Therapeutic Use of Citrulline in Cardiovascular Disease

Abstract

L-citrulline is the natural precursor of L-arginine, substrate for nitric oxide synthase (NOS) in the production of NO. Supplemental administration L-arginine has been shown to be effective in improving NO production and cardiovascular function in cardiovascular diseases associated with endothelial dysfunction, such as hypertension, heart failure, atherosclerosis, diabetic vascular disease and ischemia-reperfusion injury, but the beneficial actions do not endure with chronic therapy. Substantial intestinal and hepatic metabolism of L-arginine to ornithine and urea by arginase makes oral delivery very ineffective. Additionally, all of these disease states as well as supplemental L-arginine enhance arginase expression and activity, thus reducing the effectiveness of L-arginine therapy. In contrast, L-citrulline is not metabolized in the intestine or liver and does not induce tissue arginase, but rather inhibits its activity. L-citrulline entering the kidney, vascular endothelium and other tissues can be readily converted to L-arginine, thus raising plasma and tissue levels of L-arginine and enhancing NO production. Supplemental L-citrulline has promise as a therapeutic adjunct in disease states associated with L-arginine deficiencies.

l-Citrulline supplementation improves O2 uptake kinetics and high-intensity exercise performance in humans

“…In an attempt to overcome the well-developed interorgan system for Arg clearance, recent studies have investigated the efficacy of oral Cit supplementation as an alternative method to enhance NO production via NOS. Oral Cit supplementation is appealing in this regard, since Cit is not significantly metabolized in the gut (68) and liver (59,65) and Ͻ1% of orally ingested Cit is excreted in the urine (50). As such, the majority of an oral Cit load passes into the systemic circulation, as reflected by a significant increase in plasma [Cit] after Cit ingestion in the current study and numerous previous reports (8,16,42,51,53).…”

“…Cit is then extracted by the kidneys to be converted, in sequence, to argininosuccinate and Arg by the enzymes arginoinosuccinate synthase and arginoinosuccinate lyase, respectively (15,24,59,65,70). Synthesis of Arg from Cit is prevalent in other tissues (15,23,70), and this process is facilitated since Cit does not compete with ADMA for cell transport (50,69). Importantly, it has been shown that oral Cit supplementation more effectively increases the circulating (32,47,53,62) and tissue (63) [Arg] than an equivalent dose of Arg and that Cit supplementation can increase NOS activation (63) and NO biomarkers (46,53).…”

The metabolites of glutamine prevent hydroxyl radical-induced apoptosis through inhibiting mitochondria and calcium ion involved pathways in fish erythrocytes

“…About 80-90% of Cit is derived from Gln in the gut, and about 15% of Arg appearance is via the conversion of Cit in the kidneys [131,132]. Citrulline is the precursor of Arg [133]. Studies suggested that Arg can scavenge ROS in rat hearts [134] and abrogate oxidative stress in experimental mice [135,136] and patient [137].…”

1H NMR and GC–MS based metabolomics reveal nano-Cu altered cucumber (Cucumis sativus) fruit nutritional supply

“…Ornithine and citrulline are nonessential amino acids, which participate in central reactions in the urea cycle (Sureda and Pons, 2012). Dietary interest for ornithine and citrulline has considerably increased during the last decade (Romero et al, 2006;Rouge et al, 2007). The up-regulation of a portion of metabolites will benefit the cucumber fruit, because most of them are carbohydrates (xylose, fructose) and necessary amino acids (glycine and proline).…”