Nattokinase for Blood Pressure

Nattokinase has been studied for blood pressure reduction in two well-conducted randomized controlled trials: the Kim 2008 trial in 86 mildly hypertensive Korean adults (2,000 FU/day for 8 weeks, average reductions of 5.6 mmHg systolic and 2.8 mmHg diastolic versus placebo) and the Jensen 2016 multicenter North American trial in 79 adults with prehypertension or stage 1 hypertension (similar magnitude reductions plus a reduction in von Willebrand factor, a marker of endothelial dysfunction and cardiovascular risk). The mechanism is dual: nattokinase-derived peptides have ACE-inhibitor-like activity (the same enzyme inhibition exploited by pharmaceutical drugs like lisinopril and enalapril), and fibrinolysis-mediated improvement of microcirculation reduces peripheral vascular resistance independently. The honest summary: a modest but real effect, useful as adjunctive support for prehypertension and stage 1 hypertension alongside lifestyle change, magnesium, potassium-rich diet, and weight management. NOT a substitute for prescribed antihypertensives in moderate-to-severe hypertension; NOT to be combined with anticoagulant or antiplatelet drugs without physician supervision.

Table of Contents

1. The Kim 2008 RCT — The Pivotal Hypertension Trial
2. The Jensen 2016 North American Multicenter Trial
3. Mechanism 1: ACE-Inhibitor-Like Activity
4. Mechanism 2: Microcirculation Improvement via Fibrinolysis
5. Mechanism 3: Reduced von Willebrand Factor and Endothelial Repair
6. Magnitude of Effect — What 5/3 mmHg Actually Means
7. Prehypertension and Stage 1 Hypertension — The Ideal Use Case
8. Combination with Magnesium, Potassium, and Lifestyle Change
9. When Nattokinase Is NOT Appropriate for Blood Pressure
10. Dosing and Time-to-Effect for Blood Pressure
11. Cautions and Drug Interactions
12. Key Research Papers
13. Connections

The Kim 2008 RCT — The Pivotal Hypertension Trial

The Kim 2008 trial published in Hypertension Research is the single most-cited human study supporting nattokinase for blood pressure reduction. Design and results:

• Population: 86 Korean adults with mild hypertension (defined as untreated systolic blood pressure 130–159 mmHg or diastolic 90–99 mmHg) recruited from a university hospital outpatient clinic.
• Design: Randomized, double-blind, placebo-controlled, parallel-group design. Stratified randomization to ensure balanced baseline blood pressure between arms.
• Intervention: 2,000 FU/day nattokinase (one capsule containing standardized enzyme activity, from NSK-SD branded preparation) vs. matching placebo capsule. Daily dose, single intake.
• Duration: 8 weeks of intervention.
• Endpoints: Office systolic and diastolic blood pressure measured at baseline, 4 weeks, and 8 weeks by a blinded study clinician.

Results at 8 weeks:

• Systolic BP: The nattokinase group experienced a 5.55 mmHg reduction (95% CI −8.4 to −2.7); the placebo group showed minimal change. The between-group difference was statistically significant (P < 0.05).
• Diastolic BP: The nattokinase group experienced a 2.84 mmHg reduction (95% CI −4.7 to −1.0); also statistically significant versus placebo.
• Safety: No serious adverse events. No clinically significant changes in coagulation parameters at this dose. Tolerability was excellent.

The Kim trial established the 2,000 FU/day standard dose for blood pressure use, and the 8-week onset-to-significant-effect timeframe. The magnitude of reduction was modest but consistent and clinically meaningful in the mildly-hypertensive population studied.

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The Jensen 2016 North American Multicenter Trial

The Jensen 2016 trial published in Integrated Blood Pressure Control was the first major confirmatory trial in a North American population, addressing one of the principal questions left open by the Kim study (whether the result would replicate outside an East Asian population that consumes substantial dietary natto and soy and may have different baseline cardiovascular risk profiles).

Design and results:

• Population: 79 adults from multiple North American clinical sites with prehypertension or stage 1 hypertension (systolic 130–159 mmHg or diastolic 80–99 mmHg), untreated.
• Design: Randomized, double-blind, placebo-controlled, multicenter.
• Intervention: 2,000 FU/day nattokinase vs. placebo for 8 weeks.
• Endpoints: Office BP, plus von Willebrand factor (vWF) as a marker of endothelial activation, plus standard safety labs.

