Angiotensin II and endothelin-1 are potent vasoconstrictors which appear to play a role in retinal blood flow regulation. In the present study we investigated the possible role of the angiotensin and the endothelin (ET) system in the regulation of retinal vessel diameters during isometric exercise in healthy humans. The study design was randomized, double masked, placebo-controlled, 3-way cross-over. 12 healthy subjects performed squatting for 6 minutes during infusion of either an ACE-inhibitor (enalapril), an ET^A-receptor antagonist (BQ-123) or placebo. Retinal vessel diameters were measured continuously with the Zeiss retinal vessel analyzer. Systemic hemodynamics were assessed non-invasively and intraocular pressure was measured with applanation tonometry. Squatting induced a significant increase in blood pressure and pulse rate, which was paralleled by a vasoconstriction in retinal arteries and veins. Intraocular pressure was only slightly increased during the squatting periods. BQ-123 significantly blunted the exercise-induced decrease in venous (p < 0.01) and arterial (p < 0.02, ANOVA) vessel diameters, but had no effect on basal retinal diameters. By contrast, enalapril did neither influence vessel diameter at baseline conditions nor in response to isometric exercise. The data of the present study indicate that retinal vasoconstriction during isometric exercise is modified by ET_A-receptor blockade whereas it is not altered by ACE-inhibition. Hence, the present data indicate that endothelin 1, but not angiotensin II is involved in retinal blood flow regulation during isometric exercise.