Importance of Flaxseed and its Components in the Management of Hypertension

Abstract

This review paper describes the effects of flaxseed and its components (flax oil, secoisolariciresinol diglucoside [SDG], flax lignan complex [FLC], and flaxseed protein hydrolysate [FPH]) on blood pressure (BP) in Sprague Dawley rats (SDR), spontaneously hypertensive rats (SHR), and humans. Flaxseed, flax oil, and FLC had variable effects on BP in humans, while SDG and FPH significantly reduced the BP in SDR and SHR. The effect of SDG was dose-dependent and long lasting. The lowering of BP is mediated through inhibition of soluble epoxide by α -linolenic acid in flax oil, stimulation of guanylate cyclase and inhibition of angiotensin converting enzyme (ACE) by SDG, and inhibition of renin and ACE activity by FPH. Flaxseed, flax oil, and FLC have variable effects on BP (none, slight, and significant). They are effective in lowering BP in individuals with hypertension and metabolic syndrome but ineffective in healthy individuals' ineffectiveness of flaxseed and its compounds in lowering BP may be due to their low doses, long interval of dosing, short duration of consumption, and patient status. In conclusion, the data at present suggest that flaxseed, flax oil, and FLC cannot serve as therapeutic agents for the treatment of hypertension. However, they can be used as an adjunct in the treatment of hypertension. A clinical trial should be conducted of these agents with higher doses which would be given twice daily for long duration. Pure SDG and FPS may serve as therapeutic agents for the treatment of hypertension but they have not been tried in humans.

According to the Joint National Committee 7 (JNC-7) guidelines, hypertension (HTN) is defined as the arterial pressure of 140/90 mm Hg and greater. ¹ Recent guidelines of HTN has changed. ² Stage 1 HTN is 130/80 mm Hg to 139/89 mm Hg. Stage 2 HTN is 140/90 and higher. The global prevalence of HTN is 40%, while it is 46% in African population. ¹ Based on recent guidelines, the prevalence of HTN among U.S. adults is 45.6%, while it is 31.9% based on JNC-7 guidelines. ² Hypertension is a well-known risk factor for cardiovascular and renal diseases and also stroke. ³ It is one of the leading causes of global burden of diseases. ⁴ Hypertension is the greatest risk factor for global mortality. Approximately half of 17 million cardiovascular deaths worldwide are accounted for HTN. ⁵ The cost of antihypertensive treatment in Canada alone in 2006 was $3 billion. A search for cost-effective medication for management of hypertension is on. Flaxseed is grown in Asia, Australia, Europe, and North, Central, and South America. Many of these countries are low to middle income. Hypertension control together with reduction in other risk factors (diabetes, dyslipidemia, and smoking) would be an ideal approach to prevent atherosclerotic diseases. However, this poses a major challenge especially in the low and middle income population. Flaxseed and its components have been shown to reduce the blood pressures (BPs) in animal and humans. ^{6 7 8 9} Flaxseed and its components may prove to be a potent agent in the management of hypertension either alone or in association with other commercially available drugs. Prescriptions and expenditures for cardiovascular medications have escalated in Canada and has reached to an unsustainable levels. ¹⁰ The flaxseed and its components may be cheap and with little and no adverse effects. This review highlights the components of flaxseed and their effects on the BP in both animal model and humans with or without hypertension. This review also discusses the dosing of flaxseed and perspectives of management of hypertension with flaxseed and its components.

