Urea cycle operation in the arginine deficient rat

Ha, Young Hee; Milner, John A.

doi:10.1016/0006-2944(79)90001-2

Cited by 5 publications

(2 citation statements)

References 19 publications

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“…It serves as a substrate for various isoforms of nitric oxide synthase (NOS) to produce nitric oxide (NO), an important signaling molecule for various organs and tissues, including those in the cardiovascular, neurological and immune systems. In addition, ARG plays an important role in removing ammonia from the body through the urea cycle (Ha and Milner 1979), and serves as a substrate for the endogenous synthesis of creatinine and proline (Wu and Morris 1998). …”

Section: Introductionmentioning

confidence: 99%

Continuous exposure to l-arginine induces oxidative stress and physiological tolerance in cultured human endothelial cells

Mohan

Shin

et al. 2011

Amino Acids

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The therapeutic benefits of L-arginine (ARG) supplementation in humans, often clearly observed in short-term studies, are not evident after long-term use. The mechanisms for the development of ARG tolerance are not known and cannot be readily examined in humans. We have developed a sensitive in vitro model using a low glucose/low arginine culture medium to study the mechanisms of ARG action and tolerance using two different human endothelial cells, i.e., Ea.hy926 and human umbilical venous endothelial cells (HUVEC). Cultured cells were incubated with different concentrations of ARG and other agents to monitor their effects on eNOS expression and function, as well as glucose and superoxide (O2•−) accumulation. Short-term (2 h) exposure to at least 50 μM ARG moderately increased eNOS activity and intracellular glucose (p<0.05), with no change in eNOS mRNA or protein expression. In contrast, 7-day continuous ARG exposure suppressed eNOS expression and activity. This was accompanied by increase in glucose and O2•− accumulation. Co-incubation with 100 μM ascorbic acid, 300 U/ml PEG-superoxide dismutase (PEG-SOD), 100 μM L-lysine or 30 μM 5-chloro-2-(N-2,5-dichlorobenenesulfonamido))-benzoxazole (a fructose-1,6-bisphosphatase inhibitor) prevented the occurrence of cellular ARG tolerance. Short-term co-incubation of ARG with PEG-SOD improved cellular nitrite accumulation without altering cellular ARG uptake. These studies suggest that ARG-induced oxidative stress may be a primary causative factor for the development of cellular ARG tolerance.

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Section: Introductionmentioning

confidence: 99%

Continuous exposure to l-arginine induces oxidative stress and physiological tolerance in cultured human endothelial cells

Mohan

Shin

et al. 2011

Amino Acids

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“…It helps in removing ammonia from the body through the urea cycle (Ha and Milner, 1979) and serves as a substrate for the endogenous synthesis of creatine and proline (Wu and Morris, 1998). ARG has also gained popularity in the last decade as a dietary supplement after its role as the endogenous substrate for Nitric Oxide Synthase (eNOS) to produce Nitric Oxide (NO) was identified.…”

Section: Introductionmentioning

confidence: 99%

DIHYDROBIOPTERIN (BH<sub>2</sub>): KEY DETERMINANT IN INFLUENCING ARGININE MEDIATED ENDOTHELIAL TOLERANCE AND DYSFUNCTION

Mohan¹,

Patel²,

Bolinaga³

et al. 2012

American Journal of Biochemistry and Biotechnology

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The redox-sensitive tetrahydrobiopterin (BH 4 ) is an essential cofactor that is required by endothelial Nitric Oxide Synthase (eNOS) for L-arginine (ARG) mediated Nitric Oxide (NO) generation. Oxidation of BH 4 causes cofactor insufficiency and uncoupling of eNOS, resulting in product switching from NO to O 2•¯ production. Here we tested the hypothesis that eNOS uncoupling is not simply a consequence of BH 4 insufficiency, but rather results from a diminished ratio of BH 4 versus its catalytically incompetent oxidation product, 7,8-dihydrobiopterin (BH 2 ). Human Umbilical Vein Endothelial Cells (HUVEC) were incubated for 2 h in Locke's buffer with 100 µM ARG with or without other agents for 2 h (acute) or in medium for 7 days and challenged in buffer for 2 h (chronic). eNOS activity was determined by cellular accumulation of nitrite/nitrate and its expression was measured using ELISA method. Dihydroethidium fluorescence technique was used to measure O 2•¯ accumulation. For binding studies, cell extracts were quantified for levels of BH 4 , BH 2 , quinonoid isoform of BH 2 (qBH 2 ) and biopterin using a modified HPLC method. [3 H]BH 4 binding studies revealed BH 4 and BH 2 bind eNOS with equal affinity and BH 2 can efficiently replace BH 4 in preformed eNOS-BH 4 complexes. While the total pterin pool of HUVEC was unaffected by chronic (7 days) exposure to ARG, BH 2 levels increased from undetectable to 40% of total pterin. This BH 2 accumulation was associated with diminished NO activity and accelerated O 2 •¯ production. Reciprocally, O 2•¯ production was found to negatively correlate with intracellular ratio of BH 4 -to-BH 2 . Our findings implicate intracellular BH 4 -to-BH 2 ratio, not simply BH 4 amount, as a critical in vitro determinant of eNOS product formation during continuous ARG supplementation. Accordingly, diminished ratio of BH 4 -to-BH 2 is likely to be the fundamental molecular link between oxidative stress and endothelial dysfunction during ARG mediated tolerance development.

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Metabolic Role of Urea Cycle Intermediates: Nutritional and Clinical Aspects

Rogers

Visek

1985

The Journal of Nutrition

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Urea cycle operation in the arginine deficient rat

Cited by 5 publications

References 19 publications

Continuous exposure to l-arginine induces oxidative stress and physiological tolerance in cultured human endothelial cells

Continuous exposure to l-arginine induces oxidative stress and physiological tolerance in cultured human endothelial cells

DIHYDROBIOPTERIN (BH<sub>2</sub>): KEY DETERMINANT IN INFLUENCING ARGININE MEDIATED ENDOTHELIAL TOLERANCE AND DYSFUNCTION

Metabolic Role of Urea Cycle Intermediates: Nutritional and Clinical Aspects

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