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Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function.
N Engl J Med 2001; 344(24):1832-8NEJM

Abstract

BACKGROUND

Endogenous production of nitric oxide is vital for the decrease in pulmonary vascular resistance that normally occurs after birth. The precursor of nitric oxide is arginine, a urea-cycle intermediate. We hypothesized that low concentrations of arginine would correlate with the presence of persistent pulmonary hypertension in newborns and that the supply of this precursor would be affected by a functional polymorphism (the substitution of asparagine for threonine at position 1405 [T1405N]) in carbamoyl-phosphate synthetase, which controls the rate-limiting step of the urea cycle.

METHODS

Plasma concentrations of amino acids and genotypes of the carbamoyl-phosphate synthetase variants were determined in 65 near-term neonates with respiratory distress. Plasma nitric oxide metabolites were measured in a subgroup of 10 patients. The results in infants with pulmonary hypertension, as assessed by echocardiography, were compared with those in infants without pulmonary hypertension. The frequencies of the carbamoyl-phosphate synthetase genotypes in the study population were assessed for Hardy-Weinberg equilibrium.

RESULTS

As compared with infants without pulmonary hypertension, infants with pulmonary hypertension had lower mean (+/-SD) plasma concentrations of arginine (20.2+/-8.8 vs. 39.8+/-17.0 micromol per liter, P<0.001) and nitric oxide metabolites (18.8+/-12.7 vs. 47.2+/-11.2 micromol per liter, P=0.05). As compared with the general population, the infants in the study had a significantly skewed distribution of the genotypes for the carbamoyl-phosphate synthetase variants at position 1405 (P<0.005). None of the infants with pulmonary hypertension were homozygous for the T1405N polymorphism.

CONCLUSIONS

Infants with persistent pulmonary hypertension have low plasma concentrations of arginine and nitric oxide metabolites. The simultaneous presence of diminished concentrations of precursors and breakdown products suggests that inadequate production of nitric oxide is involved in the pathogenesis of neonatal pulmonary hypertension. Our preliminary observations suggest that the genetically predetermined capacity of the urea cycle--in particular, the efficiency of carbamoyl-phosphate synthetase--may contribute to the availability of precursors for nitric oxide synthesis.

Authors+Show Affiliations

Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11407344

Citation

Pearson, D L., et al. "Neonatal Pulmonary Hypertension--urea-cycle Intermediates, Nitric Oxide Production, and Carbamoyl-phosphate Synthetase Function." The New England Journal of Medicine, vol. 344, no. 24, 2001, pp. 1832-8.
Pearson DL, Dawling S, Walsh WF, et al. Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med. 2001;344(24):1832-8.
Pearson, D. L., Dawling, S., Walsh, W. F., Haines, J. L., Christman, B. W., Bazyk, A., ... Summar, M. L. (2001). Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. The New England Journal of Medicine, 344(24), pp. 1832-8.
Pearson DL, et al. Neonatal Pulmonary Hypertension--urea-cycle Intermediates, Nitric Oxide Production, and Carbamoyl-phosphate Synthetase Function. N Engl J Med. 2001 Jun 14;344(24):1832-8. PubMed PMID: 11407344.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neonatal pulmonary hypertension--urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. AU - Pearson,D L, AU - Dawling,S, AU - Walsh,W F, AU - Haines,J L, AU - Christman,B W, AU - Bazyk,A, AU - Scott,N, AU - Summar,M L, PY - 2001/6/16/pubmed PY - 2001/6/22/medline PY - 2001/6/16/entrez SP - 1832 EP - 8 JF - The New England journal of medicine JO - N. Engl. J. Med. VL - 344 IS - 24 N2 - BACKGROUND: Endogenous production of nitric oxide is vital for the decrease in pulmonary vascular resistance that normally occurs after birth. The precursor of nitric oxide is arginine, a urea-cycle intermediate. We hypothesized that low concentrations of arginine would correlate with the presence of persistent pulmonary hypertension in newborns and that the supply of this precursor would be affected by a functional polymorphism (the substitution of asparagine for threonine at position 1405 [T1405N]) in carbamoyl-phosphate synthetase, which controls the rate-limiting step of the urea cycle. METHODS: Plasma concentrations of amino acids and genotypes of the carbamoyl-phosphate synthetase variants were determined in 65 near-term neonates with respiratory distress. Plasma nitric oxide metabolites were measured in a subgroup of 10 patients. The results in infants with pulmonary hypertension, as assessed by echocardiography, were compared with those in infants without pulmonary hypertension. The frequencies of the carbamoyl-phosphate synthetase genotypes in the study population were assessed for Hardy-Weinberg equilibrium. RESULTS: As compared with infants without pulmonary hypertension, infants with pulmonary hypertension had lower mean (+/-SD) plasma concentrations of arginine (20.2+/-8.8 vs. 39.8+/-17.0 micromol per liter, P<0.001) and nitric oxide metabolites (18.8+/-12.7 vs. 47.2+/-11.2 micromol per liter, P=0.05). As compared with the general population, the infants in the study had a significantly skewed distribution of the genotypes for the carbamoyl-phosphate synthetase variants at position 1405 (P<0.005). None of the infants with pulmonary hypertension were homozygous for the T1405N polymorphism. CONCLUSIONS: Infants with persistent pulmonary hypertension have low plasma concentrations of arginine and nitric oxide metabolites. The simultaneous presence of diminished concentrations of precursors and breakdown products suggests that inadequate production of nitric oxide is involved in the pathogenesis of neonatal pulmonary hypertension. Our preliminary observations suggest that the genetically predetermined capacity of the urea cycle--in particular, the efficiency of carbamoyl-phosphate synthetase--may contribute to the availability of precursors for nitric oxide synthesis. SN - 0028-4793 UR - https://www.unboundmedicine.com/medline/citation/11407344/Neonatal_pulmonary_hypertension__urea_cycle_intermediates_nitric_oxide_production_and_carbamoyl_phosphate_synthetase_function_ L2 - http://www.nejm.org/doi/full/10.1056/NEJM200106143442404?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -