L Arginine

 10 supplements and drugs for stiff rbcs (red blood cells)

Potential Supplements:

1. Omega-3 Fatty Acids: May help improve RBC membrane fluidity.

2. Vitamin D: Deficiency has been linked to RBC stiffness.

3. Magnesium: Can play a role in RBC membrane function.

4. Vitamin E: Acts as an antioxidant, protecting RBC membranes.

5. L-Arginine: Precursor to nitric oxide, which can improve blood flow.

Potential Drugs (Always consult with a healthcare provider before starting any medications):

1. Pentoxifylline: Improves blood flow and reduces RBC aggregation.

2. Cilostazol: Inhibits platelet aggregation and improves RBC deformability.

3. Voxelotor: Used for sickle cell disease, improves RBC deformability.

4. L-glutamine -  for sickle cell disease. It can help protect red blood cells from damage.

5. Crizanlizumab - A monoclonal antibody used to reduce the frequency of vaso-occlusive crises in sickle cell disease.

Stiff red blood cells can be a concern because they may not flow as easily through blood vessels, potentially leading to various health issues such as poor oxygen delivery to tissues, increased risk of clotting, or complications related to diseases like sickle cell anemia. While there's no universal treatment aimed solely at "softening" red blood cells, treatments for conditions associated with stiff red blood cells often aim to improve their flexibility, reduce their tendency to clump together, or address the underlying cause. Here are some supplements and drugs that might be used in the management of conditions leading to stiff red blood cells or to improve their function:

1. Hydroxyurea - Often used in the treatment of sickle cell disease to increase fetal hemoglobin levels, which can make red blood cells more flexible.

2. Omega-3 Fatty Acids (e.g., fish oil supplements) - These can improve cell membrane flexibility, including that of red blood cells, potentially improving their ability to deform and navigate through small capillaries.

3. Magnesium Supplements - Magnesium plays a role in maintaining the flexibility of the cell membrane and may help in conditions associated with red blood cell rigidity.

4. Arginine - A supplement that may help in conditions like sickle cell disease by releasing nitric oxide, which can improve blood flow and reduce the stickiness of red blood cells.

5. Vitamin B12 and Folic Acid - These supplements are important for red blood cell formation and can help prevent conditions like anemia, which can affect red blood cell health.

6. L-glutamine - Approved for sickle cell disease, this amino acid has been shown to reduce the frequency of sickle cell crises, potentially by influencing the red blood cells' health.

7. Penicillamine - Sometimes used in the treatment of conditions like Wilson's disease, it can affect the structure of red blood cells but is not primarily used for this purpose.

8. Ivacaftor - A drug used for certain cystic fibrosis mutations, it's included because it shows how targeting the underlying cause of a disease can indirectly improve red blood cell function.

9. Corticosteroids - In certain conditions leading to altered red blood cell flexibility, such as autoimmune hemolytic anemia, corticosteroids can reduce inflammation and immune system activity against red blood cells.

10. Iron Supplements - Iron is crucial for hemoglobin production in red blood cells. While not directly making red blood cells more flexible, addressing iron deficiency anemia ensures the production of healthy red blood cells with normal functionality.

1. Omega-3 fatty acids: These essential fatty acids, particularly EPA and DHA, can help improve RBC membrane flexibility and reduce inflammation.

2. Vitamin E: This antioxidant vitamin helps protect RBC membranes from oxidative stress and may improve their flexibility.

3. Vitamin C: Another antioxidant that can help protect RBCs from oxidative damage and improve their flexibility.

4. Magnesium: This mineral is essential for maintaining RBC membrane integrity and flexibility.

5. Zinc: Zinc plays a role in maintaining RBC membrane stability and may help reduce RBC stiffness.

6. Coenzyme Q10 (CoQ10): This antioxidant can help protect RBCs from oxidative damage and improve their flexibility.

7. L-arginine: This amino acid is a precursor to nitric oxide, which can help improve blood flow and reduce RBC stiffness.

8. Pentoxifylline: This prescription medication is sometimes used to improve blood flow and reduce RBC stiffness in conditions such as peripheral artery disease.

9. Hydroxyurea: This prescription medication is used to treat sickle cell anemia, a condition characterized by stiff and abnormally shaped RBCs. It works by increasing the production of fetal hemoglobin, which can help prevent RBC sickling.

10. Statins: These prescription medications, typically used to lower cholesterol, may also help improve RBC flexibility and reduce inflammation.

Proven supplements for sickle cell disease

Arginine: An essential amino acid for individuals with SCD, arginine plays a crucial role in the synthesis of nitric oxide, which helps regulate blood flow and blood pressure. SCD patients often experience arginine deficiency, leading to endothelial dysfunction and vaso-occlusive crises. Studies have shown that supplementation with L-arginine can improve liver function, increase plasma arginine concentration and nitric oxide metabolite levels, thereby reducing oxidative stress. Additionally, arginine supplementation has been observed to enhance total antioxidant activity and erythrocyte integrity​ (Dove Med Press)​.

