l -citrulline and l -arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits

Abstract

The objective of this study was to evaluate the influence of ingested L-arginine, L-citrulline, and antioxidants (vitamins C and E) on the progression of atherosclerosis in rabbits fed a highcholesterol diet. The fatty diet caused a marked impairment of endothelium-dependent vasorelaxation in isolated thoracic aorta and blood flow in rabbit ear artery in vivo, the development of atheromatous lesions and increased superoxide anion production in thoracic aorta, and increased oxidation-sensitive gene expression [Elk-1 and phosphorylated cAMP response element-binding protein]. Rabbits were treated orally for 12 weeks with L-arginine, L-citrulline, and͞or antioxidants. L-arginine plus L-citrulline, either alone or in combination with antioxidants, caused a marked improvement in endothelium-dependent vasorelaxation and blood flow, dramatic regression in atheromatous lesions, and decrease in superoxide production and oxidation-sensitive gene expression. These therapeutic effects were associated with concomitant increases in aortic endothelial NO synthase expression and plasma NO 2 ؊ ؉ NO 3 ؊ and cGMP levels. These observations indicate that ingestion of certain NO-boosting substances, including L-arginine, L-citrulline, and antioxidants, can abrogate the state of oxidative stress and reverse the progression of atherosclerosis. This approach may have clinical utility in the treatment of atherosclerosis in humans.antioxidant ͉ nitric oxide ͉ amino acids ͉ endothelial nitric oxide synthase A therosclerosis is an inflammatory disease (1) characterized by vascular endothelial cell dysfunction and diminished production of NO (2-5). Endothelial NO synthase (eNOS) gene transfer can reduce atherogenesis in hypercholesterolemic animals (6). NO is a widespread signaling molecule in the cardiovascular system, which functions in multiple ways to protect against the initiation and progression of atherosclerosis (7-9). For example, NO aids in preventing the adhesion and aggregation of blood cells and platelets along the endothelial cell lining in blood vessels (7,8) and is a potent inhibitor of vascular smooth muscle cell proliferation (10). NO is a potent antioxidant that can elicit antiinflammatory effects by scavenging certain reactive oxygen species (11-13), and it can prevent the oxidation of low-density lipoprotein cholesterol and thereby retard the progression of atherosclerosis (5, 14). Moreover, NO deficiency is generally associated with up-regulation of oxidation-sensitive genes, whereas increased NO production leads to decreased expression of oxidation-sensitive genes (7,15). NO is synthesized by NOS, which utilizes L-arginine as substrate and produces L-citrulline as the second reaction product. L-arginine can be synthesized from L-citrulline in endothelial and other cell types, thereby providing a recycling pathway for the conversion of L-citrulline to NO via L-arginine (16)(17)(18)(19).The oral administration of L-arginine to animals (7, 12, 20-26) and humans (5,8,(27)(28)(29) has been demonstrated to slow the progressi...

The effects on plasma L-arginine levels of combined oral L-citrulline and L-arginine supplementation in healthy males

“…As previously reported in animal studies, 17,18) this study was useful in terms of confirming the combination effects on plasma L-arginine increase in humans as well as in animals. One possible reason for this combination effect might be due to the inhibiting effect of L-citrulline on arginase, which metabolizes L-arginine to urea and L-ornithine.…”

“…17) Intriguingly, we recently discovered, in an animal study, that oral supplementation with a combination of L-citrulline and L-arginine efficiently increases plasma L-arginine concentration and peripheral circulation. 18) However, the effects of this combination on humans have not as yet been investigated.…”

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

“…A hallmark of enhanced NO synthesis is a reduction in blood pressure owing to NO-induced smooth muscle relaxation (22 (46), enhanced endotheliumdependent vasorelaxation in response to acetylcholine (25), and an association between the change in the Arg-to-ADMA ratio and flow-mediated dilation (53) with Cit, we have shown for the first time that pure Cit supplementation can reduce blood pressure in healthy normotensive adults. An increase in cGMP has been reported after short-term Cit consumption (53), which suggests that the reduction in blood pressure with Cit might result from NO-cGMP-related smooth muscle relaxation.…”

Low-dose l -arginine administration increases microperfusion of hindlimb muscle without affecting blood pressure in rats

“…Although NO synthase, the enzyme that produces NO from L-arginine, is theoretically saturated with its natural substrate, exogenous L-arginine administration leads to increased NO production, and this phenomenon is known as the arginine paradox (9,10). Therefore, many investigators have been interested in the effects of supplementation with L-arginine to produce increased beneficial effects of NO, including prevention of the progression of atherosclerosis (11,12), prevention of pulmonary artery endothelial dysfunction (13,14), enhancement of cellular immune response of T lymphocytes (4), and amelioration of hypertension (15,16). Other studies indicate that oral supplementation of L-arginine also corrects endothelial dysfunction of chronic heart failure (17), and it increases exercise capacity in patients with precapillary pulmonary hypertension by increasing peak oxygen consumption and decreasing pulmonary arterial pressure and pulmonary vascular resistance thorough the action of NO (18).…”