Results:

• Systolic BP reduction of similar magnitude to the Kim trial (~5 mmHg) in the overall population, with greater reductions in the subgroup of subjects whose baseline systolic was ≥130 mmHg.
• Von Willebrand factor was significantly reduced in the nattokinase group compared to placebo. This is an important secondary finding because vWF is a marker of endothelial dysfunction; reductions in vWF suggest improvement in endothelial health beyond the direct BP effect.
• Sex differences: women had a larger response than men in some subgroup analyses, though the study was not powered for sex-stratified analysis.
• No serious adverse events; tolerability comparable to placebo.

The Jensen trial confirmed the BP-lowering signal in a non-Asian population with relatively low background dietary natto/soy intake. It also added the vWF endothelial-health finding, suggesting a mechanism beyond simple ACE-inhibitor-like activity.

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Mechanism 1: ACE-Inhibitor-Like Activity

Angiotensin-converting enzyme (ACE) is the zinc-metalloprotease that converts angiotensin I to angiotensin II, the principal effector of the renin-angiotensin-aldosterone system (RAAS) and one of the most potent endogenous vasoconstrictors. ACE inhibitors (lisinopril, enalapril, ramipril, perindopril) are first-line antihypertensive drugs precisely because blocking this enzyme reduces angiotensin II production, lowers vascular tone, reduces aldosterone-mediated sodium retention, and reduces cardiac afterload.

Nattokinase itself has direct ACE-inhibitory activity (Murakami 2012), but more importantly the fermentation process that produces nattokinase also produces a family of short bioactive peptides with documented ACE-inhibitory activity. These peptides are released by bacterial proteolysis of soy protein during fermentation. The same general phenomenon is well-documented for other fermented foods — the Yamamoto 1999 paper documenting ACE-inhibitory peptides from lactobacillus-fermented milk is a classic example, and there is now substantial literature on antihypertensive peptides from various fermented dairy and soy products.

The ACE inhibition produced by natto-derived peptides is several orders of magnitude weaker than pharmaceutical ACE inhibitors on a molar basis, but the concentrations achieved in the gastrointestinal tract and (to a lesser extent) in plasma after natto consumption are correspondingly higher. The net pharmacodynamic effect is a modest but real ACE-inhibition that contributes to the blood pressure reduction.

This mechanism is partially distinct from the fibrinolytic mechanism of nattokinase itself. Some of the ACE-inhibitory effect is from nattokinase the enzyme, and some is from co-formulated soy-fermentation peptides that may be present in greater or lesser amounts depending on how the supplement was manufactured. Pure nattokinase preparations have less of this effect than less-purified natto-extract products.

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Mechanism 2: Microcirculation Improvement via Fibrinolysis

The second mechanism by which nattokinase lowers blood pressure is fundamentally different from the ACE-inhibitor mechanism: it works through reduction of peripheral vascular resistance via improved blood rheology rather than through direct effects on the vascular wall.

The chain of logic is:

1. Nattokinase reduces plasma fibrinogen (~7–10% in the Hsia trial)
2. Lower fibrinogen reduces whole-blood viscosity (Pais 2006)
3. Lower fibrinogen also reduces red-cell aggregation at low shear rates, improving microcirculatory perfusion (Pais 2006)
4. Improved microcirculation at the level of the resistance arterioles and capillaries reduces total peripheral vascular resistance
5. By the equation BP = cardiac output × total peripheral resistance, reduced TPR translates to lower blood pressure at constant cardiac output

This mechanism is a slower-onset, lower-magnitude contributor to BP reduction than the ACE-inhibitor-like activity, but it operates through a fundamentally distinct pathway and the two effects are likely additive rather than redundant. The combined ACE-inhibitor + microcirculation-improvement mechanism explains why the magnitude of BP reduction in human trials (~5/3 mmHg) is greater than would be predicted from the ACE-inhibitory activity alone of natto-derived peptides.

