The Effects of Oral l-Arginine and l-Citrulline Supplementation on Blood Pressure

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Abstract: Nitric oxide (NO) is a well-known vasodilator produced by the vascular endothelium via the enzyme endothelial nitric oxide synthase (eNOS). The inadequate production of NO has been linked to elevated blood pressure (BP) in both human and animal studies, and might be due to substrate inaccessibility. This review aimed to investigate whether oral administration of the amino acids l-arginine (Arg) and l-citrulline (Cit), which are potential substrates for eNOS, could effectively reduce BP by increasing NO production. Both Arg and Cit are effective at increasing plasma Arg. Cit is approximately twice as potent, which is most likely due to a lower first-pass metabolism. The current data suggest that oral Arg supplementation can lower BP by 5.39/2.66 mmHg, which is an effect that is comparable with diet changes and exercise implementation. The antihypertensive properties of Cit are more questionable, but are likely in the range of 4.1/2.08 to 7.54/3.77 mmHg. The exact mechanism by which Cit and Arg exert their effect is not fully understood, as normal plasma Arg concentration greatly exceeds the Michaelis constant (Km) of eNOS. Thus, elevated plasma Arg concentrations would not be expected to increase endogenous NO production significantly, but have nonetheless been observed in other studies. This phenomenon is known as the “l-arginine paradox”.

5. Conclusions and Outlook

Endothelium-dependent vasodilation via NO is essential for cardiovascular regulation in normal human physiology. Dysfunction of the NO pathway occurs via several mechanisms, including substrate unavailability, and has been investigated as a potential pharmacological target. The administration of NO precursors in the form of Arg have shown promising results with less convincing results for Cit, despite its theoretically advantageous pharmacokinetic properties. Their ease of administration and sparse adverse effects makes them great candidates in the first-line treatment of borderline or mild hypertension in addition to lifestyle changes, but more research is needed to determine their efficacy and safety as antihypertensive compounds.

Current evidence suggests a BP-lowering effect of Cit and Arg, but more research is needed to solve the “l-arginine paradox” and understand the exact mechanism by which this occurs. The BP-lowering effect found in the above-presented meta-analyses for both Arg and Cit is based on several small trials with heterogenic study populations regarding baseline BP and comorbidity, in which highly variable intervention durations and dosages were used. More research with larger study populations is needed to confirm these observed effects, establish optimal dosing regiments, and identify possible adverse effects. Furthermore, it would be interesting to identity possible effect modifiers, such as age, gender, comorbidity, and baseline BP, with the latter already demonstrated [49]. This knowledge would be a valuable tool for both the clinician and patient when determining whether one is likely to benefit from these compounds.


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Figure 1. Mechanisms of nitric oxide-mediated vasodilation. Plasma Arg provides the substrate for the synthesis of nitric oxide (NO) via the enzyme endothelial nitric oxide synthase (eNOS) located in the vascular endothelium. The enzymatic reaction requires the co-substrates O2 and nicotinamide adenine dinucleotide phosphate (NADPH) and the cofactors BH4, flavin adenine dinucleotide (FAD), and flavin mononucleotide (FMN). NO diffuses from the endothelial cell to the smooth muscle cell and activates soluble guanylyl cyclase (sGC), resulting in increased cyclic guanosine monophosphate (cGMP) production. cGMP subsequently activates protein kinase G (PKG), resulting in decreased [Ca2+]i via at least four mechanisms: 1. Inhibition of voltage-dependent calcium channels (VDCC), reducing calcium influx. 2. Activation of plasma membrane calcium ATPases (PMCA), increasing ATP-dependent calcium efflux. 3. Inhibition of inositol triphosphate receptors (IP3R), reducing calcium release from the sarcoplasmic reticulum (SR) to the cytoplasm. 4. Activation of sarcoplasmic calcium ATPases (SERCA), increasing the ATP-dependent sequestration of calcium from the cytoplasm to the SR. Decreased [Ca2+]i mediates smooth muscle relaxation via the activation of myosin light chain kinase and the inhibition of myosin light chain phosphatase (not shown in figure), resulting in vasodilation.