Glutamine: Recognized as conditionally essential in SCD due to increased requirements, glutamine supplementation has been linked to reduced resting energy expenditure, improved glutamine nutritional status, and decreased incidents of SCD-related vaso-occlusive pain events. The FDA has approved pharmaceutical-grade L-glutamine for children and adults with SCD, recommending a specific dosage for those over five years of age who experience frequent pain events​ (Dove Med Press)​.

Vitamin D: Vitamin D deficiency is common among SCD patients and can contribute to complications such as osteopenia and osteoporosis. A study found that high-dose Vitamin D supplementation significantly reduced respiratory events in children with SCD, indicating a protective effect against respiratory infections. Ensuring adequate Vitamin D levels is crucial for bone health, immune regulation, and inflammation control​ (Dove Med Press)​.

Hydration: Proper hydration is essential for preventing sickle cell crises, as dehydration can lead to increased blood viscosity and vaso-occlusion. Recommendations for maintaining good hydration include frequent intake of water and other fluids, limiting dietary sodium intake to prevent dehydration of erythrocytes, and avoiding conditions that cause excessive sweating​ (Dove Med Press)​.

Magnesium: The role of magnesium, both intravenous and oral, in treating SCD has been studied, with mixed results. Studies have explored its impact on pain levels, hospital stay durations, and quality of life, with moderate to low quality evidence suggesting that magnesium therapy, both intravenously and orally, does not significantly affect these outcomes in SCD patients. This conclusion highlights the need for further research to clarify the potential benefits of magnesium supplementation in SCD​ (Welcome)​.

Here are some supplements that have shown promise:

1. L-Glutamine: This amino acid has been approved by the FDA as a prescription medication for reducing the frequency of sickle cell crises. It helps to reduce oxidative stress and improve the integrity of red blood cells.

2. Omega-3 Fatty Acids: Some studies suggest that omega-3 fatty acids, particularly DHA and EPA, may help reduce inflammation and blood cell adhesion, which are factors in sickle cell complications.

3. Vitamin D: Many individuals with sickle cell disease have vitamin D deficiency, which can exacerbate symptoms. Vitamin D supplementation may help to reduce pain and inflammation.

4. Folic Acid: This B vitamin is essential for red blood cell production. Supplementation may help to reduce the severity and frequency of sickle cell crises.

5. Zinc: Zinc deficiency is common in sickle cell disease and can contribute to impaired immune function. Zinc supplementation may help to reduce the risk of infections.

Nutrition in sickle cell disease: recent insights (2018)

The review emphasizes that nutritional deficiencies are fundamental to SCD severity. Both children and adults with SCD have much higher energy requirements than healthy individuals. They tend to suffer from undernutrition if energy intake is consistently low (Hibbert et al, 2018). Specific nutrient shortages may also exist, such as glutathione deficiency, which exacerbates inflammation and oxidative stress that drive disease complications (Archer et al, 2008).

Studies show SCD patients require significantly higher energy and protein intakes compared to healthy controls:

• Singhal et al (2002) found children aged 3-6 years with SCD had higher resting metabolic rates but similar energy intake vs controls, indicating a relative energy deficiency.

• Heyman et al (1985) found combined macro/micronutrient supplements improved clinical status and reduced hospitalizations in growth-delayed children with SCA vs micronutrients alone.

• In a mouse model, Manci et al (2014) showed a high protein diet (35% energy from protein vs 20%) reduced inflammatory markers CRP and IL-6, suggesting potential to decrease inflammation driving organ damage.

Specific amino acids are conditionally essential in SCD:

• Arginine deficiency impairs nitric oxide synthesis, disrupting vascular function (Morris, 2014). Supplementing 1g/day improved liver function and increased arginine/nitric oxide levels, with greater effects in SCD vs controls (Kehinde et al, 2015). In children, arginine/citrulline supplements enhanced arginine bioavailability and endothelial function (Cox et al, 2018).

• Glutamine synthesis becomes compromised, and a deficit may increase metabolic stress and muscle wasting. Supplements of 0.6g/kg/day decreased resting energy expenditure by 6%, improving nutritional status in children (Williams et al, 2004). Pharmaceutical grade L-glutamine is now FDA-approved for treating SCD.

Vitamin D deficiency affects up to 80% of SCD patients, contributing to osteoporosis and pain crises. Low serum levels <14ng/mL were linked to more annual hospital visits vs levels >34ng/mL (McCaskill et al, 2018). A 2-year trial in children found high dose vitamin D3 (100,000 IU/month ≈ 3,333 IU/day vs 12,000 IU/month ≈ 400 IU/day) reduced respiratory events and stabilized serum levels (Lee et al, 2018).

Hydration is crucial as dehydration increases blood viscosity and sickling. Even sickle cell trait carriers can have higher blood viscosity during strenuous exercise (Diaw et al, 2014). Limiting dietary sodium helps maintain hydration (Williams-Hooker et al, 2013).