For more on the cardiovascular significance of reduced fibrinogen and improved blood rheology, see the cardiovascular and fibrinolysis deep-dive.

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Mechanism 3: Reduced von Willebrand Factor and Endothelial Repair

The Jensen 2016 trial added a finding that was not the primary endpoint but is mechanistically interesting: nattokinase reduced von Willebrand factor (vWF) levels significantly compared to placebo. vWF is a large multimeric glycoprotein produced by endothelial cells and stored in Weibel-Palade bodies; it is released into circulation in response to endothelial activation, inflammation, and shear stress, and serves as a marker of endothelial dysfunction.

Elevated vWF is independently associated with cardiovascular disease risk, particularly thrombotic events. Lowering vWF is not in itself an antihypertensive mechanism, but it reflects improvement in endothelial health, which IS a fundamental driver of long-term blood pressure regulation through nitric oxide production, endothelin balance, and prostacyclin synthesis.

The proposed mechanism for the vWF reduction is reduced endothelial inflammation and reduced oxidative stress, secondary to reduced fibrinogen, reduced LDL oxidation, and improved microcirculatory perfusion of the endothelium itself. The endothelium is metabolically active tissue and is sensitive to its own perfusion; chronically under-perfused endothelium expresses more vWF, more endothelin, less nitric oxide, all of which raise blood pressure. Reversing this cascade is one of the longer-term effects of sustained nattokinase use.

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Magnitude of Effect — What 5/3 mmHg Actually Means

A 5/3 mmHg reduction sounds modest, and at the individual level it often is. But cardiovascular epidemiology has consistently shown that population-level reductions of even 2–3 mmHg in systolic BP translate to clinically meaningful reductions in cardiovascular events. The Prospective Studies Collaboration meta-analysis (61 prospective observational studies, over a million participants) showed that each 2 mmHg reduction in usual systolic BP is associated with approximately 7% lower ischemic heart disease mortality and 10% lower stroke mortality. The 5/3 mmHg reduction documented in the Kim and Jensen trials therefore corresponds to a roughly 15–20% reduction in projected cardiovascular event risk if sustained.

The key qualifier is "if sustained." The 8-week trial duration of both Kim and Jensen is too short to demonstrate event-rate reductions directly, and no long-term outcome trial of nattokinase has been performed. The benefit is inferred from the established relationship between blood pressure reduction and cardiovascular events that has been documented for pharmaceutical antihypertensives. Whether nattokinase achieves the same cardiovascular benefit per mmHg of BP reduction as an ACE inhibitor or thiazide diuretic is not established; it is plausible based on shared mechanism but is an inference.

The honest framing for patients: nattokinase can reduce systolic BP by approximately 5 mmHg, similar to what would be expected from moderate weight loss (~5 kg) or the DASH diet, and approximately half what would be expected from a low-dose pharmaceutical antihypertensive. It is meaningful as part of a multi-component blood pressure management strategy, not as a standalone substitute for prescription medication in moderate-to-severe hypertension.

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Prehypertension and Stage 1 Hypertension — The Ideal Use Case

The clinical situation where nattokinase has the strongest case is in the prehypertension (120–129 / <80 mmHg) and stage 1 hypertension (130–139 / 80–89 mmHg) range, where:

• Pharmaceutical antihypertensive therapy is often not yet indicated by current guidelines (which favor lifestyle change as first-line in this range, with medication reserved for higher BP or for patients with multiple cardiovascular risk factors)
• A 5/3 mmHg reduction can shift the patient from "borderline elevated" to "normal," with attendant reduction in long-term cardiovascular risk
• The patient is motivated to do something but not yet at the stage where the benefit/risk ratio favors starting daily prescription medication
• The relatively favorable safety profile of nattokinase (in patients NOT on anticoagulants or antiplatelet drugs) makes it a low-risk addition to lifestyle change

The typical patient profile for whom nattokinase is a reasonable addition: a 45–65 year old with average BP in the 130–140 / 82–88 range, no diabetes, normal kidney function, normal coagulation, not on any antithrombotic medication, who is already implementing weight loss, exercise, and dietary sodium reduction and is looking for an additional modality. In this patient nattokinase 2,000 FU/day for 8–12 weeks may produce a clinically meaningful additional 5 mmHg reduction beyond what lifestyle alone achieves.