Flaxseed and its Components

Flaxseed is composed of enterolignan precursors, primarily secoisolariciresinol diglucoside (SDG), fibers, and oil. It comprises 32 to 45% of its mass as oil of which 51 to 55% is α -linolenic acid and 15 to 18% is linoleic acid. ^{11 12} Flax meal, which is devoid of oil, is approximately 55 to 68% of total mass of flaxseed, and contains approximately 16.4 mg/g of SDG. ¹³ Another compound called flax lignan complex (FLC) has been isolated from flaxseed ¹⁴ which contains SDG (34–38%), cinnamic acid glucoside (15–21%), and hydroxymethylglutaric acid (9.6–11.0%) by weight. The SDG content of flaxseed varies between 0.6 and 1.6 g/100 g. ¹⁵ Besides the above ingredients, flaxseed also contains dietary fiber (25–28%), protein, carbohydrate, water, and ash. ^{16 17} Brown and gold variety of flaxseed has some differences. There is a lower amount of fiber but higher amount of soluble carbohydrates in the golden flaxseed than in the brown variety. ¹⁸ Golden variety of flaxseed has greater amount of omega-3 and omega-6, while brown variety of flaxseed has greater antioxidant activity. ¹⁹ Flaxseed is a rich source of α -linolenic acid (omega-3 fatty acid) and the richest source of plant lignans. ^{20 21}

Flaxseed and Blood Pressures

The effects of flaxseed on BP will be discussed in parts: animal models and humans.

Effects of Flaxseed in Animal Models

Ingram et al ²² have reported that renal ablation increased the arterial pressures in Sprague Dawley rats. Flaxseed diet (15% flaxseed in regular diet) in renal ablated rats prevented the rise arterial pressures markedly at 10 weeks (165 ± 22 vs. 149 ± 0.4 mm Hg) and at 20 weeks (176 ± 22 vs. 158 ± 21 mm Hg). They did not explore the mechanisms of attenuation of BP with flaxseed. However Talom et al ²³ showed that high flaxseed diet did not reduce the BP in spontaneously hypertensive rats (control, 157 ± 3 mm Hg vs. high flaxseed diet, 153 ± 3 mm Hg) or in Wistar Kyoto rats (Control, 114 ± 2 mm Hg vs. high flaxseed diet, 117 ± 2 mm Hg). 10% flaxseed diet has been reported to completely normalize the relaxation response to nitroprusside in high cholesterol fed rabbits. ²⁴

Flaxseed and Arterial Pressures in Humans

Stuglin and Prasad ⁶ were first to demonstrate that consumption of flaxseed in the dose of 30.7 g/day for 4 weeks by young adults (22–47 years) with no history any disease did not significantly alter the systolic (124.0 ± 2.82 vs. 122.8 ± 2.25 mm Hg) and diastolic (78.3 ± 2.17 vs. 79.5 ± 1.87 mm Hg) pressures. Heart rate was not affected by flaxseed. Consumption of flaxseed (40 g/day) reduced the systolic and diastolic pressures by 3.8% and 5.3%, respectively, in menopausal women. ²⁵ Caligiuri et al ²⁶ in a randomized, double blinded, controlled clinical trial in 110 patients (75% hypertensive) with peripheral arterial disease showed that consumption of flaxseed in the dose of 30 g/day for 6 months reduced the systolic pressure by 7.97 mm Hg (range: 1.5–14.4 mm Hg). The changes in the diastolic and mean arterial pressures were not significant. In a prospective double blinded, placebo controlled, randomized clinical trial in 110 patients with peripheral arterial disease, Rodriguez-Leyva et al ⁹ reported that consumption of flaxseed in the dose of 30 g/day for 6 months reduced the systolic pressure by approximately 10 mm Hg and diastolic pressure by 7 mm Hg. They also reported that the reduction in systolic and diastolic pressure were respectively 15 mm Hg and 7 mm Hg in hypertensive patients. In this series of patients 80% of patients used antihypertensive drugs. Flaxseed consumption reduced the use of antihypertensive drugs by 8%. The reduction of use of antihypertensive medication in patients who did not consume flaxseed was 3.5%. In this situation it becomes difficult to say if the effects of flaxseed were independent use of antihypertensive medications. It would be important to investigate the effects of flaxseed in hypertensive patients without peripheral vascular disease and without antihypertensive medication. Wu et al ²⁷ in a randomized controlled trial of 283 patients with various clinical features (current smokers, 28.7%; alcohol use, 64%; antihypertensive drugs, 36%; hypertension, 57.5–64.2%; antidiabetic drugs, 3.2%, and aspirin, 6.4%) reported that flaxseed consumption for 12 weeks. significantly reduced the systolic and diastolic pressure by 8.8 mm Hg (range: 6.6–11.0 mm Hg) and 5 mm Hg (range: 3.7–6.3 mm Hg), respectively. There were significant reductions in the systolic (7.7 mm Hg, range: 4.5–9.5 mm Hg) and diastolic (4.4 mm Hg, range: 3.1–5.8 mm Hg) pressures in patients without flaxseed treatment. However, the reduction in the systolic and diastolic pressures was not significantly different between the two groups. The data of this study suggest that flaxseed did not alter arterial BP.

