The blood pressure regulatory effect of L-Arginine

As a semi-essential amino acid for humans (endogenously synthesizable in adults but requiring exogenous supplementation under special physiological conditions), the blood pressure-regulating effect of L-arginine in hypertensive patients primarily centers on the "nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signaling pathway," while also involving multiple mechanisms such as vascular endothelial protection and neuroendocrine regulation. However, its effect is influenced by factors including individual differences among patients, dosage, and blood pressure type. A detailed analysis can be conducted from three aspects: mechanism of action, characteristics of clinical effects, and application precautions.

I. Core Mechanism of Action: NO-Hubbed Vasodilation Pathway

L-arginine is a key substrate for endogenous NO synthesis, and NO is a core signaling molecule regulating vascular tone. Its blood pressure-regulating mechanism follows a clear physiological pathway:

1. Initiation of NO Synthesis

In vascular endothelial cells, L-arginine reacts with oxygen (O₂) and nicotinamide adenine dinucleotide phosphate (NADPH) under the catalysis of "nitric oxide synthase (NOS)" to generate NO and citrulline. NOS is classified into three types: endothelial NOS (eNOS, mainly present in vascular endothelium), neuronal NOS (nNOS), and inducible NOS (iNOS). Hypertensive patients often exhibit decreased eNOS activity or dysfunction, leading to insufficient endogenous NO production. Exogenous supplementation of L-arginine can enhance eNOS catalytic efficiency through a "substrate activation" effect, compensating for defects in endogenous NO synthesis.

2. NO-Mediated Vasodilation

The generated NO rapidly diffuses into vascular smooth muscle cells, activating intracellular "soluble guanylate cyclase (sGC)" and promoting the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP further activates "protein kinase G (PKG)," which inhibits the influx and release of calcium ions (Ca²⁺) in smooth muscle cells through phosphorylation. Reduced intracellular Ca²⁺ concentration causes vascular smooth muscle relaxation and vascular lumen dilation, ultimately lowering peripheral vascular resistance. This is the most core pathway of L-arginine’s blood pressure regulation, particularly effective in "endothelial dysfunction-related hypertension" (e.g., essential hypertension, hypertension with diabetes).

3. Auxiliary Protective Mechanisms

Beyond directly promoting NO synthesis, L-arginine can also reduce the production of "reactive oxygen species (ROS)" (e.g., by inhibiting NADPH oxidase activity), decreasing ROS-mediated NO scavenging (ROS readily reacts with NO to form inactive peroxynitrite) and indirectly maintaining effective intravascular NO concentrations. Additionally, it improves the metabolic state of vascular endothelial cells, promotes endothelial cell proliferation and repair, and reduces vascular sclerosis caused by endothelial damage, assisting in long-term blood pressure control.

II. Characteristics of Clinical Effects: Individual Variability in Efficacy, Not a Universal Antihypertensive Method

Numerous clinical studies have shown that the blood pressure-regulating effect of L-arginine in hypertensive patients is not uniform but exhibits "selective efficacy," with the following key patterns:

1. Greater Efficacy in Specific Hypertension Types

For "hypertension associated with insufficient endogenous NO synthesis" (e.g., elderly hypertension, hypertension with obesity, salt-sensitive hypertension), exogenous supplementation of L-arginine (typically 3–6 g daily, divided into 2–3 oral doses) can reduce systolic blood pressure (SBP) by 5–15 mmHg and diastolic blood pressure (DBP) by 3–8 mmHg. Moreover, the higher the baseline blood pressure (e.g., SBP ≥ 160 mmHg), the more significant the blood pressure reduction may be. However, for "hypertension dominated by overactivation of the renin-angiotensin-aldosterone system (RAAS)" (e.g., renovascular hypertension), its effect is weak, and synergistic effects usually require combination with RAAS inhibitors (e.g., angiotensin-converting enzyme inhibitors).

2. Differences Between Short-Term and Long-Term Effects

Short-term supplementation (1–4 weeks): L-arginine exerts an acute vasodilatory effect primarily by rapidly increasing NO concentrations. The antihypertensive effect appears quickly but has a short duration (blood pressure reduction persists for 4–6 hours after a single oral dose).

