Abstract
Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development and progression of multiple age- and lifestyle-related diseases. While l-arginine is the precursor for the synthesis of NO by endothelial-nitric oxide synthase (eNOS), oral l-arginine supplementation is largely ineffective at increasing NO synthesis and/or bioavailability for a variety of reasons. l-citrulline, found in high concentrations in watermelon, is a neutral alpha-amino acid formed by enzymes in the mitochondria that also serves as a substrate for recycling l-arginine. Unlike l-arginine, l-citrulline is not quantitatively extracted from the gastrointestinal tract (i.e., enterocytes) or liver and its supplementation is therefore more effective at increasing l-arginine levels and NO synthesis. Supplementation with l-citrulline has shown promise as a blood pressure lowering intervention (both resting and stress-induced) in adults with pre-/hypertension, with pre-clinical (animal) evidence for atherogenic-endothelial protection. Preliminary evidence is also available for l-citrulline-induced benefits to muscle and metabolic health (via vascular and non-vascular pathways) in susceptible/older populations. In this review, we examine the impact of supplementing this important urea cycle intermediate on cardiovascular and metabolic health outcomes and identify future directions for investigating its therapeutic impact on cardiometabolic health.
Highlights
Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development of multiple age- and lifestyle-related risk factors and diseases including hypertension, atherosclerosis, insulin resistance, type 2 diabetes (T2D), and cardiovascular disease [1,2,3,4]
These studies suggest that L-citrulline supplementation is likely to have great clinical benefits, especially in the context of inflamm-aging, the chronic low-grade inflammation associated with aging [77], which is a well-known aggravating factor for cardiometabolic disorders [78], poor vascular health [79], and overall morbidity and mortality [80]
Increasing numbers of studies suggest that pharmaceutical/nutraceutical grade L-citrulline and watermelon extract supplementation can increase the bioavailability of L-arginine and subsequently lead to elevations in NO synthesis
Summary
Diminished bioavailability of nitric oxide (NO), the gaseous signaling molecule involved in the regulation of numerous vital biological functions, contributes to the development of multiple age- and lifestyle-related risk factors and diseases including hypertension, atherosclerosis, insulin resistance, type 2 diabetes (T2D), and cardiovascular disease [1,2,3,4]. In addition to reductions in NO synthesis, elevations in reactive oxygen species (ROS), especially superoxide (O2 − ), can reduce the bioavailability of NO through the generation of peroxynitrite (ONOO− ), which further promotes endothelial dysfunction that is commonly associated with cardiometabolic diseases [6]. Augmenting L-arginine levels in the potential therapeutic mechanism to increase NO synthesis and bioavailability. Oral L-arginine circulation may represent a potential therapeutic mechanism to increase NO synthesis and supplementation is largely ineffective due to gastrointestinal and hepatic extraction of L-arginine [8]. Oral L-arginine supplementation is largely ineffective due to (Figure 1), as well as a dose-dependent presentation of gastrointestinal distress [9]. L -citrulline supplementation consistently increases plasma and tissue levels of L -arginine and NO presentation of gastrointestinal distress [9]. Consistently increases plasma and tissue levels of L-arginine and NO bioavailability [10,11,12]
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