BACKGROUND--Some patients with angina pectoris and normal coronary arteriograms have reduced coronary flow reserve and abnormal endothelium dependent vasodilator responses. Endothelin-1 (ET-1), a potent vasoconstrictor, is an important modulator of microvascular function and may also have algogenic properties. METHOD--Plasma ET-1 was measured in peripheral venous blood in 40 patients (30 women) (mean (SD) age 56 (8) years) with angina and normal coronary arteriograms and 21 normal controls (17 women) (mean (SD) age 53 (7) years). Patients with systemic hypertension, left ventricular hypertrophy, or coronary spasm were excluded. Plasma ET-1 was measured using radioimmunoassay. RESULTS--Thirty five patients had > or = 1 mm ST segment depression during exercise. Left bundle branch block was present in four patients at rest and in one during exercise. Mean (SD) (range) concentration of ET-1 (pg/ml) was higher in patients than in controls (3.84 (1.25) (1.97-7.42) v 2.88 (0.71) (1.57-4.48) P < 0.0001). In patients with "high" (> control mean (one SD)) ET-1 concentrations (n = 23), the time to onset of chest pain during exercise was significantly shorter (6.21 (3.9) v 9.03 (3.9) min; p = 0.01) than in patients with "low" ET-1 concentrations. Of the five patients with left bundle branch block, four had plasma ET-1 concentration > 4.0 pg/ml. CONCLUSION--Plasma endothelin is raised in patients with angina and normal coronary arteriograms and is consistent with the demonstration of endothelial dysfunction in such patients. The association between "high" plasma ET-1 and an earlier onset of chest pain during exercise suggests that endothelin may also have a role in the genesis of chest pain in patients with normal coronary arteries.