Citrulline is the non-essential amino acid that is a more effective booster of the nitric oxide than the arginine — it is converted to the arginine in the kidneys (through the argininosuccinate synthetase and the argininosuccinate lyase reactions), and this conversion is a more efficient and more reliable way to increase the arginine levels and to support the nitric oxide synthesis than the direct arginine supplementation. The reason for this is that the arginine is rapidly metabolised by the arginase enzyme (which is abundant in the liver and in the endothelial cells) and by the nitric oxide synthase (which competes with the arginase for the arginine), so the arginine levels fluctuate widely after the arginine supplementation and the net increase in the nitric oxide production is modest. The citrulline, on the other hand, is not a substrate for the arginase (it is not metabolised by the arginase enzyme), and it is efficiently converted to the arginine in the kidneys (where the argininosuccinate synthetase and the argininosuccinate lyase are highly expressed) — making it a more reliable and more sustained source of the arginine for the nitric oxide synthesis. Without adequate citrulline and arginine synthesis, the nitric oxide production is reduced, the vasodilation is impaired, and the endothelial dysfunction and the hypertension develop — the hallmark of the citrulline deficiency and of the impaired nitric oxide production. The typical dietary citrulline intake from the watermelon, the cucumber, the muskmelon, and the other cucurbitaceae plants is 0.1-0.5g daily, and the therapeutic doses for the cardiovascular support are 2-8g of the citrulline supplement daily — making it one of the most evidence-based interventions for the endothelial dysfunction, the hypertension, and the cardiovascular disease.
Citrulline and the Endothelial Function
Citrulline supports the endothelial function primarily through its conversion to the arginine and the subsequent increase in the nitric oxide production by the endothelial nitric oxide synthase (eNOS). The nitric oxide is the most important signalling molecule in the cardiovascular system — it is produced by the eNOS in the endothelial cells, it diffuses to the underlying vascular smooth muscle cells, and it activates the guanylyl cyclase, which increases the cyclic GMP (cGMP) levels, causes the smooth muscle relaxation, and produces the vasodilation. This vasodilation is the primary mechanism by which the nitric oxide regulates the blood pressure, the blood flow, and the delivery of the oxygen and the nutrients to the tissues. The endothelial dysfunction (which is the condition that is characterised by the reduced nitric oxide production and the impaired vasodilation) is one of the primary drivers of the hypertension, the atherosclerosis, and the cardiovascular disease — and the citrulline supplementation has been shown to be one of the most effective interventions for the reversal of the endothelial dysfunction and for the reduction of the blood pressure.
The clinical importance of the citrulline for the cardiovascular health is underscored by the observation that the citrulline supplementation improves the endothelial function and reduces the blood pressure in people with the hypertension and in the people with the endothelial dysfunction. A meta-analysis of 8 RCTs in over 300 participants with the hypertension found that the citrulline supplementation at 2-6g daily significantly reduced the systolic blood pressure (by 5-8mmHg) and the diastolic blood pressure (by 3-5mmHg) — making citrulline one of the most effective natural interventions for the hypertension. Another study in 20 patients with the type 2 diabetes found that the citrulline supplementation at 3g daily for 8 weeks significantly improved the endothelial function (by 25-30%, as measured by the flow-mediated dilation) and reduced the fasting blood glucose (by 10-15%) — demonstrating the potent metabolic and cardiovascular effect of the citrulline in patients with the metabolic syndrome.
Practical Application
For general citrulline supplementation for the nitric oxide and for the cardiovascular support, the evidence-based approach is to supplement with 2-8g of L-citrulline daily (as the pure L-citrulline powder or capsule, taken in divided doses of 1-2g, 2-4 times per day). The citrulline should be taken on the empty stomach (30-60 minutes before the meals or 2 hours after the meals) for the optimal absorption, and it should be taken with the arginine (which is the direct product of the citrulline conversion and which works synergistically with the citrulline for the nitric oxide production — though the citrulline alone is more effective than the arginine alone because it bypasses the arginase competition). The citrulline is generally well-tolerated with no significant adverse effects at doses up to 10g daily, and it does not have any known drug interactions or contraindications — though people with the guanidinoacetate methyltransferase deficiency (a rare genetic disorder that impairs the creatine synthesis) should use the citrulline with caution and under the supervision of a qualified healthcare practitioner. For comprehensive nitric oxide and cardiovascular support, citrulline pairs well with the arginine (which is the direct product of the citrulline conversion and which works synergistically with the citrulline for the nitric oxide production), with the antioxidants (vitamin C, vitamin E, polyphenols — which protect the nitric oxide from the oxidative inactivation and which work synergistically with the citrulline for the endothelial function), with the omega-3 fatty acids (which have complementary effects on the endothelial function and on the inflammation), and with the exercise (which increases the eNOS activity and which works synergistically with the citrulline for the nitric oxide production and for the cardiovascular adaptation).
Leave a Reply