Relationship Between Carbamoyl-Phosphate Synthetase Genotype and Systemic Vascular Function

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2004-02, Vol.43 (2), p.186-191
• Main Authors: Summar, Marshall L, Gainer, James V, Pretorius, Mias, Malave, Hector, Harris, Stephanie, Hall, Lynn D, Weisberg, Alec, Vaughan, Douglas E, Christman, Brian W, Brown, Nancy J
• Format: Article
• Language: English
• Subjects: Adult; Arginine - blood; Biological and medical sciences; Blood vessels and receptors; Bradykinin - pharmacology; Carbamoyl-Phosphate Synthase (Ammonia) - genetics; Citrulline - blood; Female; Forearm - blood supply; Fundamental and applied biological sciences. Psychology; Genotype; Humans; Male; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitroprusside - pharmacology; Polymorphism, Genetic; Regional Blood Flow; Urea - metabolism; Vasodilation; Vasodilator Agents - pharmacology; Vertebrates: cardiovascular system
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.0000112424.06921.52

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.