The short-term cardiovascular and endocrine effects of an orally active angiotensin converting enzyme inhibitor, SQ14,225, were evaluated in 17 subjects with drug-resistant hypertension (10 with essential and seven with renovascular hypertension). On normal dietary sodium, SQ14,225 (after 3 days at average dose of 664 mg/day) reduced mean arterial pressure (MAP) significantly (from 141 +/- 4 to 122 +/- 4 mm Hg, (SE), p less than 0.001). However, only eight of the patients achieved blood pressures within the normotensive range. Of eight patients with residual hypertension, seven exhibited further decreases in MAP (from 132 +/- 4 to 108 +/- 6 mm Hg (SE), p less than 0.001) when dietary sodium was reduced to 10 mEq/day. No rebound hypertension was noted when treatment was temporarily discontinued for 3 days in 11 patients. The reductions in blood pressure were not associated with either orthostatic hypotension or interference with baroreceptor reflexes. The values of supine plasma renin activity (PRA) were not always predictive of blood pressure responsiveness to the drug. With treatment, plasma aldosterone concentrations (PAC) decreased modestly (values from 40 +/- 9 to 22 +/- 3 ng/dl (SE), p less than 0.05). The plasma concentrations of cortisol, norepinephrine and serum potassium were left unchanged during the period of studies. The present study has not defined the exact mechanism by which SQ14,225 lowered blood pressure. Nevertheless, it indicates that this agent may be a practical therapeutic adjunct in the treatment of certain subsets of the human hypertensive population. The lack of serious interference with cardioscular and humoral homeostasis adds to its attractiveness as a therapeutic agent.