For more on hypertension itself and its non-pharmaceutical management, see our Hypertension page.

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Combination with Magnesium, Potassium, and Lifestyle Change

Nattokinase is most effective when combined with the other established non-pharmaceutical blood pressure interventions. The combinations are mechanistically additive because they work through different pathways:

• Nattokinase — ACE-inhibitor-like activity + microcirculation improvement + endothelial vWF reduction; expected reduction ~5/3 mmHg
• Magnesium glycinate or citrate (300–400 mg/day) — vascular smooth-muscle relaxation, improved nitric oxide bioavailability; expected reduction ~2–4 mmHg systolic in deficient subjects. See Magnesium page.
• Potassium-rich diet (3,500–4,700 mg/day from food) — reduced sodium-driven volume expansion via natriuretic effect at the distal nephron; expected reduction ~3–5 mmHg systolic. See Potassium-rich foods.
• DASH or Mediterranean diet pattern — combined effect of reduced sodium, increased potassium, increased fiber, reduced refined carbohydrate; expected reduction ~5–11 mmHg systolic. See Anti-Inflammatory Diet.
• Aerobic exercise 150+ minutes per week — improved endothelial function, reduced sympathetic tone; expected reduction ~4–9 mmHg systolic.
• Weight loss in overweight patients — approximately 1 mmHg per 1 kg lost up to 5–10 kg loss.
• Reduced alcohol intake (no more than 1 drink/day women, 2 drinks/day men) — expected reduction ~2–4 mmHg systolic in heavier drinkers.

The combined effect of nattokinase + magnesium + potassium-rich diet + DASH pattern + exercise can easily exceed 15–20 mmHg systolic reduction in a motivated patient, which is comparable to a single-agent pharmaceutical antihypertensive. This combination strategy is the practical foundation of non-pharmaceutical hypertension management for prehypertension and stage 1 hypertension.

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When Nattokinase Is NOT Appropriate for Blood Pressure

• Stage 2 hypertension (≥140/90 mmHg). Pharmaceutical antihypertensive therapy is indicated; nattokinase should not be used as a substitute. It may be added as an adjunct under physician supervision, but only after pharmaceutical therapy is established and bleeding-risk assessment is documented.
• Hypertensive urgency or emergency (≥180/110 mmHg). Immediate pharmaceutical intervention is required; nattokinase has no role.
• Patients on warfarin, apixaban, rivaroxaban, edoxaban, dabigatran, aspirin, clopidogrel, or ticagrelor. The bleeding-risk interaction precludes use without specific physician supervision.
• Patients with active bleeding disorders, hemophilia, von Willebrand disease, thrombocytopenia, or recent hemorrhagic stroke.
• Pregnant or lactating women. Insufficient safety data.
• Patients within 7 days of any planned surgery or invasive procedure.
• Hypertension secondary to a treatable cause — renal artery stenosis, primary aldosteronism, pheochromocytoma, Cushing syndrome, obstructive sleep apnea. Address the underlying cause; nattokinase is not appropriate substitute therapy.
• Patients with severe soy allergy who cannot find a verified soy-free preparation.

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Dosing and Time-to-Effect for Blood Pressure

• Standard dose: 2,000 FU once daily — the dose used in both the Kim 2008 and Jensen 2016 positive trials.
• Higher-dose option: 2,000 FU twice daily (4,000 FU total) for patients who do not respond at 2,000 FU after 8 weeks. The marginal benefit of higher doses for BP alone is not well-established; most of the published positive evidence is at 2,000 FU.
• Time-of-day: evening dosing is theoretically rational because endogenous fibrinolytic activity is lowest in the early morning, and many trials used evening dosing. Whether this matters for the BP effect specifically (as opposed to the cardiovascular event prevention effect) is not established.
• With or without food: enteric-coated capsules can be taken either way; most patients take them with the evening meal.
• Time to measurable BP effect: 4–8 weeks of daily dosing. Do not expect immediate same-day or first-week effects on BP.
• Trial duration before deciding: 8–12 weeks. If no measurable effect at 12 weeks at 2,000–4,000 FU/day, the patient is likely not a responder and the supplement should be discontinued.
• Monitoring: home BP cuff readings 3–5 times per week, recorded with date/time, for objective trend assessment. Office BP alone is too noisy to detect a 5 mmHg effect reliably.

