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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 µmol per liter, P<0.001) and nitric oxide metabolites (18.8±12.7 vs. 47.2±11.2 µmol 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.
Source Information
From the Department of Pediatrics, Division of Neonatology (D.L.P., W.F.W.), the Department of Pathology (S.D.), the Department of Pediatrics, Division of Medical Genetics (J.L.H., A.B., N.S., M.L.S.), and the Department of Internal Medicine, Division of Pulmonary Medicine (B.W.C.), Vanderbilt University Medical Center, Nashville.
Address reprint requests to Dr. Summar at the Division of Medical Genetics, Vanderbilt University Medical Center, DD 2205 Medical Center North, Nashville, TN 37232, or at marshall.summar{at}mcmail.vanderbilt.edu.
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