The gut microbiome influences inflammation in SCD. Mouse models show gut bacteria regulate VOC through effects on aged neutrophils (Zhang et al, 2015). One human study found lower abundance of commensal Firmicutes and higher pathogenic Proteobacteria in SCD vs sickle cell trait, correlating with hemolysis marker LDH (Lim et al, 2018). Promoting healthy gut microbiota through diet may help optimize immunity.

Antioxidant-rich plant foods show promise as adjunct therapy, with some compounds demonstrating anti-sickling effects in early studies (Wright et al, 2017; Nurain et al, 2017; Tang et al, 2017). However, more research is needed on dosage and safety.

Commonalities between sickle cell disease and polycythemia vera

Sickle cell disease (SCD) and polycythemia vera (PV) are two distinct blood disorders that impact the body in different ways, yet they share some commonalities in terms of their effects on blood characteristics and potential complications. Here are several aspects in which they can be similar:

1. Blood Flow Problems: Both conditions can lead to issues with blood flow. In SCD, the sickle-shaped red blood cells can cause blockages in the blood vessels, leading to pain crises and potential organ damage. In PV, the increased blood viscosity due to high red blood cell counts can slow blood flow and also lead to clotting issues, which can result in similar complications such as strokes or heart attacks.

2. Increased Risk of Blood Clots: Both SCD and PV patients have an increased risk of developing blood clots. In PV, the thicker blood and higher numbers of blood cells directly contribute to this risk. In SCD, the irregularly shaped cells can lead to vascular inflammation and stasis, increasing the risk of thrombosis.

3. Complications: Both diseases come with a range of potential complications. These can include increased risk of infections, stroke, and acute chest syndrome in SCD, and thrombosis, bleeding, and spleen enlargement in PV. Both conditions may lead to serious health issues that require ongoing management.

4. Treatment Focus on Blood Characteristics: Treatment for both conditions may involve interventions aimed at modifying the characteristics or quantities of blood cells. For instance, phlebotomy (removal of blood) is a common treatment for PV to reduce hematocrit levels, while in SCD, treatments may include hydroxyurea to increase fetal hemoglobin levels or blood transfusions to replace sickle cells with normal red blood cells.

5. Genetic Factors: Both SCD and PV have genetic components. SCD is an inherited genetic condition, caused by a mutation in the gene that codes for hemoglobin. PV is often associated with a mutation in the JAK2 gene, which is acquired rather than inherited, but still reflects the role of genetic mutations in the development of the disease.

6. Chronic Management: Both conditions are chronic and require lifelong management to mitigate symptoms and manage complications. This may include regular medical check-ups, medication, lifestyle adjustments, and sometimes more invasive treatments like stem cell transplantation.

Despite these similarities, it's important to note the distinct nature of each condition. SCD is a genetic disorder affecting hemoglobin structure, leading to anemia and crises from the misshaped cells, while PV is a type of blood cancer that leads to overproduction of red blood cells, causing a different set of challenges related to blood volume and viscosity.

Sickle Cell Disease (SCD) and Polycythemia Vera (PV) are both blood disorders, but they have very different causes and effects. Here are some commonalities between them:

1. Increased Blood Viscosity:

• SCD: Sickle-shaped red blood cells can block blood flow, leading to increased viscosity.

• PV: Overproduction of red blood cells in PV also leads to increased blood thickness.

2. Thrombotic Complications:

• SCD: Blockage of blood vessels by sickled cells can cause painful crises and organ damage.

• PV: Increased red blood cell count can lead to clotting, increasing the risk of heart attacks and strokes.

3. Overlap in Symptoms

• Both: Fatigue, shortness of breath, and headaches can be present in both conditions, although they arise for different reasons.

4. Potential for Organ Damage:

• SCD:  Can lead to damage in various organs, including the spleen, kidneys, and lungs due to blockages in blood flow.

• PV: Organ damage can occur in PV, primarily due to blood clots, which can affect the heart, brain, and other organs.

5. Treatment Approaches

• Both: In some cases, treatments may overlap - for instance, hydroxyurea is used in both conditions to help manage the production of blood cells (though it's used for different reasons in each). Phlebotomy, or blood removal, might also be employed in both conditions to reduce blood viscosity, though it is a primary treatment in PV but less common in SCD.

Key Learnings from Sickle Cell Disease (SCD) for Potential Application in Polycythemia Vera (PV)

While Sickle Cell Disease (SCD) and Polycythemia Vera (PV) are distinct hematological disorders with different genetic roots, there are overlapping phenotypic manifestations that warrant a closer look. Both conditions involve red blood cell (RBC) abnormalities such as increased stiffness and stickiness, leading to microvascular occlusion and a cascade of downstream complications. These shared characteristics open the door to exploring therapeutic strategies that have shown promise in SCD for potential benefits in PV.

Therapeutic Overlap: Beyond JAK2 Inhibition

• Hydroxyurea (HU): A cornerstone in SCD management, HU has been shown to induce fetal hemoglobin (HbF) production, decreasing the frequency of painful vaso-occlusive crises. While PV doesn’t involve sickling, HU’s potential in reducing RBC count, and possibly inflammation could offer benefits.

