4+, IL-10+ and interferon gamma (IFN-y+), which are produced in the gut15. In another study, PPH also protected linoleic acid from oxidation8.
With regard to its hypotensive effects, PPH fractions, like flax seed hydrolysates, have been demonstrated to reduce the two key enzymes responsible for increasing blood pressure, ACE and renin, each by 50%16.
Following the feeding of 100mg or 200mg/kg body weight of PPH, systolic blood pressure was reduced in an animal model of hypertension: the spontaneously hypertensive rat (SHR). The greatest reduction (19mmHg) was seen with the 200mg/kg body weight dose. In contrast, a pea protein isolate had no effect on blood pressure, indicating that bioactivity resides in the hydrolysate fraction17.
The effects of PPH in an animal model of kidney disease have been documented17. Rats were fed diets as follows: a casein control, 0.5% as PPH, or 1.0% as PPH. Reductions in blood pressure were as great as 29 and 25mmHg for systolic and diastolic blood pressure, respectively, in the PPH treatment groups. The decreases were attributable to reductions in Angiotensin II levels and mRNA expression of renin. As noted, renin is responsible for converting the first substrate of the renin-angiotensin cascade; when renin is inhibited, so is Angiotensin II.
In a pilot randomized, double-blinded, placebo-controlled crossover study in seven humans, participants drank either a placebo, 1.5 g/day of PPH or 3.0 g/day of PPH in juice. By the second week, reductions in systolic blood pressure over placebo of 5 to 6mmHg were observed for the 3.0g/day PPH dose17. Larger, multi-center human studies are being planned, in order to strengthen the evidence regarding the hypotensive properties of food protein hydrolysates in humans.
The potential for treating hypertension with natural bioactives from flax seed and field peas is impressive. It may only be a matter of time before control of the silent killer may be possible—through the melding of agricultural and health research innovation. NS

References:
1. Chobanian AV, et al. 2003. Seventh joint committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 42:1206-1252.
2. World Health Organization. 2011. Top ten causes of death. Retrieved September 5th 2011 from: http://www.who.int/mediacentre/factsheets/fs310/en/index.html
3. Statistics Canada. 2010. Blood pressure in Canadian adults. Health Reports. 21(1): 1-10. Catalogue no: 82-003-XPE.
4. National Center for Health Statistics. Health, United States, 2010: With special feature on death and dying. Hyattsville, MD, 2011. Retrieved September 5th 2011 from: http://www.cdc.gov/nchs/data/hus/hus10.pdf#066
5. The World Health Organization. 2011. Cardiovascular disease: WHO/ISH hypertension guidelines. Retrieved September 5th 2011 from: http://www.who.int/cardiovascular_diseases/guidelines/hypertension/en/
6. Aluko RE. 2008. Determination of nutritional and bioactive properties of peptides in enzymatic pea, chickpea, and mung bean protein hydrolysates. J AOAC Int. 91 (4): 947-956.
7. Oomah BD and Mazza G. 1993. Flaxseed proteins – a review. Food Chem. 48:109-114.
8. Pownall TL, et al. 2010. Amino acid composition and antioxidant properties of pea seed (pisum sativum L.) enzymatic protein hydrolysate fractions. J Agric Food Chem. 58:4712-4718.
9. Udenigwe CC, et al. 2009. Kinetics of the inhibition of renin and angiotensin I-converting enzyme by flaxseed protein hydrolysate fractions. J Func Foods I. 199-207.
10. Udenigwe CC and Aluko RE. 2011. Chemometric analysis of the amino acid requirements of antioxidant food protein hydrolysates. Int J Mol Sci. 12:3148-3161.
11. Mahan KL and Escott-Stump, S. 2008. Medical nutrition therapy for hypertension. In Krause’s Food & Nutrition Therapy (pp. 869). St Louis, MO: Saunders Elsevier.
12. Segall L, et al. 2007. Direct renin inhibitors: the dawn of a new era, or just a variation on a theme? Nephrol Dial Transplant. 22:2435–2439.
13. Udenigwe CC and Aluko RE. 2010. Antioxidant and angiotensin converting enzyme-inhibitory properties of a flaxseed protein-derived high Fischer ratio peptide mixer. J Agric Food Chem. 58:4762-4768.
14. Omoni AO and Aluko RE. 2006. Effect of cationic flaxseed protein hydrolysate fractions on the in vitro structure and activity of calmodulin-dependent endothelial nitric oxide synthase.  Mol Nutr Food Res. 50:958-966.
15. Ndiaye F, et al. 2011. Anti-oxidant, anti-inflammatory and immunomodulating properties of an enzymatic protein hydrolysate from yellow field pea seeds. Eur J Nutr. March 27 [epub ahead of print].
16. Li H and Aluko RE. 2010. Identification and inhibitory properties of multifunctional peptides from pea protein hydrolysate. J Agric Food Chem. 58:11471-11476.
17. Li H, et al. 2011. Blood pressure lowering effect of a pea protein hydrolysate in hypertensive rats and humans. J Agric Food Chem. Sep 2. [Epub ahead of print].
 