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Cautions and Drug Interactions

• Anticoagulants (warfarin, apixaban, rivaroxaban, edoxaban, dabigatran) — do NOT add nattokinase without explicit physician supervision and increased bleeding-monitoring frequency. The interaction can be clinically significant.
• Antiplatelets (aspirin, clopidogrel, ticagrelor, prasugrel) — same caution.
• Pharmaceutical ACE inhibitors (lisinopril, enalapril, ramipril, perindopril) — the combined ACE inhibition could theoretically produce additive BP reduction beyond what was intended; monitor for excessive BP reduction or symptomatic hypotension. In practice this combination is generally well-tolerated but should be initiated cautiously with home BP monitoring.
• Pharmaceutical ARBs (losartan, valsartan, irbesartan, candesartan) — theoretical additive effect; monitor.
• Beta blockers, calcium channel blockers, diuretics — nattokinase can be added cautiously with home BP monitoring; the combined effect is generally well-tolerated.
• Active bleeding disorders, hemophilia, von Willebrand disease, thrombocytopenia. Contraindicated.
• Recent or planned surgery — discontinue at least 7 days before any procedure.
• Pregnancy and lactation. Insufficient safety data; avoid.
• Soy allergy. Use only verified soy-free preparations.
• Side effects. Generally mild — nausea, gastrointestinal discomfort, occasional bruising, infrequent menstrual flow increase.

For more on the broader context of cardiovascular risk reduction, see Hypertension, Atherosclerosis, and Lipid Panel.

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Key Research Papers

1. Kim JY et al. (2008). Effects of nattokinase on blood pressure: a randomized, controlled trial. Hypertension Research 31(8):1583-1588. — PubMed
2. Jensen GS et al. (2016). Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor: results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trial. Integr Blood Press Control. — PubMed
3. Murakami K et al. (2012). Inhibitory effect of nattokinase on angiotensin-converting enzyme. Phytother Res. — PubMed
4. Fujita H et al. (1995). Effect of a continuous intake of a soybean-fermented food (natto) on blood pressure in normotensive and hypertensive humans. — PubMed
5. Saito M et al. (1994). Antihypertensive peptides from fermented soybean (natto). — PubMed
6. Pino A et al. (2020). Antihypertensive peptides from fermented soybean: a review. — PubMed
7. Yamamoto N et al. (1999). Antihypertensive effect of the peptides derived from casein by an extracellular proteinase from Lactobacillus helveticus. — PubMed
8. Hsia CH et al. (2009). Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects. Nutr Res. — PubMed
9. Maruyama M, Sumi H (1998). Effect of natto diet on blood pressure. — PubMed
10. Lewington S et al. (Prospective Studies Collaboration, 2002). Age-specific relevance of usual blood pressure to vascular mortality: meta-analysis of individual data for one million adults. Lancet. — PubMed
11. Sacks FM et al. (DASH-Sodium Collaborative Research Group, 2001). Effects on blood pressure of reduced dietary sodium and the DASH dietary pattern. NEJM. — PubMed
12. Chen H et al. (2018). Nattokinase: a promising alternative in prevention and treatment of cardiovascular diseases. Biomark Insights. — PubMed

PubMed Topic Searches

• PubMed: Nattokinase blood pressure
• PubMed: Nattokinase ACE inhibition
• PubMed: Nattokinase vWF and endothelial function
• PubMed: Natto-derived antihypertensive peptides
• PubMed: DASH dietary pattern and BP

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Connections

• Nattokinase Overview
• Nattokinase Benefits Hub
• Cardiovascular & Fibrinolysis
• Stroke Prevention
• Vitamin K2 (MK-7) Connection
• Hypertension
• Atherosclerosis
• Magnesium
• Potassium-Rich Foods
• Anti-Inflammatory Diet
• Natto (Food)
• Vitamin K
• Lipid Panel
• Coagulation Panel
• Omega-3 Fatty Acids
• Aspirin
• All Superfoods

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