• L-glutamine: This amino acid supplement is FDA-approved for SCD and works by reducing oxidative stress in red blood cells. Given that oxidative stress is implicated in the pathophysiology of PV-related complications, L-glutamine’s role warrants investigation.

• Voxelotor: This drug enhances hemoglobin's affinity for oxygen, which in SCD, reduces sickling and hemolysis. For PV patients, particularly those resistant or intolerant to phlebotomy, voxelotor might improve oxygen delivery to tissues.

• Crizanlizumab: A monoclonal antibody targeting P-selectin, crizanlizumab, inhibits cellular interactions that lead to vaso-occlusion in SCD. Since increased adhesion molecules are present on PV red blood cells and platelets, this could offer a new avenue to explore in PV management.

Supplements and Dietary Considerations

• Omega-3 Fatty Acids have anti-inflammatory properties which could potentially help in mitigating the chronic inflammation seen in both conditions and improve blood flow.

• Magnesium plays a crucial role in various enzymatic reactions, including those involved in RBC deformability and aggregation.

• Vitamin D deficiency is common in SCD and emerging evidence suggests its potential role in PV. Supplementation could support overall health and potentially influence disease progression.

• Antioxidant-rich Foods like berries, leafy greens and nuts, which can combat oxidative stress, a shared feature of both SCD and PV.

Lifestyle Modifications

• Hydration is crucial for blood viscosity, particularly in PV where hematocrit levels are elevated.

• Regular Exercise but of a low-impact nature such as swimming or walking to improve cardiovascular health without exacerbating RBC fragility.

• Stress Management techniques like mindfulness meditation or yoga can help in reducing the frequency and severity of complications associated with both disorders.

• Avoiding Tobacco and excessive alcohol due to their detrimental effects on vascular health and blood rheology

[write a 2000 word article on key learnings (regarding drugs, supplements and other) from sickle cell disease that may be applicable or should be tested in polycythemia vera. Remember that PV is more than JAK2+. It's also a phenotype that involves RBC abnormalities (stiffness and stickiness), platelet abnormalities etc. I'd like to help PV patients with supplements and similar ideas that have worked in SCD.]

L-Arginine supplementation enhances antioxidant activity and erythrocyte integrity in SCA subjects (2015)

Effects of l‐arginine supplementation in patients with sickle cell disease: A systematic review and meta‐analysis of clinical trials (2023)

Supplementation with l-arginine stabilizes plasma arginine and nitric oxide metabolites, suppresses elevated liver enzymes and peroxidation in sickle cell anaemia (2016)

The effect of l-arginine on liver function in SCD has received little or no attention. The effect of a chronic, oral, low-dose supplementation with l-arginine (1gm/day for 6 weeks) on some liver enzymes, lipid peroxidation and nitric oxide metabolites was studied in 20 normal (non-sickle cell anaemia; NSCA) subjects and 20 sickle cell anaemia (SCA) subjects. Ten milliliters of blood was withdrawn from an ante-cubital vein for the estimation of plasma arginine concentration ([R]), alanine aminotransaminase (ALT), aspartate aminotransaminase (AST) and alkaline phosphatase (ALP), plasma total bilirubin concentration [TB], malondialdehyde concentration [MDA] and nitric oxide metabolites concentration [NOx]. Before supplementation, ALT, AST, ALP (p<0.05 respectively) and TB (p<0.001) were higher in SCA subjects than in NSCA subjects. [R] and [NOx] were higher in NSCA subjects (p<0.001 and p<0.05 respectively). Supplementation caused greater percent increases in [R], and [NOX] in SCA than in NSCA subjects (p<0.001 in each case). l-Arginine caused greater percent reductions in ALT and AST in SCA subjects but greater percent reduction in ALP in NSCA subjects (p<0.001 in each case). Changes in [MDA] and [TB] in the two groups were similar. Study shows that chronic, oral, low-dose supplementation with l-arginine improved liver function, oxidative stress, plasma arginine concentration and nitric oxide metabolites levels in NSCA and SCA subjects. Responses in SCA subjects to l-arginine were more sensitive than in NSCA subjects.

ED (2022)

The study included 95 men aged 20 to 75 years with ED. Participants received two grams of L-arginine three times per day or a placebo three times daily for three months. Their penile blood flow and testosterone levels were measured, and participants completed the International Index of Erectile Function six question (IIEF-6) patient questionnaires at the beginning and end of the trial. Among patients taking arginine, 74% experienced an improvement in ED degree as categorized by questionnaire responses, while only 18% of the placebo group experienced improvements. Additionally, at study completion, 24% of the men taking L-arginine had IIEF-6 scores that showed they no longer were diagnosable with ED.

The Potential Role of Arginine Supplements on Erectile Dysfunction: A Systemic Review and Meta-Analysis (2019)

Results: In total, 10 randomized controlled trials met the inclusion criteria, reporting the outcomes of 540 patients with ED. The analysis demonstrated that arginine supplements with dosage ranging from 1,500 to 5,000 mg significantly improved ED compared with placebo or no treatment (odds ratios, 3.37 [1.29, 8.77], P = .01, I2 = 44). Arginine supplements also caused significant improvements in the IIEF subdomain scores of overall satisfaction, intercourse satisfaction, orgasmic function, and erectile function, whereas the IIEF sexual desire score remain unchanged. The adverse effect rate in the arginine-treated group was 8.3%, and that in the placebo group was 2.3%, none of which were severe.

