Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: Potential therapy for postoperative pulmonary hypertension

Barr, Frederick E.; Tirona, Rommel G.; Taylor, Mary; Rice, Geraldine D.; Arnold, Judith; Cunningham, Gary; Smith, Heidi; Campbell, Adam; Canter, Jeffrey A.; Christian, Karla G.; Drinkwater, Davis C.; Scholl, Frank G.; Kavanaugh‐McHugh, Ann; Summar, Marshall

doi:10.1016/j.jtcvs.2007.02.043

Cited by 63 publications

(53 citation statements)

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“…Moreover most important, the urea cycle and the nitric oxide cycle are linked via ASS1 and ASL. Previous studies 5,6 have shown that a quantitative change in urea cycle enzyme expression and function can affect nitric oxide production by limiting substrate availability. Therefore, the abnormalities within the urea cycle result in urea cycle disorder and affect other physiological systems.…”

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confidence: 99%

DNA Methylation Suppresses Expression of the Urea Cycle Enzyme Carbamoyl Phosphate Synthetase 1 (CPS1) in Human Hepatocellular Carcinoma

Liu

Dong

Robertson

et al. 2011

The American Journal of Pathology

103

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Carbamoyl phosphate synthetase 1 (CPS1) is a liverspecific, intramitochondrial, rate-limiting enzyme in the urea cycle. A previous study showed that CPS1 is the antigen for hepatocyte paraffin 1 antibody, a commonly used antibody in surgical pathology practice; and CPS1 expression appears to be down-regulated in liver cancer tissue and cell lines. The aim of this study is to understand how the CPS1 gene is regulated in liver carcinogenesis. In this report, we show that human hepatocellular carcinoma (HCC) cells do not express CPS1, whereas cultured human primary hepatocytes express abundant levels. In addition, CPS1 was silenced or down-regulated in liver tumor tissues compared with the matched noncancerous tissues. The expression of CPS1 in HCC cells was restored with a demethylation agent, 5-azacytidine. We show that two CpG dinucleotides, located near the transcription start site, and a CpG-rich region in the first intron were hypermethylated in HCC cells. The hypermethylation of the two CpG dinucleotides was also detected in HCC tumor tissues compared with noncancerous tissues. Further molecular analysis with mutagenesis indicated that the two CpG dinucleotides play a role in promoter activity of the CPS1 gene. In conclusion, our study demonstrates that DNA methylation is a key mechanism of silencing CPS1 expression in human HCC cells, and CPS1 gene hypermethylation of the two CpG dinucleotides is a potential biomarker for HCC.

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confidence: 99%

DNA Methylation Suppresses Expression of the Urea Cycle Enzyme Carbamoyl Phosphate Synthetase 1 (CPS1) in Human Hepatocellular Carcinoma

Liu

Dong

Robertson

et al. 2011

The American Journal of Pathology

103

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“…Together, these findings suggest that superoxide production and not NO production is the predominant role for NOS-3 in the pathogenesis of VILI in this model, thus providing in vivo evidence for uncoupling of NOS as a mechanism for oxidative stress in VILI. In support of this, treatment of wild-type mice with the NOS-3 cofactor BH 4 and the antioxidant ascorbic acid led to a reduction in VILI, presumably via enhanced coupling of NOS-3. The major limitation of this study was the use of a supraphysiological tidal volume to induce VILI, limiting the potential clinical relevance of the findings.…”

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confidence: 80%

“…A second factor that can lead to uncoupling of NOS is insufficiency of the NOS cofactor tetrahydrobiopterin (BH 4 ), which is normally bound to the oxygenase domain (22). Factors that can lead to reductions in BH 4 include oxidative stress (8) and ischemia reperfusion (22). Reactive oxygen species can also react with NO to form peroxynitrite.…”

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confidence: 99%

“…In critically ill children, plasma levels of citrulline and L-arginine were also low and were associated with the severity of inflammation (20). In children at risk for postoperative pulmonary hypertension after cardiopulmonary bypass, low plasma L-arginine levels are a risk factor for postoperative pulmonary hypertension (3), and citrulline supplementation is currently being studied as a potential therapy (1,4). BH 4 supplementation is another potential target that is currently being studied in vascular diseases including systemic hypertension, peripheral arterial disease, coronary artery disease, pulmonary arterial hypertension, and sickle cell disease (7).…”

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confidence: 99%

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Understanding the role of NOS-3 in ventilator-induced lung injury: don't take NO for an answer