There are two major meta-analyses of numerous data related to the effects of flaxseed on arterial pressures. Khalesi et al ²⁸ performed the meta-analysis of 11 studies (14 trial) to assess the effects of flaxseed on the BP in humans. Four out of 11 studies used whole or ground flaxseed. Each three other studies out of 11 used flaxseed oil or flaxseed lignin. They reported that flaxseed supplement of 30–50 g/day for various durations (3–48 weeks) reduced systolic and diastolic BP by 1.77 mm Hg and 1.588 mm Hg, respectively. They also showed that the reduction in systolic pressures was more in patients with pressures ≥ 130 mm Hg. The reduction in the diastolic pressure was by 1.93 mm Hg. They also reported that duration of consumption of flaxseed over 12 weeks produced slightly more reduction in diastolic pressure. They concluded that flaxseed may reduce blood pressure slightly. They concluded that there is a slight reduction in BP with flaxseed and that reduction in BP, especially diastolic pressures may be greater when used as a whole seed and for duration greater than 12 weeks. Ursoniu et al ²⁹ performed meta-analysis of 15 controlled clinical trials in 1,302 patients who consumed flaxseed supplements (flaxseed powder, flaxseed oil, and flax lignan extracts). They reported that flaxseed supplements reduced systolic pressure by 2.85 mm Hg and diastolic pressure by 2.39 mm Hg. Stratification with duration, they found that consumption of flaxseed products for 12 weeks or more reduced the systolic and diastolic pressure by 3.10 mm Hg and 2.62 mm Hg, respectively. The consumption of flaxseed for less than 12 weeks, the reduction in systolic and diastolic pressures were 1.60 and 1.74 mm Hg, respectively. When the effects of flaxseed on BP were categorized with type of flaxseed products, it was observed that flaxseed reduced the systolic blood pressure significantly (1.81 mm Hg) but not oil (4.6 mm Hg) and lignin extract. ²⁹ Diastolic pressure was reduced significantly with flaxseed powder (−1.28 mm Hg) and oil (−4.10 mm Hg). Lignan extract did not reduce diastolic pressure significantly. They concluded that flaxseed products reduce the systolic and diastolic pressures but the reduction in pressures do not seem great.

Flax Oil and BP

Effects of flax oil on BP are divided into two classes: animal and human studies.

Effects of Flax Oil on BP in Experimental Animals

There are quite few papers on the effects of flaxseed oil on BP in spontaneous hypertensive rats (SHR). Hoffman and Förster ³⁰ reported that dietary linseed oil (flaxseed oil) rich in α -linolenic acid reduced the arterial pressure in SHR. Ogawa et al ³¹ showed that 10% flaxseed oil in diet administered for 4 weeks reduced the systolic pressures by 11 mm Hg in SHR. Angiotensin converting enzyme (ACE) activity was significantly lower in in this group suggesting that the BP lowering activity of flaxseed oil may be mediated through ACE pathway. Diet containing 2.5% linseed oil reduced the systolic BP by 6.3 mm Hg in SHR. ³² High dose of linseed oil in diet (10% oil in diet) reduced the systolic pressures markedly by 59 mm Hg within first 30 days in SHR. ³³ Sekine et al ³⁴ reported that systolic BP was reduced by 14 mm Hg at 4 hours after oral administration of 1 mL of flaxseed oil in SHR. They also reported that this effect was associated with increases in prostaglandin I metabolites, nitric oxide metabolites, and bradykinin. It is known that plasma levels of bradykinin are elevated in with α -linolenic acid. ³⁴ Bradykinin increases calcium ions with subsequent of constitutive cyclooxygenase-1 and nitric oxide synthase-3. ³⁵ Ogawa et al ³¹ showed that diet containing 10% flaxseed oil significantly reduced the systolic BP at 2, 3, and 4 weeks by 8, 18, and 11 mm Hg, respectively, in SHR rats. Reduction in systolic BP (SBP) was associated with reduction in ACE activity and ACE mRNA (messenger ribonucleic acid) expression levels in aorta suggesting that antihypertensive effect of flaxseed oil may be due to reduction in ACE levels in aorta. These data suggest that flaxseed oil reduces systolic BP markedly and the decreases in pressure are dose dependent. The data also suggest that the reduction in BP may be mediated through reduction in ACE and increases in prostaglandin I and nitric oxide.

