Since plasma endothelin concentration increases with upright posture and decreases with volume expansion, a study was conducted to test whether activation of the baroreceptor reflex releases endothelin into plasma. The effect of passive upright tilt on the plasma concentrations of endothelin and vasopressin was examined in: (1) normal subjects; (2) patients with impaired baroreceptor reflex due to primary autonomic failure; (3) patients with normal afferent baroreceptor function but acute inhibition of vasoconstrictor sympathetic outflow (ie, with vasovagal syncope); and (4) patients with hypophysial diabetes insipidus. In normal subjects, upright tilt did not change arterial pressure and significantly increased the plasma concentrations of endothelin and vasopressin. In patients with autonomic failure, upright tilt induced a considerable fall in arterial pressure, no rise in plasma endothelin, and a slight increase in plasma vasopressin. In subjects with vasovagal syncope, arterial pressure dropped and the plasma concentrations of endothelin and vasopressin rose. In the subjects with diabetes insipidus, arterial pressure fell slightly, without change in plasma concentration of endothelin. The results suggest that activation of the baroreceptor reflex induces the release of endothelin into plasma, probably from the neurohypophysis, and they raise the possibility that impaired endothelin release contributes to the orthostatic hypotension of patients with primary autonomic failure.