Dietary Citrulline but Not Ornithine Counteracts Dietary Arginine Deficiency in Rats by Increasing Splanchnic Release of Citrulline

Abstract

Ornithine and citrulline have different arginine-sparing capabilities when provided in an arginine-deficient diet. Rats were fed arginine-deficient diets containing ornithine or citrulline to see the effect on net fluxes of free arginine, ornithine and citrulline across the portal-drained viscera (PDV) and liver. The diets contained either 10 g arginine/kg diet (+Arg) or no arginine: the -Arg/+Ala diet contained additional alanine and the -Arg/+Orn and -Arg/+Cit diets contained ornithine and citrulline, respectively, in amounts isomolar to the amount of arginine in the control (+Arg) diet. Blood arginine concentrations were 50% lower than control values (P < 0.001) in rats fed the -Arg/+Ala or the -Arg/+Orn diet. However, addition of citrulline to the arginine-deficient diet restored blood arginine concentrations. The source of the circulating arginine in the rats fed the -Arg/+Cit diet was neither the PDV nor the liver; net splanchnic uptake of arginine was 0.3 mumol/min. Net citrulline release was substantial from the PDV (0.65 mumol/min) as well as from the splanchnic bed (0.67 mumol/min) of rats fed the -Arg/+Cit diet, such that blood citrulline concentrations were more than double (P < 0.001) those in rats fed the +Arg or -Arg/+Orn diet. Splanchnic release of citrulline in rats fed the -Arg/+Cit diet but not in rats fed the -Arg/+Orn diet supported the production of arginine in non-splanchnic organs such as, presumably, the kidney.

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

“…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). Thereafter, the bulk of plasma Cit is converted to Arg, mostly in the kidneys (15,24,59,65,70), but also in several other tissues (15,23,70). This is compatible with the significant increase in plasma [Arg] in this study and several previous studies (32,47,53,62) following Cit supplementation.…”

“…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).…”

Arginine synthesis does not occur during first-pass hepatic metabolism in the neonatal piglet

“…Although urea cycle enzymes are abundant in the liver, hepatic release of arginine is low or absent in adult and growing rats (17,20,32), mice (19), and humans (3), even when fed an arginine-free diet (20,21). Adult mammalian hepatocytes have high arginase (EC 3.5.3.1) activity (15,16,22), and there is tight channeling of urea cycle between the cytoplasmic urea cycle enzymes (13), presumably resulting in efficient ammonia detoxification to urea.…”

Feeding and arginine deficient diets differentially alter free amino acid concentrations of hindlimb muscle in young rats

“…Although arginine is synthesized by the liver and kidney, this amino acid, in a manner similar to dietary essential amino acids, shows a decreased concentration in plasma or blood if omitted from the diet of rats (Gross et al, 1991;Hartman and Prior, 1992;Hartman et al, 1994). An imbalanced pattern of essential amino acids in the diet produces an imbalanced pattern of amino acids in muscle tissue, characterized by an exaggerated decrease in the concentration of the most-limiting amino acid in the diet (Leung et al, 1968).…”

“…We have previously reported Prior, 1992 and1996;Hartman et al, 1994) effects of four arginine-free diets on blood concentrations and organ fluxes of amino acids. When alanine, glutamate, ornithine or citrulline were individually substituted for arginine in the diet, concentration of the substituted amino acid was increased in the blood with the exception of glutamate.…”