Flaxseed Oil and Arterial Pressures in Humans

Epidemiological study show that dietary alpha-Linolenic acid (ALA) (1.0 g/day) is associated with lower prevalence of hypertension and lower systolic pressure. ³⁶ Tsukamoto and Sugawara ³⁷ reported that following adjustment for age, body mass index, lifestyle, and serum glucose and HbA1c, higher quartile of serum ALA were significantly associated with lower prevalence of hypertension. They showed that 3.3 times increase in mean ALA (from 15–21 mol%) decreased the prevalence of hypertension to 39%. The data showed that elevated levels of ALA in plasma prevented development of hypertension. The effects of flaxseed oil on BP are variable. Consumption of 1.2, 2.4, and 3.6 g of flax oil/day for 12 weeks did not affect systolic or diastolic BP significantly in firefighters. ³⁸ Schwab et al ³⁹ investigated the effects of flaxseed oil on the BP in healthy volunteers, aged between 25 and 60 years. They showed that administration of flaxseed oil (30 mL/day) for 4 weeks did not alter the systolic or diastolic BP. However, Takeuchi et al ⁴⁰ reported that flaxseed oil (ALA 2.6 g/day) for 12 weeks reduced the systolic and diastolic pressures significantly in individuals with high normal and mild hypertension. Singer et al ⁴¹ also reported that linseed oil reduced the systolic BP in patients with mild hypertension. ALA rich diet has been shown to reduce the diastolic BP by 4 mm Hg in hypercholesterolemic subjects. ⁴² Paschos et al ⁴³ showed that consumption of flaxseed oil rich in ALA (8 g/day) for 12 weeks significantly reduced the systolic, diastolic, and mean BP by 3.1, 6.3, and 6.0 mm Hg, respectively, in dyslipidemia subjects. The consumption of low dose of flaxseed oil (2.2 g ALA/day) and high dose flaxseed oil (6.0 g/day) for 8 weeks, did not produce any significant change in the systolic or diastolic pressure in patients with metabolic syndrome. ⁴⁴ Nestel et al ⁴⁵ reported that administration of flaxseed oil (20 g/day) to obese adults with insulin resistance significantly reduced the systolic, diastolic, and mean arterial pressures. It has been also shown that total levels of α -linolenic acid is inversely associated with BP. ⁴⁶ Berry and Hirsch ⁴⁷ have reported that a 1% increase in serum α -linolenic acid is associated with a decrease in 5 mm Hg in systolic, diastolic, and mean arterial pressures.

These data suggest that the effects of flaxseed oil are variable. It lowers BP in patients with hypertension, dyslipidemia, and metabolic syndrome. However, it is ineffective in healthy subjects. The data also suggest that α -linolenic levels in the blood is inversely associated with the BP.