Ware

Summar

2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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ALTHOUGH NITRIC OXIDE SYNTHASES (NOSs) were first described in 1989 (12), these complex enzymes are still not fully understood, and their role in human lung disease remains unclear. Three NOS isoforms have been described in humans: neuronal or nNOS (NOS-1), inducible or iNOS (NOS-2), and endothelial or eNOS (NOS-3). All isoforms of NOS are modular enzymes with a reductase domain and an oxygenase domain. When electron transfer between the reductase and oxygenase domains is coupled, synthesis of nitric oxide (NO) and Lcitrulline from the substrate L-arginine is catalyzed via coupling of L-arginine oxidation with O 2 reduction. Dimerization of NOS monomers is required for this NO synthesis and occurs in the presence of heme protein. The NOS product NO is a ubiquitous signaling molecule that regulates vascular tone and blood flow, leukocyte adhesion, platelet aggregation, and mitochondrial oxygen consumption (9).There are several conditions under which the tightly linked reductase and oxygenase functions of NOS can become uncoupled, inhibiting NO production. Under uncoupled conditions, NOS preferentially catalyzes the reduction of molecular oxygen to form superoxide ion. One well-described factor leading to NOS uncoupling is substrate deficiency (5). LArginine is the only known substrate for NO synthesis by NOS. Although not an essential amino acid, L-arginine can become conditionally essential in situations of metabolic stress such as sepsis. L-Arginine can be synthesized in vivo from the urea cycle intermediate product L-citrulline (also generated by NOS), by argininosuccinate synthase, and argininosuccinate lyase. Factors that lead to reductions in citrulline/arginine availability include ischemia reperfusion and physiological stress (3,13,18). A second factor that can lead to uncoupling of NOS is insufficiency of the NOS cofactor tetrahydrobiopterin (BH 4 ), which is normally bound to the oxygenase domain (22). Factors that can lead to reductions in BH 4 include oxidative stress (8) and ischemia reperfusion (22). Reactive oxygen species can also react with NO to form peroxynitrite. Peroxynitrite can, in and of itself, lead to uncoupling of NOS. Another factor that can contribute to NOS uncoupling is endogenous production of asymmetric dimethyl arginine (ADMA), a competitive inhibitor of NOS that has been shown to cause uncoupling of NOS-3 (2, 17). Chronic uncoupling of NOS has been implicated in several human diseases including diabetes (9), hypertension (9), and diastolic dysfunction (16).The role of NOS in ventilator-induced lung injury is not well understood, and data from experimental models have provided conflicting results. Frank and colleagues (6) reported that ventilator-induced lung injury (VILI) in rats was associated with induction of NOS-2. Inhibition of NOS-2 in this model ameliorated VILI. Peng and colleagues (14) reported that in a mouse model of VILI using NOS-2Ϫ/Ϫ mice, NOS-2 deficiency was protective. Peng and colleagues also studied NOS-3Ϫ/Ϫ mice (15). Contrary to their findings in NOS-2Ϫ/Ϫ mi...

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“…In clinical studies, oral L-citrulline increased both plasma citrulline and arginine levels in highrisk children undergoing cardiopulmonary bypass [45]. Intravenous L-citrulline has been shown to be safe and well tolerated in children undergoing cardiopulmonary bypass [46], and clinical trials are underway. …”

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confidence: 99%

Pharmacotherapy of Pulmonary Hypertension

2013

Handbook of Experimental Pharmacology

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Pulmonary arterial hypertension is a serious disease with significant morbidity and mortality. While it can occur idiopathically, it is more commonly associated with other cardiac or lung diseases. While most of the available therapies were tested in adult populations, and most therapies in children remain off-label, new reports and randomized trials are emerging that inform the treatment of pediatric populations. This review discusses currently available therapies for pediatric pulmonary hypertension, their biologic rationales, and evidence for their clinical effectiveness. KeywordsPulmonary hypertension; Pulmonary vasculature; Vasodilator; Nitric Oxide; Phosphodiesterase; Prostacyclin; Endothelin NORMAL PULMONARY VASCULAR TRANSITIONDuring fetal life, the placenta serves as the organ of gas exchange, and the fetal circulation uses a series of adaptive mechanisms to maximize delivery of oxygen to metabolically active organs such as the brain, gut and kidney. The most highly oxygenated blood enters the fetus via the umbilical vein. To efficiently direct oxygenated blood to the systemic circulation and minimize oxygen loss, almost 90% of fetal blood flow is diverted past the lungs through anatomic shunts through the foramen ovale and the ductus arteriosus. While the lung rapidly grows its network of small pulmonary arteries during the second half of gestation [1], blood flow in the pulmonary circulation remains highly restricted by hypoxic pulmonary vasoconstriction of small pulmonary arteries, which is reversed at birth by the sudden increase in lung oxygenation when the newborn takes his or her first breath. After birth, the first few breaths induce a rapid decrease in pulmonary vascular resistance and increase in pulmonary vascular flow in response to lung expansion, increased oxygen tension, and increased pH. Pulmonary artery pressure and vascular resistance decrease more slowly, with pulmonary arterial pressure reaching its nadir ~2-3 weeks after birth. However, the responsiveness to hypoxia is retained into adulthood, and pulmonary hypertension can be easily triggered in the newborn period by hypoxic lung disease, apnea, or other causes.© 2012 Elsevier Inc. All rights reserved. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptPediatr Clin North Am. Author manuscript; available in PMC 2013 October 01. DEFINITION AND CLASSIFICATION OF PEDIATRIC PULMONARY HYPERTENSIONPulmonary hypertension is necessary to support gas exchange in the fetus, but if pulmonary arterial pressure is elevated after birth or during infancy or childhood,...

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Pharmacokinetics and safety of intravenously administered citrulline in children undergoing congenital heart surgery: Potential therapy for postoperative pulmonary hypertension

Cited by 63 publications

References 11 publications

DNA Methylation Suppresses Expression of the Urea Cycle Enzyme Carbamoyl Phosphate Synthetase 1 (CPS1) in Human Hepatocellular Carcinoma

DNA Methylation Suppresses Expression of the Urea Cycle Enzyme Carbamoyl Phosphate Synthetase 1 (CPS1) in Human Hepatocellular Carcinoma

Understanding the role of NOS-3 in ventilator-induced lung injury: don't take NO for an answer

Pharmacotherapy of Pulmonary Hypertension

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