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PMID:14718356

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Citation

Summar, ML, Gainer, JV, Pretorius, M, Malave, H, Harris, S, Hall, LD, Weisberg, A, Vaughan, DE, Christman, BW and Brown, NJ (2004) Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function. Hypertension 43:186-91

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 microg/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 micromol/L), lowest in individuals homozygous for the A allele (9.1+/-3.1 micromol/L), and intermediate (11.8+/-6.6 micromol/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.

Links

PubMed Online version:10.1161/01.HYP.0000112424.06921.52

Keywords

Adult; Arginine/blood; Bradykinin/pharmacology; Carbamoyl-Phosphate Synthase (Ammonia)/genetics; Citrulline/blood; Female; Forearm/blood supply; Genotype; Humans; Male; Nitric Oxide/metabolism; Nitric Oxide Donors/pharmacology; Nitroprusside/pharmacology; Polymorphism, Genetic; Regional Blood Flow; Urea/metabolism; Vasodilation; Vasodilator Agents/pharmacology

Significance

Annotations

Gene product Qualifier GO ID GO term name Evidence Code with/from Aspect Notes Status


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References

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