Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function
Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function
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DOI：
10.1161/01.hyp.0000112424.06921.52
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发表时间：
2004-02-01
期刊：
影响因子：
8.3
通讯作者：
Brown, NJ
中科院分区：
文献类型：
--
作者：
Summar, ML;Gainer, JV;Brown, NJ
内皮细胞可以将l -瓜氨酸转化为l -精氨酸，即一氧化氮的前体。本研究验证了一种假设，即编码氨基甲酰磷酸合成酶1（催化l-瓜氨酸形成限速步骤的酶）中的C-to-A核苷酸逆转（T1405N）会影响人类一氧化氮代谢物浓度或一氧化氮介导的血管舒张。106例（CC: AC: AA = 40:54: 12）健康受试者经肱动脉输注缓激素（100,200和400ng /min）。87例（CC: AC: AA = 31:46: 10）患者同时输注硝普钠（1.6、3.2和6.4马克/分）。采用体积描记仪测定前臂血流量，采集血样检测组织型纤溶酶原激活物抗原、一氧化氮代谢物和环GMP。氨甲酰磷酸合成酶1基因型与一氧化氮代谢物有显著的相关性，其中C等位基因纯合子的一氧化氮代谢物浓度最高（平均+/- SD， 14.0 +/- 8.5 mumol/L）， a等位基因纯合子的一氧化氮代谢物浓度最低（9.1 +/- 3.1 mumol/L），杂合子的一氧化氮代谢物浓度居中（11.8 +/- 6.6 mumol/L） （P = 0.036）。氨甲酰磷酸合成酶1基因型对缓激肽期间前臂血流有显著影响（P = 0.028），因此C等位基因纯合子的血管舒张反应最大（在400 ng/min时为22.2 +/- 9.1 mL/min/100 mL）， a等位基因纯合子的血管舒张反应最小（13.6 +/- 6.2 mL/min/100 mL），杂合子的血管舒张反应居中（19.4 +/- 10.7 mL/min/100 mL）。同样，氨基甲酰磷酸合成酶1基因型影响硝普组前臂血流量（CC: AC: AA组最大血流量分别为19.2 +/- 8.3、18.1 +/- 8.3和11.5 +/- 4.9 mL/min/100 mL, P = 0.022）。而氨甲酰磷酸合成酶1基因型对一氧化氮非依赖性组织型纤溶酶原激活物对缓激肽的反应无影响（P = 0.943）。这些数据表明，编码氨甲酰磷酸合成酶1基因的多态性影响一氧化氮的产生以及血管平滑肌的反应性。
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 mug/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 mumol/L), lowest in individuals homozygous for the A allele (9.1 +/- 3.1 mumol/L), and intermediate (11.8 +/- 6.6 mumol/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.