Secoisolariciresinol Diglucoside (SDG) and BP

Prasad ⁸ investigated the effects of various intravenous doses (3, 5, 10, 15, 20 mg/kg) of SDG on the arterial pressures of anesthetized Sprague Dawley rats. He observed that maximum drop in the systolic, diastolic, and mean arterial pressures, at 15 minutes after administration, were 32, 41, and 40% with 10 mg/kg; 34, 44, and 41% with 15 mg/kg; and 40, 48, and 43% with 20 mg/kg, respectively.The pressures tended to recover after 15 minutes but did not recover to the pretreatment level even after 4 hours. The systolic, diastolic, and mean arterial pressures, at the end of 4 hours, were 32, 36, and 33% lower with 10 mg/kg; 15, 24, and 22% lower with15 mg/kg; and 20, 33, and 29% lower with 20 mg/kg, respectively, of SDG compared with the pretreatment levels. The drop in the BP with 10, 15, and 20 mg/kg of SDG were similar suggesting that even 10 mg/kg was maximum dose. Lower doses (3 and 5 mg/kg) of SDG reduced the systolic, diastolic, and mean arterial pressures markedly, and the response was dose-dependent. Prasad ⁸ reported that the hypotensive effects of SDG is not due to stimulation of nitric oxide (NO) synthase because the hypotensive effect was not blocked by N ^G -monomethyl–L-arginine (L-NMMA), an inhibitor of NO-synthase. ⁴⁸ He demonstrated that the hypotensive effects of SDG is due to stimulation of guanylate cyclase activity. Prasad ⁷ also reported that SDG-induced hypotension is mediated through inhibition of angiotensin-converting enzyme.

These data suggest that pure SDG isolated from flaxseed markedly reduces systolic, diastolic, and mean arterial pressures and decreases in pressures are dose-dependent. The effects of oral pure SDG on arterial pressure in rats and humans have not been tested. The data also suggest that the hypotensive effects of SDG are mediated through stimulation of guanylate cyclase activity and through ACE inhibition.

Flax Lignan Complex and Blood Pressures

In Humans

FLC, as mentioned earlier, contains SDG (34–38%), cinnamic acid glucoside (15–21%), and hydroxymethylglutaric acid (9.6–11.0%) by weight. The effects of FLC on arterial pressures are variable, no effect or reduction in BP. In a double-blind, randomized, crossover, placebo-controlled study on type 2 diabetic patients, Barre et al ⁴⁹ reported that FLC (equivalent to 600 mg SDG/day for 3 months) did not significantly altered the systolic (133.6 ± 4.8 vs. 124.4 ± 4.7 mm Hg; p  = 0.805) and diastolic (82.1 ± 1.9 vs. 74.9 ± 3.2 mm Hg; p  = 0.112) pressures. In another study, Viveky et al ⁵⁰ reported that FLC (equivalent to 300 mg SDG/day) for 6 months administered to older adults did not change systolic (122.1 ± 16.0 Vs. 125.9 ± 15.3 mm Hg), and diastolic (75.6 ± 10.3 vs. 79.3 ± 12.0 mm Hg) pressures. In a randomized, double-blind, placebo-controlled, crossover trial, Pan et al ⁵¹ reported that administration of FLC extract (equivalent to 300 mg SDG/day) for 12 weeks to Chinese patients with type 2 diabetes did not significantly alter the systolic (139.3 ± 21.4 vs. 138.9 ± 19.9 mm Hg, absolute change, 0.4 ± 18.7 mm Hg) and diastolic (79.2 ± 10.7 mm Hg vs. 77.7 ± 9.5 mm Hg, absolute change, 1.5 ± 6.7 mm Hg). Cornish et al ⁵² in a randomized, double-blind, placebo controlled study investigated the effects of FLC 4,050 mg containing 543 mg SDG/day for 6 months in older adults with walking exercise. They found no difference in the systolic BP between flax lignan treated group and control (130 ± 3 vs. 130 ± 3 mm Hg in male; 128 ± 3 vs. 128 ± 3 mm Hg in female). However, there was a significant decrease in diastolic BP with the lignan complex (88.7 ± 2.8 vs. 82.0 ± 2.8 mm Hg) in subgroup of patient's metabolic syndrome. There was no change in in the diastolic pressure in the placebo group. In a randomized, double-blind, placebo-controlled crossover study, Hallund et al ⁵³ demonstrated that FLC providing SDG 500 mg/day for 6 weeks did not change the systolic (−2.0 ± 9.2 mm Hg; p  = 0.799) and diastolic (−2.0 ± 9.2 mm Hg; p  = 0.642) pressures in healthy postmenopausal women. The dose of 500 mg/day corresponds to approximately 21 to 42 g defatted flaxseed or 38 to 82 g whole flaxseed. ⁵⁴ Billinsky et al, ⁵⁵ in a randomized, double-blind clinical trial, reported that FLC (Beneflax, 543 mg/day of SDG) for 6 months did not produce any significant alteration in systolic (127 ± 12 vs. 127 ± 14 mm Hg) and diastolic (81 ± 8 vs. 80 ± 9 mm Hg) pressures. However, Di et al ⁵⁶ observed that administration of FLC (38% SDG content, 600 mg/day) for 6 months to older healthy adults significantly reduced the systolic BP (155 ± 13 vs. 144 ± 10.3 mm Hg) at 24 weeks.