Clinical implications: Arginine supplements can be recommended to patients with mild to moderate ED.

Long-term high-dose l-arginine supplementation in patients with vasculogenic erectile dysfunction: a multicentre, double-blind, randomized, placebo-controlled clinical trial (2022)

Methods

The current randomized, double-blind, placebo-controlled clinical trial addressed the effects on penile erectile function of relatively high daily oral doses (6 g/day) of l-ARG for 3 months (N = 51) compared to placebo (N = 47), in patients with vasculogenic ED, with comparison between mild–moderate and severe vasculogenic ED.

The outcome measures included IIEF-6 score and cavernous arteries peak systolic flow velocity (PSV) at dynamic penile duplex ultrasonography (PDU).

Results

l-ARG supplementation for 3 months significantly increased IIEF-6 score in the overall cohort (p < 0.0001) and in subgroups of patients with mild–moderate (p < 0.0001) and severe (p = 0.007) vasculogenic ED; PSV was significantly increased in the overall cohort (p < 0.0001) and in patients with mild–moderate (p < 0.0001), but not severe vasculogenic ED. At study completion, 74% of patients improved ED degree category, although only 24% of patients, mainly belonging to the baseline category of mild ED, reached IIEF-6 scores compatible with absence of ED; moreover, 20% of patients, exclusively belonging to the baseline category of mild–moderate vasculogenic ED, reached PSV values compatible with absence of ED.

Conclusion

The results of the current study demonstrated that supplementation with relatively high doses of l-ARG as a single compound for 3 months significantly improved penile erectile function, assessed by both IIEF-6 score and PSV at dynamic PDU in patients with mild–moderate, and improved IIEF-6 score, but not PSV, in patients with severe vasculogenic ED, therefore suggesting that l-ARG might be an alternative treatment in mild–moderate vasculogenic ED patients experiencing adverse effects or with contraindications for chronic treatment with PDE5i compounds.

L-arginine supplementation to mitigate cardiovascular effects of walking outside in the context of traffic-related air pollution in participants with elevated blood pressure: A randomized, double-blind, placebo-controlled trial

Exposure to traffic-related air pollution (TRAP) increases blood pressure (BP) and cardiovascular morbidity and mortality. We aimed to evaluate the potential efficacy of L-arginine supplementation in mitigating the adverse cardiovascular effects of adults with elevated BP walking outside under TRAP using a randomized, double-blind and placebo-controlled trial. 118 adults with elevated BP were recruited and were randomly assigned to either the placebo group or the intervention group with 9 g/day L-arginine supplementation for 2 weeks. On the 14th day, paired participants from the two groups walked along a traffic road for 2 h. Resting BP, L-arginine-nitric oxide metabolites and inflammatory biomarkers were measured before, during and after the 2 h exposure scenario, and ambulatory BP and Holter were measured during the 2 h outdoor walk. Participants in the intervention group had significantly elevated plasma L-arginine levels compared to the placebo group after supplementation. The two groups had similar exposures to traffic-related air pollutants. However, participants in the intervention group showed significant reductions of 5.3 mmHg (95% CI: −9.9, −0.7) in resting systolic BP (SBP), 4.3 mmHg (95% CI: −7.2, −1.3) in resting diastolic BP (DBP) and 4.6 mmHg (95% CI: −7.9, −1.3) in resting mean arterial pressure (MAP) at 30 min after the 2 h outdoor walk compared with the placebo group. There were also significant decreases in ambulatory SBP, DBP and MAP (7.5–9.9 mmHg, 5.3–7.6 mmHg and 4.7–7.9 mmHg, respectively) during the walk in the intervention group compared with the placebo group. There were no substantial changes in ST-segment level, L-arginine-NO metabolites and inflammatory biomarkers, and no significant associations were found between specific traffic-related air pollutants and cardiovascular health indicators. Specifically, our study shows that oral L-arginine supplementation was safe and well-tolerated, and could improve BP levels in adults with elevated BP during outside walk under TRAP.

Influence of L-citrulline and watermelon supplementation on vascular function and exercise performance (2017)

L-citrulline, either as a supplement or in watermelon, may improve vascular function by increasing L-arginine bioavailability and nitric oxide synthesis. Recent studies have shown that:

• Acute L-citrulline ingestion increases plasma L-arginine, the substrate for endothelial nitric oxide synthesis, by up to 10-fold (Kim et al, 2015). However, this does not consistently lead to acute improvements in nitric oxide production and vasodilation in young or older adults (Kim et al, 2015; Churchward-Venne et al, 2014). This likely explains why acute L-citrulline or watermelon intake does not improve exercise tolerance.

