The potential of L-Arginine in the treatment of pulmonary arterial hypertension

L-Arginine shows significant potential in the treatment of pulmonary arterial hypertension (PAH) by regulating nitric oxide (NO) production and improving vascular remodeling. It can serve as an adjuvant therapy to relieve symptoms and delay disease progression, but its clinical application requires strict control of dosage and patient selection.

I. Core Mechanisms of Action

1. Promoting Nitric Oxide Synthesis and Dilating Pulmonary Vessels

L-Arginine is a substrate for nitric oxide synthase (NOS). Under the action of NOS, it generates NO, which activates guanylate cyclase in vascular smooth muscle cells, increases cyclic guanosine monophosphate (cGMP) levels, induces smooth muscle relaxation, dilates pulmonary vessels, and reduces pulmonary arterial pressure.PAH patients exhibit decreased NOS activity and impaired L-arginine utilization. Exogenous L-arginine supplementation improves insufficient NO production, reverses pulmonary vasospasm, and lowers pulmonary vascular resistance.

2. Inhibiting Vascular Remodeling and Inflammatory Responses

It inhibits the proliferation of pulmonary arterial smooth muscle cells and reduces collagen deposition, delaying the remodeling process of small pulmonary arterial wall thickening and lumen stenosis, and improving pulmonary vascular compliance.It regulates cytokine secretion, lowers the levels of pro-inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), alleviates inflammatory damage to pulmonary vascular endothelium, and protects the integrity of endothelial function.

3. Improving Right Heart Function

Reduced pulmonary vascular resistance alleviates the afterload of the right ventricle, improves right ventricular hypertrophy and dilation, enhances right ventricular pumping function, and relieves symptoms such as fatigue and dyspnea in PAH patients.

II. Clinical Evidence and Efficacy

1. Preclinical and Clinical Research Performance

Animal experiments have shown that L-arginine supplementation significantly reduces pulmonary arterial systolic pressure in PAH model rats, improves pulmonary vascular remodeling, and prolongs survival.Small-scale clinical studies indicate that after intravenous infusion or oral administration of L-arginine in PAH patients, the 6-minute walk distance increases, the mean pulmonary arterial pressure (mPAP) decreases by an average of 5–8 mmHg, cardiac output improves, and it remains effective in some patients with poor response to traditional drugs.

2. Synergistic Advantages of Combination Therapy

When used in combination with traditional PAH therapeutic drugs such as sildenafil and bosentan, it exerts synergistic effects through the NO-cGMP pathway and other pathways, further enhancing pulmonary vasodilation, improving treatment response rates, and reducing single-drug dosage dependence and adverse reactions.

III. Application Limitations and Challenges

1. Individual Differences in Dosage and Efficacy

The effective dosage range is narrow: low doses may fail to achieve therapeutic effects, while high doses (>10 g/d) are prone to adverse reactions such as gastrointestinal discomfort and hyperkalemia. Additionally, patients vary significantly in their sensitivity to L-arginine.Some patients experience "L-arginine resistance," which may be related to insufficient NOS activity and elevated endogenous inhibitors (e.g., asymmetric dimethylarginine), affecting treatment outcomes.

2. Limitations of Clinical Evidence

Currently, there is a lack of large-sample, long-term follow-up Phase III clinical trials. Its impact on the long-term survival rate of PAH patients remains unclear, and it cannot be used as a first-line therapeutic drug for the time being.The applicable population needs further clarification, and the efficacy differences in PAH associated with congenital heart disease and connective tissue diseases have not been fully elucidated.

IV. Future Research and Application Directions

1. Optimizing Administration Regimens and Formulations

Develop sustained-release formulations targeting pulmonary vessels to increase local drug concentration and reduce systemic adverse reactions; explore combinations with NOS agonists or inhibitors to address L-arginine resistance.

2. Expanding Clinical Research Scope

Conduct large-sample, multi-center clinical trials to clarify its efficacy, optimal dosage, and long-term safety in different PAH subtypes, and verify its impact on patient survival rates.

3. Integrating Precision Medicine Strategies

Screen patients suitable for L-arginine treatment by detecting biomarkers such as NO metabolism levels and NOS activity in the body, realizing personalized treatment and improving clinical benefits.