The improvement effect of L-arginine HCl on vascular endothelial function

L-Arginine HCl is a conditionally essential amino acid in humans. The L-arginine dissociated from it serves as the sole substrate for nitric oxide (NO) synthesis in vascular endothelial cells. As a core signaling molecule that regulates vascular tone, inhibits platelet aggregation, and maintains endothelial homeostasis, NO underpins the multi-dimensional improvement of vascular endothelial function by L-Arginine HCl. Through mechanisms including promoting NO production, regulating endothelial metabolic pathways, and suppressing oxidative stress, L-Arginine HCl holds significant physiological and clinical value in the prevention and treatment of cardiovascular diseases.

I. Core Mechanism of Action: Activation of the L-Arginine-NO Pathway

Endothelial nitric oxide synthase (eNOS) in vascular endothelial cells catalyzes the conversion of L-arginine to NO and citrulline, with the involvement of cofactors such as tetrahydrobiopterin (BH₄) and calcium ions (Ca²⁺). This pathway constitutes the central mechanism through which L-Arginine HCl exerts its endothelial protective effects.

1. Directly Elevating Substrate Concentration for NO Synthesis

Under normal physiological conditions, the intracellular concentration of L-arginine in endothelial cells ranges from 0.1 to 0.5 mmol/L, while the Michaelis constant (Kₘ) of eNOS is only 1–5 μmol/L. Despite the seemingly sufficient substrate availability, the arginine paradox exists: exogenous supplementation of L-Arginine HCl still significantly boosts NO production. The underlying reason lies in the compartmentalization of L-arginine pools within endothelial cells: most intracellular L-arginine is allocated to protein synthesis or the urea cycle, with only a small fraction accessible to eNOS. Exogenous L-Arginine HCl supplementation disrupts this compartmentalization, expands the eNOS-accessible arginine pool, and directly drives NO biosynthesis.

2. Enhancing eNOS Activity and Stability

L-Arginine HCl modulates eNOS function through two primary mechanisms:

First, it acts as an allosteric activator of eNOS. By binding to the enzyme’s substrate-binding domain, L-arginine stabilizes the active conformation of eNOS, reducing its dissociation and inactivation.

Second, it promotes the phosphorylation of eNOS. L-Arginine HCl activates the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, which induces phosphorylation of eNOS at serine residue 1177, thereby markedly enhancing the enzyme’s catalytic efficiency.

In addition, the citrulline generated during L-Arginine HCl metabolism can be recycled back to L-arginine via the arginine-citrulline cycle, continuously supplying substrates for NO synthesis and maintaining the steady release of NO.

II. Multi-Dimensional Effects of L-Arginine HCl in Improving Vascular Endothelial Function

Based on the core role of NO, L-Arginine HCl improves endothelial function through NO-mediated signaling pathways, encompassing vascular tone regulation, endothelial barrier maintenance, anti-inflammation, and antioxidation.

1. Regulating Vascular Tone and Improving Vasodilatory Function

Upon diffusing into vascular smooth muscle cells, NO activates soluble guanylate cyclase (sGC), leading to increased levels of cyclic guanosine monophosphate (cGMP). Elevated cGMP subsequently reduces intracellular Ca²⁺ concentrations in smooth muscle cells, resulting in vasodilation. Exogenous L-Arginine HCl supplementation increases the release of endothelium-derived NO, significantly improving flow-mediated dilation (FMD)—the gold standard for evaluating endothelial function. Clinical studies have demonstrated that oral administration of L-Arginine HCl (3–6 g/day) can increase brachial artery FMD by 10%–20% in patients with hypertension or coronary heart disease, effectively reducing peripheral vascular resistance and enhancing tissue perfusion.

2. Maintaining Endothelial Barrier Integrity and Inhibiting Vascular Leakage

Tight junctions between vascular endothelial cells are critical for preserving barrier function. NO stabilizes the expression and distribution of tight junction proteins (e.g., occludin, claudin) by inhibiting actin rearrangement in endothelial cells, thereby reducing the leakage of intravascular fluids and macromolecules. Additionally, L-Arginine HCl stimulates endothelial cells to synthesize vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), accelerating the repair of damaged endothelium. This protective effect is particularly pronounced against endothelial barrier disruption induced by ischemia-reperfusion injury and inflammatory responses.

