Splanchnic metabolism of dietary arginine in relation to nitric oxide synthesis in normal adult man.

Abstract

Urinary nitrate (NO3) is the stable end product of nitric oxide, which is formed, in turn, from a guanidino nitrogen of arginine. We have conducted two experiments, each in four healthy adult men receiving a low nitrate diet for 7-10 days, to investigate the in vivo conversion of arginine to nitrate.In the first study [guanidino-'5N2, 5,5-2H2]arginine was given on day 7 via a primed continuous intravenous infusion for 8 h. In the second study, the labeled arginine was given for 8 h by the intragastric route on day 7 and by the intravenous route on day 10. Measurement of 1IN03 output in urine collected for 24 h beginning at the time of the arginine tracer infusion revealed a more extensive transfer of 15N when the arginine tracer was given intragastricly. From the comparative labeling of 1IN03 after administration of the tracer arginine via the intragastric and intravenous routes, we estimate that 16% ± 2% of the daily production of nitrate arises from the metabolism of dietary arginine that is taken up during its "first pass" in the splanchnic region. Hence, nitric oxide production occurs, to a measurable extent, in this area in healthy subjects, raising the question as to how various pathophysiological states might alter the relations between exogenous and endogenous sources of arginine as precursors of NO-and the relative contributions made by various organs to whole body (NOB) NO3 formation. These results also raise important questions about the use of nitric oxide synthase inhibitors in animal and human studies.The endogenous synthesis of nitrate by mammals (1, 2) was demonstrated to occur via oxidation of trivalent nitrogen (i.e., amino nitrogen) and to be greatly stimulated by an endotoxin challenge (3). Studies by Marletta and coworkers (4, 5) with murine macrophages disclosed an enzymatic pathway that involved the oxidation of a guanidino nitrogen of L-arginine to nitric oxide (NO-) and its subsequent oxidation and excretion as urinary nitrate (e.g., refs. 6 and 7). Numerous other investigations concerning problems of cardiovascular physiology, neuronal signaling, and endotoxic shock have resulted in the discovery of a large family of NOsynthase enzymes (NOS; EC 1.14.23.-). These NOS include both constitutive and inducible forms and may be membrane bound or cytosolic depending on cell type; the physiological roles of these enzymes have been recently reviewed (8-11). In addition, reports have appeared recently on the isolation and cloning of some of the key genes encoding NOS (12-14), which revealed close sequence similarity to cytochrome P450 reductase (15) and also with functional characteristics of a P450-type hemoprotein (16). Thus, given the apparently large number of isoforms of NOS, their varying distribution in human tissues, and their multiple mechanisms of activation, it is of importance to define the in vivo relationships between arginine metabolism and urinary nitrate in man.In an earlier study, Leaf et al. (6) gave a large oral bolus dose (85 mg-kg-' of body weight) of [15N]arginine t...

l-Arginine-Nitric Oxide Kinetics in Normal and Type 2 Diabetic Subjects

“…This study supports the finding of Castillo et al (3), who showed that NO synthesis represents only 1.2% of the flux of plasma arginine in adults. The fraction of NO synthesis from arginine agrees also in terms of daily amino acid intake; the same group given 28 mmol arginine per day, a figure similar to our estimated intake, found a fractional conversion of labeled arginine to nitrates of 1.95% (18). They found that the contribution of arginine to NO based on intravenous [ 15 N]arginine infusion is lower than that obtained with intragastric infusion (18).…”

Two weeks of watermelon juice supplementation improves nitric oxide bioavailability but not endurance exercise performance in humans

“…However, while oral L-arginine supplementation can increase circulating [L-arginine] [4,5], and therefore one of the substrates for nitric oxide synthase, whether oral Larginine supplementation increases nitric oxide biomarkers (nitrate and nitrite) and improves exercise performance is controversial [4,[6][7][8][9], see 10 for review]. These conflicting findings might be linked, at least in part, to significant pre-systemic [11,12] and systemic [11,[13][14][15][16] breakdown of orally ingested L-arginine.…”

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

“…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. Orally ingested L-arginine is strongly trapped in the gastrointestinal tract and the hepatic tissue, where it is extensively catabolized by arginase, [9][10][11]15) leading to very limited oral bioavailability.…”

“…8) However, relatively large doses of Larginine are required to produce these effects in humans. Approximately 40% of oral L-arginine is metabolized by arginase on the first pass, 9,10) and a further 15% of systemic L-arginine is abstracted and metabolized by the liver. 11) L-Citrulline is present in the body and is a potent endogenous precursor of L-arginine as part of the recycling system within the L-citrulline-NO cycle.…”