Relationship Between Carbamoyl-Phosphate Synthetase Genotype and Systemic Vascular Function
作者:
Marshall Summar,
James Gainer,
Mias Pretorius,
Hector Malave,
Stephanie Harris,
Lynn Hall,
Alec Weisberg,
Douglas Vaughan,
Brian Christman,
Nancy Brown,
期刊:
Hypertension: Journal of The American Heart Association
(OVID Available online 2004)
卷期:
Volume 43,
issue 2
页码: 186-191
ISSN:0194-911X
年代: 2004
出版商: OVID
关键词: nitric oxide;bradykinin;genetics;endothelium;vasodilation
数据来源: OVID
摘要:
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 &mgr;g/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 &mgr;mol/L), lowest in individuals homozygous for the A allele (9.1±3.1 &mgr;mol/L), and intermediate (11.8±6.6 &mgr;mol/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.
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