Abstract
BACKGROUND: Raised homocysteine is a risk factor for vascular disease. Homocysteine is formed from methionine, and dietary manipulation of homocysteine in primates and humans with oral methionine is associated with endothelial dysfunction. A cause-effect relation has not been clearly established. AIM: To study the effect of oral methionine and then oral homocysteine on endothelial function. METHODS: 22 healthy adults were recruited for two randomised crossover studies, each containing 11 subjects. Endothelial function was determined by measuring forearm blood flow in response to intra-arterial infusion of acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent). Subjects received methionine or placebo (study 1), or homocysteine or placebo (study 2). Methionine and homocysteine were determined at baseline and t = 4 hours. Endothelial function was determined at four hours. The responses to the vasoactive substances are expressed as the area under the curve of change in forearm blood flow from baseline. RESULTS: Study 1: plasma methionine and homocysteine concentrations increased significantly versus placebo. The increases were associated with a reduction of endothelium dependent responses (mean (95% confidence interval), arbitrary units), from 48.8 (95% CI 36.4 to 61.2) to 29.9 (95% CI 18.0 to 41.1), p < 0.04; endothelium independent responses were unchanged. Study 2: homocysteine concentration increased significantly while methionine remained unchanged. Endothelium dependent responses were reduced from 34.6 (95% CI 20.6 to 48.6) to 22.8 (95% CI 12.0 to 33.6), p < 0.03. CONCLUSIONS: Homocysteine and not methionine is responsible for the changes in endothelial function. This supports the hypothesis that homocysteine promotes atherosclerosis by inducing endothelial dysfunction.