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.