• In contrast, chronic L-citrulline supplementation (1-8 weeks) has been shown to increase nitric oxide synthesis by 21-37%, decrease blood pressure, and potentially increase peripheral blood flow in middle-aged and older adults with cardiovascular risk factors (Bailey et al, 2015; Ochiai et al, 2012; Wong et al, 2016). These changes are accompanied by improvements in skeletal muscle oxygenation and endurance exercise performance (Bailey et al, 2015; Suzuki et al, 2016).

• The antihypertensive effect of L-citrulline/watermelon supplementation for 6-8 weeks is evident in adults with prehypertension or hypertension, with reductions of 7-9 mmHg in systolic and 3 mmHg in diastolic blood pressure (Wong et al, 2016; Figueroa et al, 2012). However, in young normotensive adults, the evidence is mixed, with some studies showing no effect (Bailey et al, 2016) and others reporting blood pressure lowering of 7/11 mmHg after just 7 days of supplementation (Alsop & Hauton, 2016).

• Even in normotensive young men, 2 weeks of L-citrulline supplementation (6 g/day) has been shown to attenuate the blood pressure response to exercise and cold exposure, suggesting a potentially cardioprotective effect during stress (Figueroa et al, 2016).

• Regarding exercise performance, most studies using L-citrulline alone (without malate) have not found acute supplementation to improve metrics like VO2max, time to exhaustion, anaerobic threshold, or blood lactate, likely because it does not acutely enhance nitric oxide bioavailability (Cutrufello et al, 2015).

• However, with longer L-citrulline supplementation of at least 6-7 days, studies have reported improvements in cycling power output, time to exhaustion, and time trial performance by 1.5-12% (Bailey et al, 2015; Suzuki et al, 2016). This is paralleled by increased muscle oxygenation, attributed to enhanced nitric oxide mediated vasodilation and blood flow. Interestingly, similar ergogenic effects were not seen with watermelon juice supplementation (Bailey et al, 2016).

In summary, while acute L-citrulline intake can markedly elevate plasma L-arginine, it does not consistently enhance vascular function or exercise performance. In contrast, chronic L-citrulline supplementation shows more promise for increasing nitric oxide bioavailability, reducing blood pressure especially in adults with hypertension, improving muscle oxygenation, and boosting endurance exercise performance. The vascular benefits likely stem from L-citrulline's ability to increase L-arginine levels while escaping breakdown by arginase. However, higher doses (6 g/day) and longer supplementation periods (>7 days) may be needed to maximize these effects. More research is warranted on the clinical implications, especially in at-risk populations.

l-Citrulline Supplementation: Impact on Cardiometabolic Health (2018)

Introduction and Background:

• Reduced nitric oxide (NO) bioavailability contributes to development of hypertension, atherosclerosis, insulin resistance, type 2 diabetes, and cardiovascular disease.

• L-citrulline supplementation is more effective than L-arginine at increasing L-arginine and NO levels, since L-citrulline is not extracted by the gastrointestinal tract or liver.

• Watermelon is a natural source of L-citrulline. The L-citrulline concentration in watermelon ranges from 1.6-3.5 g/kg.

Pharmacokinetics and Metabolism:

• Oral L-citrulline increases plasma L-arginine concentrations, peaking after 1-2 hours. Levels return to baseline within 8 hours.

• The effective L-citrulline dose ranges from a minimum of 3 g/day up to 10 g/day. Higher doses (e.g. 15 g/day) may saturate transporters.

• L-citrulline is transported across the intestines, likely via neutral amino acid transporters. It is not metabolized by the liver. The kidneys convert L-citrulline to L-arginine.

Vascular and Blood Pressure Effects:

• L-citrulline increases L-arginine and NO levels, which improves vascular endothelial function and reduces blood pressure in pre-/hypertensive adults.

• 7 days of L-citrulline (5.6 g/day) reduced arterial stiffness in middle-aged men (Ochiai et al. 2012).

• 6 weeks of watermelon extract (6 g/day L-citrulline) reduced aortic blood pressure, arterial stiffness, and carotid-femoral pulse wave velocity in obese postmenopausal women with hypertension (Figueroa et al. 2013).

• L-citrulline attenuates the blood pressure response to acute stressors like the cold pressor test and isometric handgrip exercise (Sanchez-Gonzalez et al. 2013, Figueroa et al. 2016).

• L-citrulline may improve cardiac function by decreasing right ventricular systolic pressure in heart failure patients (Orozco-Gutierrez et al. 2010).

Metabolic Effects:

• L-citrulline may improve skeletal muscle protein synthesis via both NO-dependent and independent pathways. It stimulated muscle protein synthesis in malnourished older rats (Osowska et al. 2006).

• L-citrulline may increase mitochondrial biogenesis in skeletal muscle by activating PGC-1α. Supplementation (250 mg/kg) for 15 days increased PGC-1α in mice (Villareal et al. 2018).

• In adipose tissue, L-citrulline promotes lipolysis and fatty acid oxidation while reducing re-esterification. It increased expression of uncoupling protein-1 in rat adipose explants (Joffin et al. 2015).

