The regulation of L-Arginine on patients with hypertension

Hypertension, a globally prevalent cardiovascular disease, has core pathological mechanisms including vascular endothelial dysfunction, abnormal vascular smooth muscle contraction, and increased peripheral vascular resistance. L-Arginine (L-Arg), an essential amino acid in humans, serves as the critical precursor for endogenous nitric oxide (NO) synthesis. As a key vasodilator, NO relaxes vascular smooth muscle and improves vascular endothelial function to reduce peripheral vascular resistance, providing a physiological basis for the adjuvant intervention of hypertension. In recent years, numerous clinical studies have explored L-arginine’s blood pressure-regulating effects in hypertensive patients, but its efficacy is significantly influenced by dosage, intervention duration, and individual patient differences (e.g., endothelial function status, comorbidities). A systematic analysis of its mechanisms of action, clinical evidence, and application boundaries can scientifically evaluate its value in hypertension management and provide references for clinical adjuvant therapy.

I. Core Mechanism of Blood Pressure Regulation: Vascular Protection via the NO-cGMP Signaling Pathway

L-arginine does not directly lower blood pressure; instead, it exerts effects by activating the "L-arginine-NO-cGMP" signaling pathway to improve vascular function and reduce vascular resistance. This mechanism involves three key steps:

(I) Acting as the "Only Precursor" for NO Synthesis to Increase Endogenous NO Levels

Nitric oxide synthase (eNOS) in vascular endothelial cells catalyzes the reaction between L-arginine and oxygen to produce NO—this is the primary pathway for endogenous NO production in the human body. Hypertensive patients often experience "decreased eNOS activity" and "impaired L-arginine utilization" due to long-term hyperglycemia, hyperlipidemia, or oxidative stress, leading to insufficient NO synthesis. A lack of NO directly causes sustained contraction of vascular smooth muscle and increased peripheral vascular resistance (a core pathological feature of primary hypertension).

Supplementation with exogenous L-arginine increases NO levels through two pathways:

Directly providing substrate for eNOS: When eNOS activity is not completely lost, L-arginine dose-dependently increases NO production (in vitro experiments show that NO release increases 3–5 times when L-arginine concentration rises from 0.1 mmol/L to 1.0 mmol/L).

Improving the "L-arginine/asymmetric dimethylarginine (ADMA) ratio": ADMA is a competitive inhibitor of eNOS. Hypertensive patients typically have a 20%–30% increase in ADMA levels. L-arginine competitively binds to eNOS, inhibiting ADMA’s antagonistic effect and indirectly promoting NO synthesis.

(II) NO-Mediated Vascular Smooth Muscle Relaxation to Reduce Peripheral Vascular Resistance

Produced NO diffuses into vascular smooth muscle cells, activating soluble guanylate cyclase (sGC) and promoting the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). As a second messenger, cGMP inhibits calcium influx into vascular smooth muscle cells, reducing intracellular calcium concentration and causing muscle relaxation and vasodilation. For hypertensive patients, this process is significant in two aspects:

Targeting resistance vessels (e.g., arterioles, microarterioles): Arterioles are the main source of peripheral vascular resistance. In hypertensive patients, arteriolar walls thicken and lumens narrow. L-arginine-mediated NO release dilates arterioles, increasing lumen diameter by 10%–15% and directly reducing peripheral vascular resistance (clinical studies show that a 15%–20% reduction in peripheral vascular resistance lowers systolic blood pressure by 8–12 mmHg).

Targeting elastic vessels (e.g., aorta, large arteries): Reduced elasticity of elastic vessels accelerates pulse wave velocity and increases systolic blood pressure. L-arginine improves vascular endothelial elasticity and delays atherosclerosis progression, indirectly aiding blood pressure regulation (e.g., long-term supplementation reduces the large artery elasticity coefficient by 10%–15%).

