In-vivo effects of Glu298Asp endothelial nitric oxide synthase polymorphism.
Endothelial nitric oxide synthase catalyses the formation of the vasodilator nitric oxide, a major regulator of vascular tone. The Asp298 polymorphism of the nitric oxide synthase gene is associated with altered function and expression of the enzyme in vitro and myocardial infarction and coronary artery spasm in vivo. We examined the effect of the Glu298Asp polymorphism on: (1) local vascular responses to phenylephrine, acetylcholine, glyceryl trinitrate and prostaglandin E1 in the dorsal hand vein; (2) changes in forearm blood flow during mental stress, a measure of nitric oxide-mediated effect on resistance vessels; (3) excretion of urinary nitrite/nitrate as a measure of total body nitric oxide production; and (4) F2-isoprostane metabolite, a measure of oxidative stress, in healthy Glu298 (n = 12) and Asp298 (n = 13) homozygotes. There were no significant differences in acetylcholine dose responses (P = 0.29) in Glu298 and Asp298 homozygotes. Responses to glyceryl trinitrate, prostaglandin E1 and the alpha-adrenergic agonist phenylephrine did not differ by genotype. Forearm blood flow was similar at rest and increased significantly (from 7.5 ml/min/100 ml to 12.2 ml/min/100 ml; P = 0.003), but similarly (P = 0.2), during mental stress in both genotypes. Asp298 homozygotes excreted significantly less nitrate/nitrite than Glu298 homozygotes (nitrate + nitrite/creatinine ratio 0.05 +/- 0.01 vs. 0.09 +/- 0.01, respectively; P < 0.005). Urinary F2-isoprostane metabolite excretion did not differ (Glu298, 2.04 +/- 0.25 ng/mg creatinine; Asp298, 1.85 +/- 0.37 ng/mg creatinine; P = 0.7). We conclude that in healthy volunteers the Glu298Asp polymorphism affects endogenous nitric oxide production without affecting nitric oxide-mediated vascular responses. This polymorphism may only have clinical significance in the presence of endothelial dysfunction.
Sofowora
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G
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
Dishy
V
V
Xie
H G
HG
Imamura
H
H
Nishimi
Y
Y
Morales
C R
CR
Morrow
J D
JD
Kim
R B
RB
Stein
C M
CM
Wood
A J
AJ
D000328:Adult; D001224:Aspartic Acid / Q000235:genetics; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000502:physiology; D028441:F2-Isoprostanes / Q000652:urine; D005260:Female; D005542:Forearm / Q000098:blood supply; D005838:Genotype; D018698:Glutamic Acid / Q000235:genetics; D006225:Hand / Q000098:blood supply; D006720:Homozygote; D006801:Humans; D008297:Male; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000652:urine; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D012039:Regional Blood Flow / Q000235:genetics / Q000502:physiology; D014655:Vascular Resistance / Q000235:genetics / Q000502:physiology; D014664:Vasodilation / Q000235:genetics / Q000502:physiology
D028441:F2-Isoprostanes; D009566:Nitrates; D009573:Nitrites; D001224:Aspartic Acid; D009569:Nitric Oxide; D018698:Glutamic Acid; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III