Conclusions:

In summary, oral L-citrulline supplementation, either as a nutraceutical or from watermelon, increases L-arginine and NO bioavailability. This improves vascular function and reduces resting and stress-induced blood pressure in pre-/hypertensive adults. L-citrulline also has direct metabolic effects in skeletal muscle and adipose tissue that may improve body composition and mitochondrial function. The vascular and metabolic benefits occur at doses of 3-10 g/day. More research is needed on the long-term safety and efficacy of L-citrulline supplementation. Overall, L-citrulline shows promise as a nutritional approach to improve cardiometabolic health.

Effects of L-citrulline supplementation on blood pressure: A systematic review and meta-analysis (2019)

We searched MEDLINE, SCOPUS, PUBMED and Google scholar databases from inception to November 16, 2017 and 811 papers were identified, of which 8 trials with 10 data sets met the inclusion criteria. Inclusion criteria were: (1) application of randomized clinical trial with either crossover or parallel designs; (2) studies conducted in adults (≥18 y); (3) oral supplementation with L-citrulline compared to control group; (4) expression of sufficient data about systolic and diastolic BP at baseline and at the end of the study in each group. BP effects were pooled by random-effects models, with trials weighted by inverse variance.

The included studies’ sample size ranged between 12 and 34 subjects. The mean age of the participants in these trials ranged between 22 and 71 years. Dosage of L-citrulline supplementation varied from 3 to 9 g/day. Duration of the intervention ranged between 1 and 17 weeks. The pooled changes in systolic and diastolic BP were (MD, −4.10 mm Hg; 95% CI [−7.94, -0.26]; p=0.037) and (MD −2.08 mm Hg; 95% CI [−4.32, 0.16]; P=0.069), respectively. The subgroup analysis showed a significant diastolic BP reduction in studies that used doses of ≥6 g/day (MD −2.75 mm Hg; 95% CI [−5.37, -0.12]; p=0.04).

Our results suggest that L-citrulline supplementation may reduce systolic BP. A significant reduction in diastolic BP was observed only in the studies that used doses ≥ 6 g/day.

Effects of Oral L-Citrulline Supplementation on Lipoprotein Oxidation and Endothelial Dysfunction in Humans with Vasospastic Angina (2013)

Should You Take Citrulline Supplements? (link)

Ways to increase your NO

1. Beets and Beetroot Juice: Beets are rich in dietary nitrates, which the body can convert to nitric oxide. Consuming beets or beetroot juice has been shown to enhance NO levels, thereby improving vascular health. However, individuals should monitor their intake carefully to manage carbohydrate intake.

2. Leafy Green Vegetables: Vegetables such as spinach, arugula, and kale are excellent sources of dietary nitrates. Incorporating these into the diet can support NO synthesis without significantly impacting blood sugar levels, making them ideal for diabetics.

3. Watermelon: Rich in the amino acid L-citrulline, watermelon can enhance NO production. L-citrulline is converted to L-arginine in the body, a precursor for nitric oxide. However, due to its sugar content, portion control is essential to avoid blood sugar spikes.

4. Garlic: Studies suggest that garlic can stimulate the production of nitric oxide synthase, the enzyme responsible for converting L-arginine into NO. Garlic also offers the added benefit of potentially improving cardiovascular health without adversely affecting blood glucose levels.

5. Nuts and Seeds: Almonds, walnuts, and flaxseeds, among others, contain high levels of L-arginine, an amino acid that serves as a direct substrate for the production of nitric oxide. They also provide healthy fats, fiber, and other nutrients beneficial for cardiovascular health and diabetes management.

6. Supplements: Certain supplements can be beneficial in increasing nitric oxide levels. L-arginine and L-citrulline supplements are among the most researched in this context. However, it is crucial for individuals with diabetes to consult with a healthcare professional before starting any new supplement, as they can interact with medications or affect blood sugar levels.

7. Antioxidant-rich Foods: Foods high in antioxidants, such as berries, oranges, and pomegranates, can support NO levels by protecting NO molecules from oxidative stress. This is particularly relevant for diabetics, who may experience higher levels of oxidative stress.

Web reference: https://www.healthline.com/nutrition/how-to-increase-nitric-oxide#antioxidants

L-Arginine: anti-aging pilot study (2010)

In an open-label randomised limited study conducted by the author, 5 g/day l-arginine base was administered orally once at night for 28 days in 21 subjects with age ranging between 41 and 75 years old (14 between 41 and 49 years, 4 between 50 and 59 years, 2 between 60 and 69 years, and 1 between 70 and 79 years), 16 were males and 5 females, 17 were non-smokers and 4 smokers, and 18 of the 21 subjects were taking other medications to control either hypertension, myocardial ischemia, diabetes, gastro-oesophageal reflux disease (GERD) and hyperacidity, hypothyroidism, neuritis, or rheumatoid. 

A questionnaire was given to the subjects to be completed weekly for 4 weeks. The subjects were advised to write their health status before and after taking l-arginine. The questionnaire included 30 points regarding their mental, muscular, sexual, circulatory, GIT, and other functions during the 4-week administration. Scoring was recorded from 1 to 5; 1 was a remarkable improvement, 2 was a mild improvement, 3 no difference, 4 was worse than before, and 5 was not applicable. The subjects were also advised to report any adverse reactions developed during the administration of the supplement. In addition, they were asked if they wanted to continue taking the supplement after termination of the study.