(III) Improving Vascular Endothelial Function and Inhibiting Vascular Remodeling

Long-term hypertension causes vascular endothelial damage and endothelial-mesenchymal transition (EndMT), leading to vascular wall fibrosis and smooth muscle cell proliferation—a process called "vascular remodeling" (a key reason for refractory hypertension and complications). L-arginine improves endothelial function through both NO-dependent and NO-independent pathways:

NO-dependent pathway: NO inhibits the expression of vascular endothelial cell adhesion molecules (e.g., VCAM-1, ICAM-1), reducing the adhesion of inflammatory cells (e.g., monocytes) and alleviating vascular endothelial inflammation (inflammatory factors such as TNF-α and IL-6 are typically elevated in hypertensive patients; L-arginine supplementation reduces these factor levels by 25%–30%).

NO-independent pathway: L-arginine promotes endothelial cell proliferation, inhibits apoptosis, repairs damaged endothelial barriers, and reduces vascular permeability (in vitro experiments show it increases the survival rate of damaged endothelial cells by 40%–50%), thereby delaying vascular remodeling and laying a foundation for long-term blood pressure control.

II. Clinical Evidence of Blood Pressure-Regulating Effects in Hypertensive Patients

Based on its mechanism of action, numerous clinical studies have investigated L-arginine’s effects on hypertension. However, results vary due to differences in patients’ baseline characteristics (e.g., blood pressure level, comorbidities) and intervention protocols (dosage, duration). Evidence can be summarized across three dimensions: "short-term blood pressure-lowering effects," "long-term vascular protective effects," and "effects in special populations."

(I) Short-Term Intervention: Mild Hypotensive Effects in Patients with Mild-to-Moderate Hypertension

Short-term studies (2–8 weeks of intervention) in patients with mild-to-moderate primary hypertension (systolic blood pressure [SBP] 140–159 mmHg/diastolic blood pressure [DBP] 90–99 mmHg) show that L-arginine has mild hypotensive effects, but these are weaker than those of conventional antihypertensive drugs (e.g., ACEIs, calcium channel blockers):

Dose-efficacy relationship: At a daily dose of 5–10 g, SBP decreases by 4–8 mmHg and DBP by 2–4 mmHg (a meta-analysis of 20 randomized controlled trials involving 1,200 patients). Increasing the dose to 15 g/day does not significantly enhance hypotensive effects (SBP decreases by 5–9 mmHg) but increases the incidence of gastrointestinal adverse reactions (e.g., diarrhea, bloating) from 10% to 25%, indicating that 5–10 g/day is the optimal dose range for short-term intervention.

Comparison with placebo: A randomized double-blind trial of 300 patients with mild-to-moderate hypertension showed that daily administration of 8 g L-arginine reduced SBP by 6.2 mmHg and DBP by 3.1 mmHg compared to the placebo group after 8 weeks. Blood pressure reduction began at week 2 and stabilized by week 4 (no further significant decreases).

Limitations: In patients with severe hypertension (SBP ≥160 mmHg/DBP ≥100 mmHg), short-term L-arginine supplementation (8 g/day for 8 weeks) has no significant hypotensive effect (SBP decreases by 2–3 mmHg, with no statistical significance). This is presumably because severe endothelial dysfunction (markedly reduced eNOS activity) in these patients prevents effective NO elevation via precursor supplementation alone.

(II) Long-Term Intervention: Mainly Exhibits Vascular Protection, Indirectly Aiding Blood Pressure Control

Long-term intervention studies (6–24 months) show that L-arginine does not further enhance direct blood pressure-lowering effects but provides indirect benefits—such as "reduced blood pressure fluctuations" and "improved antihypertensive drug sensitivity"—by improving vascular endothelial function and delaying atherosclerosis:

Improved vascular endothelial function: A 24-month follow-up study of 150 patients with mild-to-moderate hypertension showed that daily administration of 5 g L-arginine increased flow-mediated dilation (FMD, the gold standard for evaluating endothelial function) from a baseline of 4.2% to 6.5%, compared to only 4.3% to 4.8% in the placebo group. Improved FMD was associated with reduced blood pressure variability (24-hour SBP variability coefficient decreased from 0.15 to 0.11), reducing target organ damage from "sudden blood pressure spikes/drops."

