Neonatal pulmonary hypertension - Urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function

Background: Endogenous production of nitric oxide is vital for the decrease in pulmonary vascular resistance that normally occurs after birth. The pre cursor of nitric oxide is arginine, a urea-cycle intermediate. We hypothesi zed that low concentrations of arginine would correlate with the presence o f 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-phosph ate synthetase, which controls the rate-limiting step of the urea cycle. Methods: Plasma concentrations of amino acids and genotypes of the carbamoy l-phosphate synthetase variants were determined in 65 near-term neonates wi th respiratory distress. Plasma nitric oxide metabolites were measured in a subgroup of 10 patients. The results in infants with pulmonary hypertensio n, as assessed by echocardiography, were compared with those in infants wit hout pulmonary hypertension. The frequencies of the carbamoyl-phosphate syn thetase genotypes in the study population were assessed for Hardy-Weinberg equilibrium. Results: As compared with infants without pulmonary hypertension, infants w ith 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 nitri c 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-phos phate synthetase variants at position 1405 (P<0.005). None of the infants w ith 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 path ogenesis of neonatal pulmonary hypertension. Our preliminary observations s uggest that the genetically predetermined capacity of the urea cycle - in p articular, the efficiency of carbamoyl-phosphate synthetase - may contribut e to the availability of precursors for nitric oxide synthesis. (N Engl J M ed 2001;344:1832-8.) Copyright (C) 2001 Massachusetts Medical Society.