Nitric Oxide in MPNs (2011)

In addition to releasing substances that stimulate thrombus generation following injury, endothelial cells and activated platelets release the platelet inhibitor nitric oxide (NO), providing a negative feedback mechanism for the propagation of thrombus formation[33]. NO is a free radical product generated through the oxidation of L-arginine to L-citrulline by NO synthases (NOS). The endothelial-derived NO is one of the main mediators influencing vascular hemodynamics and the interaction of leukocytes and platelets with endothelial cells. In fact, NO mediates vascular relaxation in response to vasoactive substances and shear stress; inhibits platelet adhesion, activation, secretion, and aggregation; and promotes platelet disaggregation. Moreover, NO inhibits expression of P-selectin on platelets as well as it impairs leukocyte adhesion to the endothelium. 

Clinical conditions have been reported in which a deficiency of endogenous NO production may contribute to a thrombotic event [33]. For example, impaired platelet-derived NO may contribute to the development of acute coronary syndromes by influencing platelet function or recruitment and consequent thrombus formation [34]. Our group recently studied circulating NO in MPN patients [32]. We found reduced plasma levels of NO in patients with ET compared to controls. This finding confirms previous observations that in MPN patients with thrombocytosis, the production of NO by platelets is impaired [35]. However, in the same study and for the first time, we observed that ET patients treated with hydroxyurea presented with the highest levels of plasma NO. 

A similar effect of hydroxyurea on NO plasma levels has been reported in patients with sickle cell anemia [36] and it may contribute to the well-known ability of hydroxyurea to prevent thromboembolic complications in ET patients [37] In the same study, PV patients showed high plasma NO levels compared to controls and these levels were not affected by hydroxyurea treatment. This is expected as it has been shown that high hematocrit levels are associated with increased NO levels in the blood [38]. This may represent a compensatory mechanism in a situation of high thrombotic risk. 

The metabolic adaptation evoked by arginine enhances the effect of radiation in brain metastases (2021)

Selected patients with brain metastases (BM) are candidates for radiotherapy. A lactatogenic metabolism, common in BM, has been associated with radioresistance. We demonstrated that BM express nitric oxide (NO) synthase 2 and that administration of its substrate l-arginine decreases tumor lactate in BM patients. In a placebo-controlled trial, we showed that administration of l-arginine before each fraction enhanced the effect of radiation, improving the control of BM. Studies in preclinical models demonstrated that l-arginine radiosensitization is a NO-mediated mechanism secondary to the metabolic adaptation induced in cancer cells. We showed that the decrease in tumor lactate was a consequence of reduced glycolysis that also impacted ATP and NAD+ levels. These effects were associated with NO-dependent inhibition of GAPDH and hyperactivation of PARP upon nitrosative DNA damage. These metabolic changes ultimately impaired the repair of DNA damage induced by radiation in cancer cells while greatly sparing tumor-infiltrating lymphocytes.

L-Arginine supplementation inhibits the growth of breast cancer by enhancing innate and adaptive immune responses mediated by suppression of MDSCs in vivo (2016)

Background

L-Arg is involved in many biological activities, including the activation of T cells. In breast cancer patients, L-Arg is depleted by nitric oxide synthase 2 (NOS2) and arginase 1 (ARG-1) produced by myeloid-derived suppressor cells (MDSCs). Our aim was to test whether L-Arg supplementation could enhance antitumor immune response and improve survivorship in a rodent model of mammary tumor.

Methods

Tumor volumes in control and L-Arg treated 4 T1 tumor bearing (TB) BALB/c mice were measured and survival rates were recorded. The percentages of MDSCs, dendritic cells (DCs), regulatory T cells (Tregs), macrophages, CD4+ T cells, and CD8+ T cells were examined by flow cytometry. Additionally, levels of IL-10, TNF-α, and IFN-γ were measured by enzyme-linked immunosorbent assay (ELISA) and nitric oxide (NO) levels were measured by the Griess reaction. IFN-γ, T-bet, Granzyme B, ARG-1 and iNOS mRNA levels were examined by real-time RT-PCR.

Results

L-Arg treatment inhibited tumor growth and prolonged the survival time of 4 T1 TB mice. The frequency of MDSCs was significantly suppressed in L-Arg treated TB mice. In contrast, the numbers and function of macrophages, CD4+ T cells, and CD8+ T cells were significantly enhanced. The IFN-γ, TNF-α, NO levels in splenocytes supernatant, as well as iNOS, IFN-γ, Granzyme B mRNA levels in splenocytes and tumor blocks were significantly increased. The ARG-1 mRNA level in tumor blocks, the frequency of Tregs, and IL-10 level were not affected.

Conclusion

L-Arg supplementation significantly inhibited tumor growth and prolonged the survival time of 4 T1 TB mice, which was associated with the reduction of MDSCs, and enhanced innate and adaptive immune responses.