In Experimental Animals

Park and Velasquez ⁵⁷ showed that 0.02% SDG lignan-enriched flaxseed powder (FLC containing 35% SDG) in diet for 12 weeks did not affect the systolic BP under control diet; however, it reduced the systolic pressure by 45% in high fat fed rats in the last 4 weeks of duration of feeding. FLC did not reduce the diastolic pressure.

The data suggest that systolic pressure was unaffected with FLC in most of the studies, except in one case where the patient population were hypertensive. ⁵⁶ The diastolic pressure was unaltered with FLC in most of the studies except patient with metabolic syndrome and that also in female group. ⁵² The data suggest that FLC is effective in lowering systolic pressure in hypertensive patients and not in normotensive population. Diastolic pressures are reduced in diseased persons but not in healthy subjects. In animal study, FLC was effective in lowering systolic BP in high fat fed rats but not in control rats. Diastolic pressure was not altered by FLC.

Flaxseed Protein and Blood Pressures

Flaxseed and its defatted flax meal contains high amount of protein. ¹¹ The protein content of flaxseed no. 1 Canada western ranges between 19.4 and 30.8% with a mean of 24.3%. ⁵⁸

Udenigwe et al ⁵⁹ investigated the effects of flaxseed protein hydrolysate (FPH) given orally in the dose of 200 mg/kg body weight to spontaneously hypertensive rats on systolic BP. They reported that systolic BP decreased significantly (−17.9 and −11.7 mm Hg, respectively) after 2 hours of administration of flaxseed hydrolysate. Doyen et al ⁶⁰ have also reported that flaxseed protein isolate (200 mg/kg, body weight, orally) reduced the systolic pressure by 27 mm Hg in spontaneously hypertensive rats. Udenigwe et al ⁶¹ investigated the mechanism of reduction in BP by flaxseed protein hydrolysate. They reported that flaxseed protein hydrolysate that contains peptide amino acid sequences, inhibited the activity of ACE and renin. The data suggest that hypotensive effects of flaxseed protein hydrolysate is mediated through inhibition of renin a ACE activity. This compound is very effective in lowering BP but has not been tried in humans.

Mechanism of Hypertensive Effects of Flaxseed and Its Components

There appears to be numerous mechanisms by which flaxseed and its components may reduce BP. Caligiuri et al ²⁶ have reported that hypotensive effects of flaxseed is mediated through reduction in oxylipins by α -linolenic acid-induced inhibition of soluble epoxide hydrolase activity. Some oxylipins are known to produce vasoconstriction. ⁶¹ Therefore, reduction in the levels of oxylipins would reduce BP. Prasad ⁸ has shown that hypotensive effect of SDG (pure lignin isolated from flaxseed) in rat is mediated through the stimulation of guanylate cyclase. In other study, Prasad ⁷ has reported that hypotensive effect of SDG is mediated through inhibition of ACE. Other component of flaxseed is protein. Flaxseed protein hydrolysate, induced hypotension, has been shown to be mediated through inhibition of renin and ACE activity. ⁶² These data suggest that the hypotensive effects of flaxseed may be mediated through reduction in the levels of oxylipins, and through stimulation of guanylate cyclase and through inhibition of renin and ACE activity.

