To examine the relationship between metabolic syndrome and endothelial dysfunction, we investigated cross-sectionally the correlation between metabolic risk factors and urinary excretion of cyclic guanosine 3',5'-monophosphate (cGMP), a second messenger of nitric oxide (NO), in 1541 Japanese men and women aged 40-79 years. The 24-h urinary excretion of cGMP was measured using a (125)I-labeled cGMP radioimmunoassay and was adjusted for urinary creatinine excretion (nmol/mmol creatinine). The components of metabolic syndrome were defined based on the following criteria: body mass index (BMI)> or =25.0 kg/m(2), fasting plasma glucose> or =6.11 mmol/l or non-fasting plasma glucose level> or =11.1 mmol/l, systolic blood pressure> or =130 mm Hg or diastolic blood pressure> or =85 mm Hg, high-density lipoprotein (HDL)-cholesterol<1.03 mmol/l for men and <1.29 mmol/l for women, and triglyceride> or =1.69 mmol/l. The number of components of metabolic syndrome correlated inversely with urinary cGMP excretion; means of cGMP excretion for the whole group adjusted for age, sex, and cardiovascular risk factors were 53.6, 48.6, 47.9, 44.4 and 42.3 nmol/mmol for 0, 1, 2, 3, and 4-5 components of metabolic syndrome, respectively (p=0.002). Our data suggest that a reduction of NO bioactivity concur with clustered features of the metabolic syndrome.