Neonatal Pulmonary Hypertension

Marshall L. Summar, MD
Vanderbilt University
P01ES06052

Background: Nitric oxide(NO.) is well known for its vasodilation properties. Normal levels of NO. are especially important in newborns to allow the normal decrease in blood flow resistance in pulmonary vessels just after birth. NO. is produced from the amino acid arginine which is an urea-cycle intermediate. These investigators hypothesized that low concentrations of arginine would lead to persistent pulmonary hypertension and that arginine concentration could be affected by a polymorphism in the gene coding for the enzyme carbamoyl-phosphate synthetase, which is a very important enzyme in the urea cycle.

Advance: Human infants with and without pulmonary hypertension were tested in this study. Infants with hypertension had an almost two-fold decrease in plasma arginine concentrations compared to controls. NO. metabolites were severely reduced as well. The infants with pulmonary hypertension were also more likely to have polymorphisms for the carbamoyl-phosphate synthetase gene.

Implication: The results prove that infants with low concentrations of arginine leading to decreased NO. are highly likely to have pulmonary hypertension. These biochemical deficits are most likely due to variants in the gene coding for a critical enzyme in the urea cycle, carbamoyl-phosphate synthetase. This association is only one of many potential genetic differences that may interact to influence the physiologic response to the tremendous stress experienced at birth. Potentially, infants carrying this or similar polymorphisms could be identified before or very soon after birth and given effective treatments much sooner. This is just one example of how learning about the interactions of genes and the environment, the goal of the NIEHS Human Genome Project, may lead to new methods to identify and treat infants who are at high risk for perinatal diseases or conditions.

Publication: Pearson DL, Dawling S, Walsh WF, Haines JL, Christman BW, Bazyk A, Scott N, Summar ML.Neonatal pulmonaryhypertension-urea-cycle intermediates, nitric oxide production, and carbamoyl-phosphate synthetase function. N Engl J Med. 2001 Jun 14;344(24):1832-8.