The mechanisms causing high blood pressure in patients with Cushing's syndrome were investigated by measurements of humoral factors and pharmacological maneuvers. Twelve patients with adrenal adenomas were studied. The mean systolic and diastolic pressures of the patients were 171 +/- 28 and 109 +/- 15 mm Hg (+/- SEM), respectively, which were significantly higher than those of normal subjects. PRA, plasma renin concentration, plasma renin substrate, plasma cortisol, plasma aldosterone, urinary kallikrein, and urinary prostaglandin E2 were measured as the humoral factors. PC values were markedly elevated in patients with Cushing's syndrome. Among the components of the renin-angiotensin system, only plasma renin substrate was increased. Urinary kallikrein and prostaglandin E2 were decreased in patients with Cushing's syndrome. Oral administration of captopril lowered blood pressure, but infusion of an angiotensin II analog did not. Furthermore, the pressor responses to infusion of both norepinephrine and angiotensin II were increased. We conclude that blood pressure is elevated in patients with Cushing's syndrome because they have enhanced pressor responses to vasoactive substances, suppression of depressor systems, and some abnormalities of the renin-angiotensin system.