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. 2019 Jul 22;11(7):1679.
doi: 10.3390/nu11071679.

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

Free PMC article

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

David Khalaf et al. Nutrients. .
Free PMC article


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".

Keywords: amino acids; blood pressure; eNOS; hypertension; nitric oxide; nutrition.

Conflict of interest statement

The authors declare no conflict of interest.


Figure 1
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.
Figure 2
Figure 2
Chemical structure of (a) l-arginine and (b) l-citrulline.

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