The Glu298Asp polymorphism of the NOS 3 gene as a determinant of the baseline production of nitric oxide.
BACKGROUND
The endothelial nitric oxide synthase Glu298Asp polymorphism has been suggested to play a role in the development of hypertension, atherosclerosis and coronary artery disease.


OBJECTIVE
To investigate functional differences between the various genotypes with respect to basal nitric oxide (NO) production, we estimated the response to endothelial NO synthase (ecNOS) inhibition by infusion of increasing doses of N(G)-monomethyl-L-arginine (L-NMMA) into the brachial artery during venous occlusion plethysmography.


METHODS
In 41 healthy subjects forearm blood flow responses to intra-arterial infusion of increasing doses of L-NMMA (0.05, 0.1 and 0.2 mg/min per dl) and norepinephrine (10, 20 and 40 ng/min per dl) were measured. The genotype of the ecNOS Glu298Asp polymorphism was assessed.


RESULTS
Nineteen subjects had the Glu/Glu genotype, 19 subjects had the Glu/Asp genotype and three subjects had the Asp/Asp genotype. Groups were comparable concerning demographic, hemodynamic and possible confounding factors. Subjects with the Asp allele showed a reduced response to infusion of L-NMMA as compared to subjects with the Glu/Glu genotype (ANOVA, = 0.01). There was no significant difference in the response to infusion of the NO-independent vasoconstrictor, norepinephrine, between both groups.


CONCLUSIONS
The ecNOS Glu298Asp polymorphism is associated with reduced basal NO production and might therefore have functional implications in the development of atherosclerosis or hypertension.
D000293:Adolescent; D000328:Adult; D000483:Alleles; D004151:Dipeptides / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005542:Forearm / Q000098:blood supply; D005838:Genotype; D006801:Humans; D007261:Infusions, Intra-Arterial; D008297:Male; D009569:Nitric Oxide / Q000235:genetics* / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III; D009638:Norepinephrine / Q000008:administration & dosage; D011110:Polymorphism, Genetic / Q000235:genetics*; D012016:Reference Values; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000008:administration & dosage; D019323:omega-N-Methylarginine / Q000008:administration & dosage
D004151:Dipeptides; D004791:Enzyme Inhibitors; D014662:Vasoconstrictor Agents; C021030:gamma-glutamylaspartic acid; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D009638:Norepinephrine