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Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610-0274
2To whom correspondence should be addressed. E-mail: baylisc{at}ufl.edu.
Much of the discussion after this session centered on whether arginine supplementation would be beneficial in various pathophysiological states such as atherothrombosis, renal disease, and hypertension. As Dr. Jaimes indicated (1), the clinical studies in renal disease patients have been disappointing because neither acute nor chronic arginine administration to renal patients has either improved endothelial function or slowed down the rate of progression of the renal disease (2–5). This was unanticipated because plasma asymmetric dimethylarginine (ADMA)3 levels rise to high values in patients with renal disease, reducing the arginine-to-ADMA ratio to values that will inhibit endothelial nitric oxide (NO) production (6–9). Because ADMA is a competitive inhibitor of the NO synthase (NOS), arginine supplementation should reverse the damaging actions of high ADMA. However, it is possible that the lack of response to arginine loading in renal patients might reflect the presence of some factor(s) in uremic plasma that inhibits arginine uptake into the cell. Studies in cell culture confirmed this possibility (10) and showed that a factor in plasma from both peritoneal dialysis and immediately prehemodialysis, end stage renal disease (ESRD) patients, significantly reduced arginine uptake by endothelial cells. Subsequent studies showed that uremic levels of urea (above 
15 mmol/L) inhibit arginine entry into the endothelial cell in vitro by a noncompetitive mechanism that requires urea entry, which in turn means that endothelial cells possess urea transporters (11). Thus, it is possible that one reason why renal disease patients are not responsive to arginine loading is that the arginine cannot reach the active site of the endothelial NOS. Most likely, the urea transporters on the endothelial cell membrane normally function to remove intracellular urea formed by local arginases, although it is unknown whether arginase activity in endothelial cells modulates the urea transporters.
The other conditions within the cell will also affect the response to arginine loading. For example, the availability of cofactors will also affect endothelial NO production in a variety of states where endothelial dysfunction occurs, including atherosclerosis, hypertension, and renal disease. For example, tetrahydrobiopterin availability is very important and will be depleted in states of oxidant stress, such as renal disease and hypertension. When tetrahydrobiopterin is scarce, the endothelial NOS will switch to generate superoxide anion as well as NO (12), and in this situation arginine loading may be damaging by causing peroxynitrite formation. This could explain the lack of benefit in some patients with established atherothrombosis (13) and the variability in response to arginine loading seen in hypertensive states (12,14). Furthermore, endothelial NOS activity is regulated by many mechanisms, some of which could affect the response to arginine loading. For example, in the presence of oxidized LDL, endothelial NOS leaves the caveolae (15), which could limit the access of administered arginine to the active site of the enzyme.
Finally, it was pointed out that most of the data presented involved investigations of the responses to infusions or dietary supplementation of arginine alone, and that arginine concentrations were the primary concern. Additional insights might be gained by investigating arginine-ornithine ratios or arginine-ornithine-lysine ratios.
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FOOTNOTES |
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3 Abbreviations used: ADMA, asymmetric dimethylarginine; ESRD, end stage renal disease; NO, nitric oxide; NOS, nitric oxide synthase;
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LITERATURE CITED |
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 TOP LITERATURE CITED |
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1. Cherla, G. & Jaimes, E. A. (2004) Role of L-arginine in the pathogenesis and treatment of renal disease. J. Nutr. 134:2801S-2806S.
2. Cross, J. M., Donald, A. E., Kharbanda, R., Deanfield, J. E., Woolfson, R. G. & MacAllister, R. J. (2001) Acute administration of L-arginine does not improve arterial endothelial function in chronic renal failure. Kidney Int. 60:2318-2323.[Medline]
3. Bennett-Richards, K. J., Kattenhorn, M., Donald, A. E., Oakley, G. R., Varghese, Z., Bruckdorfer, K. R., Deanfield, J. E. & Rees, L. (2002) Oral L-arginine does not improve endothelial dysfunction in children with chronic renal failure. Kidney Int. 62:1372-1378.[Medline]
4. De Nicola, L., Bellizzi, V., Minutolo, R., Andreucci, M., Capuano, A., Garibotto, G., Corso, G., Andreucci, V. E. & Cianciaruso, B. (1999) Randomized, double-blind, placebo-controlled study of arginine supplementation in chronic renal failure. Kidney Int. 56:674-684.[Medline]
5. Zhang, X. Z., Ardissino, G., Ghio, L., Tirelli, A. S., Dacco, V., Colombo, D., Pace, E., Testa, S. & Claris-Appiani, A. (2001) L-arginine supplementation in young renal allograft recipients with chronic transplant dysfunction. Clin. Nephrol. 55:453-459.[Medline]
6. Vallance, P., Leone, A., Calver, A., Collier, J. & Moncada, S. (1992) Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 339:572-575.[Medline]
7. Xiao, S., Schmidt, R. J. & Baylis, C. (2000) Plasma from ESRD patients inhibits nitric oxide synthase (NOS) activity in cultured human and bovine endothelial cells. Acta Phys. Scand. 168:175-179.[Medline]
8. Kielstein, J. T., Boger, R. H., Bode-Boger, S. M., Schaffer, J., Barbey, M., Koch, K. M. & Frolich, J. C. (1999) Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J. Am. Soc. Nephrol. 10:594-600.
9. Zoccali, C., Bode-Boger, S., Mallamaci, F., Benedetto, F., Tripepi, G., Malatino, L., Cataliotti, A., Bellanuova, I., Fermo, I., Frolich, J. & Boger, R. (2001) Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 358:2113-2117.[Medline]
10. Xiao, S., Wagner, L., Mahaney, J. & Baylis, C. (2001) Uremic levels of urea inhibit L-arginine transport in cultured endothelial cells. Am. J. Physiol. Renal. 280:F989-F995.
11. Wagner, L., Klein, J., Sands, J. & Baylis, C. (2002) Urea transporters are widely distributed in endothelial cells and mediate inhibition of L-arginine transport. Am. J. Physiol. Renal 283:F578-F582.
12. Landmesser, U., Dikalov, S., Price, S. R., McCann, L, Fukai, T., Holland, S. M., Mitch, W. E. & Harrison, D. G. (2003) Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension. J. Clin. Invest. 111:1201-1209.[Medline]
13. Loscalzo, J. (2004) L-Arginine and atherothrombosis. J. Nutr. 134:2798S-2800S.
14. Gokce, N. (2004) L-arginine and hypertension. J. Nutr. 134:2807S-2811S.
15. Blair, A., Shaul, P. W., Yuhanna, I. S., Conrad, P. A. & Smart, E. J. (1999) Oxidized low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation. J. Biol. Chem. 274:32512-32519.
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