Perspectives

Variable Effects of Flaxseed and its Components

The effects of flaxseed on BP are variable in both experimental animals and in humans. It has no effect on BP of normal and SHR rats. ²³ However, it prevented the rise in BP in renal ablated Sprague Dawley rats. ²² Meta-analysis of control clinical trials of numerous studies with flaxseed have shown that reduction in systolic and diastolic BP was very small (−1.81 to −2.85 mm Hg systolic; and −1.28 to −2.39 mm Hg diastolic). ^{28 29} However, in the study of Caliguiri et al, ²⁶ the reduction in systolic BP was 7.97 mm Hg. The diastolic and mean arterial pressures were not affected in this study.

Flax oil reduced the systolic pressure in SHR (−6.3 to –59 mm Hg) and the effects were dose dependent. ³³ Flax oil in various doses were not effective in healthy humans. ^{38 39} However, flax oil reduced the systolic and diastolic pressures significantly in patients with high normal and mild hypertension. ⁴⁰ The data show that flax oil is effective in lowering BP in patients with hypertension, dyslipidemia, and metabolic syndrome. SDG given intravenously reduced the systolic and diastolic pressures markedly in anaesthetized Sprague Dawley rats and the effects were long lasting. The effects were dose dependent between 3 and 10 mg/kg. ^{7 8} The doses more than 10 mg had similar effects. FLC (SDG equivalent to 300 and 600 mg/day) given orally for various duration did not affect the systolic and diastolic pressures in healthy individuals with different age groups ^{49 50 51 52 53 54 55 56} in rats. ⁵⁷ It is surprising that intravenous doses of SDG (3–5 mg/kg) were effective in lowering systolic and diastolic pressures in Sprague Dawley rats, but SDG in the dose of 4.28 to 8.57 mg/kg given orally in the form of FLC was not effective in lowering BP in humans. It is possible that SDG is destroyed given orally or the doses of FLC were low. It is known that oral dose should be four times higher than the intravenous dose. The effects of flaxseed and its compounds on BP do not seem to be age or sex dependent.

Mechanism(s) of BP Lowering Effects of Flaxseed and Its Components

As mentioned in the early section, BP lowering effects of α -linolenic acid is mediated through reduction of oxylipins. ²⁶ SDG lowers the BP through stimulation of guanylate cyclase ⁸ and inhibition of ACE. ⁷ BP reduction by flax protein is mediated through inhibition of renin and ACE activity. ⁶¹ Considering the mechanism(s) by which different components of flaxseed lower the BP, one would have expected a greater effect of flaxseed than components of flaxseed individually. However, it did not happen. The reasons could be that the amount of flaxseed used in these studies. Forty g of flaxseed contain 15.4 g α -linolenic acid. The flax oil used in these studies were 2.6, 6.0, 8.0, and 20 g/day. The only effective dose of α -linolenic acid in lowering BP was 20 g/day. Thus 40 g of flaxseed containing 15.4 g α -linolenic acid may be not enough to lower BP. SDG content of flaxseed is between 0.6 and 1.6 g/100 g of flaxseed. Thus, 40 g of flaxseed would approximately contain 400 mg of SDG. The effective doses of SDG in rat given intravenously (IV) are 3 and 5 mg/kg ⁸ and effective dose of SDG given orally in rabbit for reducing cholesterol-induced atherosclerosis is 15 mg/kg body weight. ⁶³ Thus, IV dose of SDG for an adult human weighing 70 kg should be 350 mg/day but oral dose should at least three times of IV dose (1,050 mg/day). In conclusion, 40 g of flaxseed does not have effective amount of SDG to lower the BP. The protein content of flaxseed is approximately 24%. ⁵⁸ Thus, 40 g of flaxseed would contain 9.6 g of protein. The effective dose of protein to lower BP is 200 mg/kg, orally. ⁵⁹ Thus, for an adult of 70 kg, the required dose to lower BP should be 14 g/day. Thus, the amount of protein in 40 g of flaxseed (9.6 g) is not sufficient to lower BP. It is possible that BP lowering component in 40 g flaxseed is not sufficient to reduce BP significantly. A small reduction in BP with flaxseed may the additive effects of active components of flaxseed.