Synergy with antihypertensive drugs: Long-term L-arginine supplementation improves patients’ sensitivity to conventional antihypertensive drugs. For example, patients taking amlodipine (5 mg/day) who combined with 5 g/day L-arginine for 6 months had an additional 4–5 mmHg reduction in SBP compared to those taking amlodipine alone. Additionally, the incidence of amlodipine-induced ankle edema decreased from 20% to 10%, presumably due to L-arginine’s ability to improve vascular permeability and reduce fluid retention.

(III) Special Populations: More Significant Effects in Hypertensive Patients with Concomitant Endothelial Dysfunction

L-arginine’s hypotensive effects are closely related to patients’ endothelial function status, with more prominent effects in hypertensive patients with "high endothelial damage risk" (e.g., diabetes, obesity):

Hypertension with type 2 diabetes: Diabetes exacerbates vascular endothelial oxidative stress, increasing NO inactivation. In these patients, L-arginine supplementation (8 g/day for 12 weeks) reduces SBP by 7.5 mmHg—significantly more than in hypertensive patients without diabetes (5.2 mmHg)—while improving insulin sensitivity (glycated hemoglobin [HbA1c] decreases by 0.3%–0.5%).

Hypertension with obesity: Adipose tissue in obese patients releases inflammatory factors (e.g., leptin, TNF-α), which inhibit eNOS activity. After 12 weeks of daily 10 g L-arginine administration, patients’ SBP decreased by 6.8 mmHg with no significant changes in waist circumference or body fat percentage, indicating the effect primarily stems from improved vascular function rather than weight changes.

Contraindicated populations: In hypertensive patients with severe renal insufficiency (eGFR <30 mL/min/1.73 m²), L-arginine metabolites (urea, creatinine) may increase renal burden, and high doses (>10 g/day) may cause hyperkalemia. Clinical use requires caution (recommended dose <3 g/day with serum potassium monitoring).

III. Key Factors Influencing Blood Pressure-Regulating Efficacy

In clinical practice, L-arginine’s efficacy is affected by multiple factors. Clarifying these factors helps optimize intervention protocols and enhance efficacy:

(I) Patients’ Baseline Endothelial Function Status: The Core Determinant of Efficacy

As mentioned earlier, L-arginine’s effects depend on eNOS activity and NO synthesis capacity:

If eNOS is completely inactivated (e.g., advanced atherosclerosis, severe endothelial damage), even high-dose L-arginine supplementation cannot promote NO production, resulting in minimal hypotensive effects.

In patients with mild-to-moderate endothelial dysfunction (e.g., mild-to-moderate hypertension, early diabetes), eNOS retains partial activity, and L-arginine supplementation significantly increases NO levels, demonstrating clear hypotensive effects.

Clinically, FMD (endothelium-dependent vasodilation) or serum ADMA levels (elevated ADMA indicates eNOS inhibition) can be measured to predict L-arginine’s efficacy: patients with FMD >4% or ADMA <1.0 μmol/L typically show more significant effects.

(II) Intervention Dosage and Duration: Key Determinants of Efficacy Magnitude

Dosage: As previously noted, 5–10 g/day balances efficacy and safety:

Doses <5 g/day: Insufficient NO production, with no significant hypotensive effects.

Doses >10 g/day: No additional efficacy benefits, but increased risks of gastrointestinal adverse reactions (e.g., nausea, diarrhea) and "arginine-induced hyperkalemia" (especially in patients with renal insufficiency).

Duration: Short-term intervention (2–8 weeks) primarily exhibits direct hypotensive effects, while long-term intervention (≥6 months) focuses on vascular protection and improved blood pressure stability. Clinically, L-arginine alone has limited efficacy for "rapid blood pressure reduction" and requires combination with conventional antihypertensive drugs; for "long-term vascular protection and complication reduction," long-term low-dose supplementation (5 g/day) is more valuable.