 

Immune-stimulating Effects of ß-Glucans
Research indicates that ß-glucans derived from oats, yeast and mushrooms play a positive role in modulating the immune system in athletes, allergy sufferers and those who frequently contract colds and the flu. In the following section, contributing editor Stephanie Caligiuri reviews supporting research for these ingredients.
Dietary supplements and food ingredients are being developed to enhance the immune system, the biological processes which provide protection against disease by identifying and destroying pathogens and tumor cells. Colds, which are the most common infection in humans, are a viral immune disease of the upper respiratory system and can result in significant impacts on productivity. A study reported that among 3,249 university students surveyed, 91% had more than one upper respiratory tract infection (URTI) within a 6-month period. The cumulative effects of the URTI were estimated at 6,023 bed days, 4,263 days of missed school and 45,219 days of illness. Academic performance was compromised with 27.8 and 46.3% of the study population reporting less than optimal performance on exams and assignments, respectively, due to illness1.
Allergic rhinitis (inflammation of the nasal passages), also known as hay fever, affects about 8% of adults and 9% of children in the U.S.2. The affliction was reported to be responsible for a decrease in concentration, increased stress, alteration in mood and a decrease in career performance in more than 1,200 healthcare practitioners surveyed3.
Weakening of immune health represents a particular challenge to athletes, because of the physical demands associated with exertion. In particular, reductions in immune-enhancing natural killer T cells, immunoglobulin A, macrophages, neutrophils and monocytes have been observed. These immune system alterations result in athletes being more susceptible to contracting colds and flu4.
Disorders in the immune system can result in more serious diseases, including autoimmune diseases, inflammatory diseases and even cancer. Immunodeficiency diseases occur when the activity of the immune system is compromised.
Natural health products that can selectively stimulate or modulate the immune system in response to pathogens and allergens are being actively investigated. An important focus is the improvement of the quality of life for people with allergies, as well as for those who frequently contract colds or the flu.
Beta-glucans are polysaccharides comprised of the sugar glucose linked by ß-glycosidic bonds. They are most commonly found in oats, barley, baker’s yeast and mushrooms and are being studied for immunomodulating effects. ß-glucans from yeast and mushrooms are linked in the ß-1,3 position, whereas ß-glucans from oats and barley are mostly ß-1,4 and ß-1,3 linkages.
 

