Relationship Between Carbamoyl-Phosphate Synthetase Genotype and Systemic Vascular Function

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Abstract
Endothelial cells can convert l -citrulline to l -arginine, the precursor of nitric oxide. The present study tests the hypothesis that a C-to-A nucleotide transversion (T1405N) in the gene-encoding carbamoyl-phosphate synthetase 1, the enzyme catalyzing the rate-limiting step in l -citrulline formation, influences nitric oxide metabolite concentrations or nitric oxide-mediated vasodilation in humans. Bradykinin (100, 200, and 400 ng/min) was infused via brachial artery in 106 (CC:AC:AA=40:54:12) healthy subjects. Sodium nitroprusside (1.6, 3.2, and 6.4 μg/min) was also infused in 87 (CC:AC:AA=31:46:10) subjects. Forearm blood flow was measured by plethysmography and blood samples were collected for tissue-type plasminogen activator antigen, nitric oxide metabolites, and cyclic GMP. There was a significant relationship between carbamoyl-phosphate synthetase 1 genotype and nitric oxide metabolites, such that nitric oxide metabolite concentrations were highest in individuals homozygous for the C allele (mean±SD, 14.0±8.5 μmol/L), lowest in individuals homozygous for the A allele (9.1±3.1 μmol/L), and intermediate (11.8±6.6 μmol/L) in heterozygotes ( P =0.036). There was a significant effect of carbamoyl-phosphate synthetase 1 genotype on forearm blood flow during bradykinin ( P =0.028), such that the vasodilator response was greatest in C allele homozygotes (22.2±9.1 mL/min/100 mL at 400 ng/min), least in A allele homozygotes (13.6±6.2 mL/min/100 mL), and intermediate (19.4±10.7 mL/min/100 mL) in heterozygotes. Similarly, carbamoyl-phosphate synthetase 1 genotype influenced forearm blood flow during nitroprusside (maximal flow 19.2±8.3, 18.1±8.3, and 11.5±4.9 mL/min/100 mL in the CC:AC:AA groups, respectively; P =0.022). In contrast, there was no effect of carbamoyl-phosphate synthetase 1 genotype on the nitric oxide–independent tissue-type plasminogen activator response to bradykinin ( P =0.943). These data indicate that a polymorphism in the gene encoding carbamoyl-phosphate synthetase 1 influences nitric oxide production as well as vascular smooth muscle reactivity.