Interactions between L-arginine and L-glutamine change endothelial NO production. An effect independent of NO synthase substrate availability.

Abstract

The effect of extracellular L-arginine and L-glutamine on nitric oxide (NO) release was studied in cultured bovine aortic endothelial cells and in rabbit aortic rings. Increasing L-arginine (0.01 to 10 mM) did not alter NO release from cultured endothelial cells or modify endothelium-dependent relaxation to acetylcholine in isolated vessels. L-Glutamine (0.6 and 2 mM) inhibited NO release from cultured cells (in response to bradykinin) and from aortic rings (in response to acetylcholine or ADP). L-Arginine (0.1-10 mM) dosedependently reversed the L-glutamine inhibition of receptorstimulated NO release in both models. In contrast to its inhibitory response to receptor-mediated stimuli, glutamine alone slightly potentiated NO release in both models when the calcium ionophore, A23187, was added. Furthermore, cultured cells incubated with L-arginine (0.01-10 mM), in the presence or absence of glutamine, released similar amounts of NO in response to A23187. L-Glutamine did not affect intracellular L-arginine levels. Neither D-glutamine nor D-arginine affected NO release or endothelium-dependent vascular relaxation. L-Glutamine had no effect on the activity of endothelial NOS assessed by L-arginine to L-Citrulline conversion. These findings show that in the absence of L-glutamine, manipulating intracellular L-arginine levels over a wide range does not affect NO release. L-Glutamine in concentrations circulating in vivo may tonically inhibit receptor-mediated NO release by interfering with signal transduction. One mechanism by which L-arginine may enhance NO release is via reversal of the inhibitory effect of L-glutamine, but apparently independently of enhancing NO synthase substrate. (J. Clin. Invest. 1995. 95:2565-2572

Effect of Atherosclerosis on Endothelium-Dependent Inhibition of Platelet Activation in Humans

“…3 Because intracellular concentrations of L-arginine approach 1 mmol/L and the K m for L-arginine ranges between 1 and 3 mol/L, it is believed that the availability of L-arginine is not rate limiting for NO synthesis. [61][62][63][64] Incubation of platelets with L-arginine at concentrations estimated to be produced in vivo in the present study resulted in inhibition of whole blood platelet aggregation to the same extent as during intra-arterial infusion of L-arginine, suggesting that the effect of L-arginine is exerted directly on platelets in the lumen and not via stimulation of the endothelial NO pathway. This direct platelet inhibitory effect of L-arginine appears to be secondary to increased platelet NO activity, 14,65 and human studies that used oral supplementation of L-arginine, which increases plasma L-arginine levels by up to 2-fold, have also shown inhibition of platelet aggregation in normal individuals and patients with hypercholesterolemia.…”

Not Acute but Chronic Hypertriglyceridemia Is Associated With Impaired Endothelium-Dependent Vasodilation

“…It is not likely that the endothelial cells are depleted of L-arginine, because the intracellular concentration of L-arginine has shown to be many times higher than necessary for optimal activity of nitric oxide synthase. 31 Whether deficiency of the cofactor tetrahydrobiopterin plays a role in HTG, as has been demonstrated in diabetes, smoking, and hypercholesterolemia, remains to be elucidated. [32][33][34] Finally, it is conceivable that high amounts of triglyceride-rich lipoproteins accumulate in endothelial cells, as was recently demonstrated in endothelial cells from atherosclerotic plaques in human coronary arteries.…”

Arginine metabolism: nitric oxide and beyond

“…A typical example is the ' arginine paradox ' for NO synthesis, as discussed in the section on arginine transport. Moreover, glutamine does not affect eNOS activity, but inhibits NO production by endothelial cells, and this inhibition can be antagonized by arginine [295,296]. This regulatory property of glutamine may contribute to the ' arginine paradox ' in endothelial cells, and is likely to be of physiological importance.…”