ß-glucans From Oats and Yeast
Nieman investigated the potential of oat ß-glucans to improve resting immunity; exercise-induced alterations in immunity; and self-reported URTI in athletes4. Twenty-six male cyclists were randomly assigned to consume either 5.6g/day of oat ß-glucans or a placebo 2 weeks before, during and one day after a 3-day cycling event. Blood was collected at several time points: before and after the 2-week supplementation, immediately after the 3-hour cycling on the third day, and 14 hours after exercise. After analysis of many markers of immunity, including natural killer T cells, interleukin-6, interleukin-10, interleukin-1 and polymorphonuclear respiratory burst activity, no significant differences between the placebo and treatment groups were noted.
In contrast, the supplementation of ß-glucans (ß-1,3 and ß-1,6 linkages) derived from a proprietary trademarked baker’s yeast resulted in an improvement in immunity in athletes5. The trial included 29 men and 31 women who were required to cycle for approximately 49 minutes at 37°C. Significantly greater monocyte and plasma cytokine levels 2 hours post-exercise were reported. Lipopolysaccharide stimulated cytokine production during or post-exercise was also improved. This research suggests that yeast ß-glucans can stimulate the innate and humoral dependent immune system, resulting in a strengthening of defences against pathogens.
In other research, the administration of the proprietary trademarked baker’s yeast ß-glucans at a level of 500mg/day for 12 weeks did not result in significant improvements in the incidence of URTIs6. However, the placebo group missed, on average, 1.38 days of work or school due to colds or flus, whereas the treatment group did not miss any days. Additionally, the treatment group had significantly lower fever and better quality-of-life scores. 
A placebo-controlled, double-blinded study of the same product in 48 individuals subjected to high pollen counts has recently been conducted7. The treatment group received 250mg ß-glucans daily for 4 weeks and showed significantly fewer (and less severe) allergy symptoms at the end of the trial. In particular, the treatment group experienced reductions in nasal- and eye-related allergy symptoms, as well as improvement in their quality of life.

ß-glucans from Mushrooms
Proprietary, trademarked ß-glucans (ß-1,3 and ß-1,6) from mycelia of shiitake mushrooms have been investigated in 42 elderly subjects8. The study was a cross-over, double-blind, placebo-controlled assessment of 2.5mg/day for 6 weeks.  The results showed an increase in the number of circulating B-cells (+0.44%) which are involved in antibody production, compared to placebo (-0.57%). There were no significant differences between other markers of immunity.
Proprietary, trademarked ß-glucans from the mushroom Pleurotus ostreatus  have been examined for immuno-stimulatory effects in a double-blind study of 20 athletes receiving 100mg daily for 2 months9. Natural killer T cells, cytotoxic lymphocytes that play an important role in immune responses to stressors, were measured.  In the placebo group, natural killer T cell activity was reduced by 28% after 20 minutes of exercise, and no decrease was observed in the treatment group. Other immune cell counts were not significantly different between groups.
Beta-glucans derived from oats, yeast and mushrooms appear to play a positive role in modulating the immune system in athletes, allergy sufferers, and those who frequently contract colds and flus. Strengthening the immune system can have significant impact on overall well-being, mood and performance. Further investigation into the effects of ß-glucans extracted from different food sources holds promise in the promotion of health and in the treatment of diseases. NS

References:
1. Nichol KL, et al. 2005. Colds and influenza-like illnesses in university students: impact on health, academic and work performance, and health care use. Clin Infect Dis. 40(9):1253-70.
2. Pleis JR and Lethbridge-Çejku M. 2007. Summary health statistics for U.S. adults: National Health Interview Survey, 2006. National Center for Health Statistics. Vital Health Stat 10 (235).
3. Van Cauwenberge P, et al. 2009. The current burden of allergic rhinitis amongst primary care practitioners and its impact on patient management. Prim Care Respir J. 18(1):27-33.
4. Nieman DC, et al. 2008. ß-glucan, immune function, and upper respiratory tract infections in athletes. Med Sci Sports Exerc. 40(8):1463-71.
5. Carpenter KC, et al. 2011. The effects of yeast ß-glucan supplementation on monocytes and cytokine response to exercise. Biothera News Release.
6. Feldman S, et al. 2009. Randomized phase II clinical trials of Wellmune WGP® for immune support during cold and flu season. J of Appl Res. 9(1,2):30-42.
7. Wellmune WGP®. Presentation by Biothera. Experimental Biology Conference. Washington DC. April 2011.
8. Gaullier JM, et al. 2011. Supplementation with a soluble beta-glucan exported from shiitake medicinal mushroom, Lentinus edodes (Berk.) Singer Mycelium: a crossover, placebo-controlled study in healthy elderly.
9. Bobovčák M, et al. 2010. Effect of Pleuran (ß-glucan from Pleurotus ostreatus) supplementation on cellular immune response after intensive exercise in elite athletes. Appl Physiol Nutr Metab. 35:755-762.