3.Inhibiting Platelet Aggregation and Leukocyte Adhesion: Anti-Inflammatory and Antithrombotic Effects

Activated endothelial cells express adhesion molecules (e.g., ICAM-1, VCAM-1), which promote leukocyte adhesion and platelet aggregation, triggering thrombosis and inflammatory reactions. NO inhibits this process through three pathways:

First, it elevates intracellular cGMP levels in platelets, suppressing platelet adhesion and aggregation.

Second, it downregulates the expression of endothelial adhesion molecules, reducing leukocyte-endothelial binding.

Third, it inhibits the activation of the nuclear factor κB (NF-κB) pathway, decreasing the release of proinflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6).

By increasing NO levels, L-Arginine HCl significantly reduces platelet aggregation rates under hypercoagulable conditions and alleviates endothelial inflammatory responses.

4. Antioxidative Stress and Attenuation of Endothelial Oxidative Damage

Oxidative stress is a key contributor to endothelial dysfunction. Reactive oxygen species (ROS) inactivate NO, generating inactive peroxynitrite anions (ONOO⁻), while directly damaging endothelial DNA and proteins. The antioxidative effects of L-Arginine HCl are manifested in two aspects:

On one hand, by promoting NO production, NO directly scavenges superoxide anions (O₂⁻), mitigating ROS-induced endothelial damage.

On the other hand, it increases intracellular glutathione (GSH) levels, enhancing the antioxidant defense system of endothelial cells.

Furthermore, L-Arginine HCl ameliorates the "uncoupling" state of eNOS. In the absence of sufficient BH₄, eNOS produces ROS instead of NO. Supplementation with L-Arginine HCl promotes the binding of BH₄ to eNOS, restoring the enzyme’s normal catalytic function and reducing ROS generation.

III. Key Factors Influencing the Efficacy of L-Arginine HCl

The efficacy of L-Arginine HCl in improving endothelial function is not absolute but is regulated by multiple factors:

1. Dosage and Administration Route

Low doses (< 3 g/day) of L-Arginine HCl exert no significant effect on endothelial function in healthy individuals.

Moderate to high doses (3–10 g/day) effectively improve endothelium-dependent vasodilation in patients with cardiovascular diseases.

However, excessive supplementation (> 15 g/day) may overactivate the urea cycle, leading to hyperuremia, and even exacerbate vascular smooth muscle cell proliferation by promoting polyamine synthesis.

In addition, intravenous infusion yields better results than oral administration, as a portion of orally administered arginine is metabolized and degraded in the intestines, resulting in a bioavailability of only 50%–70%.

2. Pathological Status of the Body

L-Arginine HCl shows significant improvement effects in populations with mild endothelial dysfunction (e.g., early-stage hypertension, obesity). However, in patients with severe endothelial damage (e.g., advanced coronary heart disease, diabetic nephropathy), the efficacy of L-Arginine HCl alone is limited due to severe eNOS activity decline and massive ROS accumulation. In such cases, combination therapy with BH₄ and antioxidants (e.g., vitamins C and E) is required.

3. Genetic Polymorphism

Polymorphisms in the eNOS gene (e.g., the Glu298Asp mutation) can affect enzyme activity, and individuals carrying the mutant gene exhibit significantly reduced responsiveness to L-Arginine HCl. Additionally, polymorphisms in the arginase gene influence the metabolic rate of arginine, thereby regulating NO production.

IV. Clinical Application Prospects and Limitations

1. Clinical Application Directions

L-Arginine HCl has been used as an adjunctive therapy for various cardiovascular diseases, including hypertension, coronary heart disease, and peripheral arterial disease, improving patients’ endothelial function and reducing the frequency of angina attacks. Furthermore, supplementation with L-Arginine HCl has demonstrated therapeutic potential in diseases such as pulmonary arterial hypertension and diabetic vascular complications.

2. Limitations

First, there is substantial interindividual variability, with some patients showing no response to L-Arginine HCl treatment.

Second, the long-term safety of L-Arginine HCl remains unclear; long-term high-dose supplementation may increase renal burden.

Third, it cannot replace conventional treatments. L-Arginine HCl serves only as an adjunctive intervention for cardiovascular diseases and cannot substitute for first-line therapies such as antihypertensive drugs and statins.

L-Arginine HCl improves vascular endothelial function through multiple dimensions—regulating vascular tone, maintaining endothelial barriers, resisting inflammation and oxidation, and inhibiting thrombosis—by activating the arginine-NO pathway. Its efficacy depends on dosage, administration route, and the body’s pathological state. Future research should focus on developing precision dosing regimens and combination therapy strategies to further enhance its clinical value in the prevention and treatment of cardiovascular diseases.