Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function.
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.
Summar
Marshall L
ML
Department of Pediatrics, Division of Medical Genetics, Vanderbilt University Medical Center, Nashville, Tenn 37232-6602, USA.
Gainer
James V
JV
Pretorius
Mias
M
Malave
Hector
H
Harris
Stephanie
S
Hall
Lynn D
LD
Weisberg
Alec
A
Vaughan
Douglas E
DE
Christman
Brian W
BW
Brown
Nancy J
NJ
D000328:Adult; D001120:Arginine / Q000097:blood; D001920:Bradykinin / Q000494:pharmacology; D002222:Carbamoyl-Phosphate Synthase (Ammonia) / Q000235:genetics*; D002956:Citrulline / Q000097:blood; D005260:Female; D005542:Forearm / Q000098:blood supply; D005838:Genotype; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D011110:Polymorphism, Genetic; D012039:Regional Blood Flow; D014508:Urea / Q000378:metabolism; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
D020030:Nitric Oxide Donors; D014665:Vasodilator Agents; D009599:Nitroprusside; D002956:Citrulline; D009569:Nitric Oxide; D014508:Urea; D001120:Arginine; D002222:Carbamoyl-Phosphate Synthase (Ammonia); D001920:Bradykinin