Long-term supplementation (3–6 months): In addition to maintaining NO levels, it achieves dual effects of "stable blood pressure control + vascular protection" by improving vascular endothelial elasticity and reducing atherosclerotic risk factors (e.g., lowering levels of vascular wall inflammatory factors). It is particularly suitable for patients with mild-to-moderate hypertension requiring long-term management.

3. Cases of Inefficacy or Adverse Effects

Approximately 20%–30% of patients show no significant blood pressure change after L-arginine supplementation, potentially due to:

Severe insufficient endogenous NOS activity (e.g., inherently low enzyme activity caused by eNOS gene polymorphism), where substrate supplementation fails to enhance NO synthesis;

Severe vascular structural lesions (e.g., severe atherosclerosis, vascular calcification), where increased NO production cannot promote vasodilation.

Furthermore, high-dose supplementation (>10 g daily) may cause gastrointestinal discomfort (e.g., nausea, diarrhea), or excessive vasodilation due to overproduction of NO in a small number of patients, leading to symptoms such as dizziness and orthostatic hypotension. Strict dosage control is therefore essential.

III. Application Precautions: Positioned as "Adjuvant Intervention," Not a Replacement for Standard Treatment

The blood pressure-regulating effect of L-arginine in hypertensive patients must be applied rationally under clinical guidance, with core precautions including:

1. Clarify Applicable Scenarios

It is positioned as an "adjuvant intervention for hypertension" and cannot replace antihypertensive drugs (e.g., calcium channel blockers, β-blockers). Particularly for patients with moderate-to-severe hypertension (SBP ≥ 160 mmHg or DBP ≥ 100 mmHg), L-arginine supplementation (if deemed appropriate by a doctor) must be administered alongside regular antihypertensive medication. Discontinuation of drugs in favor of supplements to avoid blood pressure rebound is strictly prohibited.

2. Dosage and Formulation Selection

For oral supplementation, the recommended daily dosage is 3–6 g (divided into 2 doses, taken after meals to reduce gastrointestinal irritation), with overdosage avoided. In terms of formulations, "L-arginine hydrochloride" or "L-arginine glutamate" are preferred: these formulations have good solubility and high bioavailability (oral absorption rate of approximately 60%–70%) and are less likely to cause acid-base imbalance in the body. In contrast, pure L-arginine free base formulations are prone to moisture absorption and have poor stability.

3. Exclude Contraindicated Populations

The following hypertensive patients should avoid or use L-arginine with caution:

Patients with severe renal insufficiency (creatinine clearance < 30 mL/min): L-arginine is mainly metabolized by the kidneys, and decreased renal function can lead to its accumulation, increasing the risk of hyperkalemia;

Patients with hemophilia or those taking anticoagulants (e.g., warfarin, aspirin): NO may enhance anticoagulant effects, increasing bleeding risk;

Patients allergic to L-arginine (rare, but allergic reactions such as rash and dyspnea require vigilance).

4. Monitoring and Adjustment

During supplementation, regular blood pressure monitoring is required (at least twice a week, including supine and standing blood pressure to avoid missed diagnosis of orthostatic hypotension), along with monitoring of liver and kidney function and electrolytes (especially blood potassium). If blood pressure fails to improve, or if gastrointestinal discomfort, dizziness, or other symptoms occur, dosage adjustment or discontinuation is necessary, and the intervention plan should be re-evaluated by a doctor.

L-arginine exerts a clear blood pressure-regulating effect in specific types of hypertensive patients through "NO-mediated vasodilation + vascular endothelial protection." However, its efficacy varies among individuals, and it must be strictly positioned as an "adjuvant intervention" rather than a replacement for standard antihypertensive treatment. In clinical practice, personalized regimens should be developed based on factors such as the patient’s hypertension type, underlying diseases, and genetic background to ensure safety and effectiveness while leveraging its blood pressure-regulating benefits.