Can Citrulline Supplementation Lower Blood Pressure?
First let's explain what is citrulline and how does it have any relationship to blood pressure control. Citrulline is an amino acid, although it is not used in the context of the synthesis of proteins. Citrulline can be obtained in the diet from plants of the cucurbitaceae (cucurbits) family such as squash, pumpkin, cucumbers, melons, and watermelon.
Within the body, specifically within cells of the liver, citrulline is produced in the context of the urea cycle. The urea cycle is the metabolic pathway responsible for the elimination of waste nitrogen derived primarily through the oxidation of amino acids but also from nucleotide metabolism. Urea is a small molecule containing two -NH2 groups bonded to a carbon atom to which an oxygen is also attached via a double bond. One of the nitrogen atoms comes from ammonium ion, NH4+, while the other is from the amino acid, aspartic acid. Within the context of the urea cycle to ammonium ion and a bicarbonate ion (HCO3–) are condensed to form carbamoyl phosphate. The carbamoyl phosphate is then condensed with ornithine (one of the two end products of the urea cycle, the other being urea) to form citrulline. Citrulline is then condensed with aspartic acid to form argininosuccinate. Argininosuccinate is hydrolyzed to fumarate and arginine. The generation of arginine from citrulline explains the potential utility of citrulline in blood pressure control. Arginine, along with being an intermediate in the urea cycle and an amino acid incorporated into protein, is the precursor for the potent naturally occurring vasodilator, nitric oxide, NO. Nitric oxide is produced from arginine via the action of the enzyme called nitric oxide synthase, NOS. NOS exists in three distinct forms with the one involved in blood pressure regulation being expressed in the endothelial cells that line the vessels. When produced by endothelial cells the nitric oxide diffuses out and enters the underlying smooth muscle cells, the cells that contract and relax to regulate blood pressure. NO induces the relaxation of smooth muscle cells which leads to vessel relaxation and decreases in blood pressure.
Outside the context of the urea cycle, which only occurs in the liver, citrulline is metabolized to arginine via the action of argininosuccinate synthetase (ASS) in tissues, such as vascular endothelial cells, that produce NO. Within the gut citrulline can be synthesized from glutamine via the action of ornithine carbamoyltransferase (OCT).
High blood pressure (hypertension) is a clearly defined high yield risk factor for heart disease and stroke and remains one of the leading causes of mortality globally. The current therapeutic interventions used in the treatment of hypertension include beta blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs). These drugs can lead to bradycardia (low heart rate), hypotension (low blood pressure), dizziness, constipation, nausea, and sexual dysfunction, particularly in older patients. The use of dietary intervention in hypertension has proven to be successful in many but not all patients. Plant-derived bioactive compounds including polyphenols, as well as cod liver oil, and arginine have been investigated for their potential in reducing hypertension. Recently, several studies have indicated that dietary supplementation with L-citrulline may also have potential beneficial effects on central aortic pressure and peripheral arterial stiffness through its ability to affect endothelial cell arginine levels.
A recent publication performed a meta analysis of publications related to the use and efficacy of citrulline supplementation for blood pressure control:
This meta analysis looked at a total of six reported studies that utilized dietary supplementation with L-citrulline and included control participants in addition to the treated individuals. Two of the trials included postmenopausal women, three enrolled healthy subjects, and one trial included men and non-pregnant women with systolic heart failure. Participant age ranged from 58 to 71 years. Duration of L-citrulline supplementation differed from 1 week to 4 months. The range of the dose of L-citrulline supplementation was between 3 grams and 6 grams per day. In none of the studies was there found to be any specific adverse effects associated with the L-citrulline supplementation.
In the short-term studies there was no finding of significant with respect to L-citrulline supplementation on both systolic and diastolic blood pressure. However, longer-term supplementation of L-citrulline (>8 weeks) revealed a marginally significant decrease in systolic blood pressure.
In comparison of studies using different doses of L-citrulline it was demonstrated that doses of <6 gram per day did not have any significant effect on systolic nor diastolic pressures. Higher doses of L-citrulline (> 6 grams per day) did demonstrate a marginally significant decrease in diastolic blood pressure but was not associated with any significant lowering of systolic blood pressure.
TAKE HOME: Although there is some data that suggests that L-citrulline supplementation may have potential for lowering blood pressure in at risk individuals when taken for long periods of time and at higher doses in individuals there is no clear evidence that L-citrulline can be used in place of more traditional medications for the treatment of hypertension. It is possible that supplementation with L-citrulline may allow for lower doses of traditional pharmaceuticals but there have not been any carefully controlled studies of this type.
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