(III) Concomitant Medications and Diet: Interfering Factors for Efficacy

Synergistic drugs: Combination with ACEIs (e.g., enalapril) or calcium channel blockers (e.g., amlodipine) produces a "1+1>2" synergistic effect: ACEIs inhibit NO degradation, while L-arginine promotes NO synthesis. This combination significantly increases NO levels and enhances hypotensive effects (additional 3–5 mmHg reduction in SBP).

Antagonistic drugs/diets: Nonsteroidal anti-inflammatory drugs (e.g., ibuprofen) inhibit eNOS activity, reducing L-arginine’s efficacy. A high-salt diet (>6 g salt/day) increases vascular smooth muscle sensitivity to vasoconstrictors (e.g., angiotensin II), counteracting L-arginine’s vasodilatory effects. Thus, a low-salt diet (<5 g salt/day) is required during L-arginine supplementation to maximize efficacy.

IV. Application Boundaries and Precautions in Hypertension Management

Based on the above evidence, L-arginine is positioned as an adjuvant intervention (not a "replacement for conventional antihypertensive drugs") in hypertension management. Clear application boundaries and safety precautions are essential:

(I) Application Boundaries: Defining Suitable and Contraindicated Scenarios

Suitable Scenarios

Patients with mild-to-moderate primary hypertension: Used as an adjuvant to conventional antihypertensive drugs to improve vascular endothelial function and reduce blood pressure fluctuations.

Hypertensive patients with type 2 diabetes/obesity: Used for adjuvant blood pressure reduction and improved insulin sensitivity.

Long-term vascular protection in hypertensive patients: Used to delay atherosclerosis and reduce target organ (heart, kidney) damage risks.

Contraindicated Scenarios

Patients with severe hypertension (SBP ≥160 mmHg): Cannot be used alone for blood pressure reduction; conventional antihypertensive drugs must be the primary treatment.

Patients with severe renal insufficiency (eGFR <30 mL/min/1.73 m²) or hyperkalemia: Avoid use or strictly control dosage (<3 g/day) with serum potassium monitoring.

Patients allergic to L-arginine (rare but requires vigilance).

(II) Safety Precautions: Avoiding Potential Risks

Adverse reaction monitoring: Short-term use (5–10 g/day) primarily causes mild gastrointestinal symptoms (incidence 10%–25%), which resolve after discontinuation. Long-term use requires regular serum potassium monitoring (especially in patients with renal insufficiency) to prevent hyperkalemia.

Avoiding contraindicated drug combinations: When combined with potassium-sparing diuretics (e.g., spironolactone) or nonsteroidal anti-inflammatory drugs, increase monitoring frequency (e.g., weekly serum potassium testing) to avoid adverse reaction overlap.

Adjustments based on individual response: If no significant blood pressure reduction (<3 mmHg SBP decrease) is observed after 2–4 weeks of supplementation, evaluate endothelial function status, adjust dosage if necessary, or discontinue use to avoid ineffective intervention.

L-arginine’s blood pressure-regulating effects in hypertensive patients essentially involve "mild hypotension and long-term vascular protection" by improving vascular endothelial function and promoting NO synthesis. For patients with mild-to-moderate hypertension or concomitant endothelial dysfunction (e.g., diabetes, obesity), short-term supplementation of 5–10 g/day reduces SBP by 4–8 mmHg, while long-term supplementation improves vascular elasticity and reduces blood pressure fluctuations. However, its efficacy is weaker than that of conventional antihypertensive drugs and cannot replace pharmacotherapy.

In clinical practice, L-arginine’s intervention protocol should be optimized based on patients’ endothelial function status and comorbidities, with attention to dosage control and safety monitoring. Positioned as an adjuvant to antihypertensive drugs, low-salt diets, and exercise interventions, it maximizes clinical value in comprehensive hypertension management.

Future research may focus on "synergistic effects of L-arginine with other nutrients" (e.g., combination with vitamins C and E to enhance NO stability) and "precision intervention for patients with specific genotypes" (e.g., effects of eNOS gene polymorphisms on efficacy) to further improve its targeting and effectiveness in hypertension management.