Duration of Effects of Flaxseed and Its Components

The question arises, if the BP lowering effects of flaxseed constituents last long enough to maintain low pressure for long time. The effects of intravenous doses of SDG in rat lasts for more than 4 hours. ⁸ Even after 4 hours, the systolic, diastolic, and mean arterial pressures were 32, 36, and 33%, respectively, lower with 10 mg/kg compared with the pretreatment levels. The hypotensive effect of oral flaxseed protein hydrolysate lasts up to 6 hours ⁹ Duration of hypotensive effects of a single dose of flaxseed oil or α -linolenic acid on BP is not available. Based on the above information, single dose per day may not be as effective as they should be.

Dosing of Flaxseed and Its Constituents

It is possible that low effects of flaxseed and its constituents in lowering BP is due to single and low dose/day. First, studies should be conducted in experimental animal for the effect of flaxseed (0.7 g/kg), SDG (15 mg/kg), FLC (40 mg/kg) and flaxseed protein hydrolysate (200 mg/kg) given orally. After this, studies should be performed with 25 g of flaxseed, 550 mg of SDG, 1,500 mg of FLC, and protein hydrolysate twice daily orally individually for 4 weeks in humans to determine the effectiveness of these drugs on BP. The question arises, if these doses of flaxseed and its components may have adverse effects on the body. There are few studies which suggest that FLC did not have adverse effects. Stuglin and Prasad ⁶ have reported that 32.7 g/day of flaxseed does not have deleterious effects on the hemopoietc system, renal, and hepatic organs in humans. Prasad ⁶⁴ has shown that FLC (40 mg/kg body weight) did had deleterious effects on liver, kidney, intestine, skeletal muscle, and bone of rabbits as determined by changes in serum electrolytes, and enzymes. Prasad ⁶⁵ has also reported that chronic use of FLC (40 mg/kg orally) does not have adverse effects on hemopoietin system in rabbits.

It is puzzling that flaxseed and its components are effective in lowering of the BP in persons affected with hypertension, peripheral vascular disease, and metabolic syndrome but not in healthy subjects. Its reasons needs to be investigated.

The present data suggest that flaxseed and flax oil cannot serve as a therapeutic agent for hypertension. They may be used as an adjunct therapeutic agents for the treatment of hypertension. Pure SDG may serve as a therapeutic agent for hypertension because its BP lowering effect is excellent and long-lasting. The SDG in pure form has not been tried in patients. A clinical trial with SDG in hypertensive patients should be tried in future. FLC in higher doses twice daily may serve as therapeutic agent for the treatment of hypertension. Flax oils my serve as an adjunct therapeutic agent for treatment of hypertension. Flaxseed and its components may be used for prevention of hypertension especially in individual with family history of hypertension.

Conclusions

Flaxseed supplement of 30 to 40 g/day for various duration had variable effects on BP (no effect, small reduction, and significant reduction). Reduction in systolic and diastolic BP was respectively between 1.77 and 11.00 mm Hg and between 1.58 and 5.8 mm Hg. There was one study where 30 g/day of flaxseed markedly reduced the systolic (10 mm Hg) and diastolic (7 mm Hg) pressures. Flax oil also had variable effects on BP. Pure SDG given intravenously in Sprague Dawley rats significantly reduced the systolic, diastolic, and mean arterial pressures and these effects were dose-dependent and long lasting. FLC in the doses of 300 and 600 mg, equivalent of SDG/day, orally, in most studies did not reduce BP in experimental animals or humans. However, in one study of patient with metabolic syndrome, diastolic pressure decreased significantly. In other study FLC (equivalent to 600 mg/day) reduced the systolic pressure significantly in older healthy subjects. Flaxseed protein hydrolysate was effective in lowering BP significantly in spontaneously hypertensive rats. The data show that the hypotensive effects of flaxseed is due to inhibition of soluble epoxide hydrolase activity by α -linolenic acid, stimulation of guanylate cyclase, and inhibition of ACE by SDG, and inhibition of renin and ACE activity. Ineffectiveness of flaxseed and its components may be due to low dose, long interval of dosing and short duration of consumption, and patient status. Presently flaxseed and its components may not serve as therapeutic agent for hypertension. However, they might be used as adjunct to other therapeutic agents for the treatment for hypertension.