The effects of enalapril alone and in combination with the cyclooxygenase inhibitors sulindac and indomethacin on blood pressure (BP), plasma aldosterone, renin activity and converting enzyme activity were evaluated in 29 patients with mild to moderate essential hypertension, 26 of whom had low plasma renin activity. Patients were randomly assigned to one of three treatment groups. All patients underwent a 4-week placebo phase (phase I), then received enalapril (20 mg BID) for 4 weeks (phase II). In phase III, group I (n = 10) continued on enalapril alone; group II (n = 9) received sulindac 200 mg BID plus enalapril, and group III (n = 10) received indomethacin 50 mg BID plus enalapril, all for 4 weeks. Enalapril lowered BP significantly (mean supine BP 149/100 in phase I vs. 134/90 in phase II,p< 0.05) without inhibiting aldosterone production. The BP effect was not blunted by concomitant administration of sulindac or indomethacin. Enalapril lowered converting enzyme activity to 25% to 30% of baseline and tended to increase renin activity. In the 10 patients who received indomethacin (group III), the effects of enalapril alone and enalapril plus indomethacin on urinary excretion of 6-keto prostaglandin F1α(PGF1α, a stable metabolite of prostacyclin (PGI2), were examined. Enalapril increased urinary 6-keto PGF1αin group III from 118 ± 23 to 194 ± 38 ng/g creatinine (p< 0.05), while addition of indomethacin reduced 6-keto PGF1αto basal levels (138 ± 26 ng/g creatinine). There was no significant correlation between the fall in blood pressure and the increase in 6-keto PGF1αexcretion in enalapril-treated patients. These data indicate that the antihypertensive effect of enalapril in essential hypertension occurs in the absence of an active renin-angiotension system and is associated with increased excretion of 6-keto PGF1αbut is not blunted by cyclooxygenase inhibitors. These findings indicate (1) enalapril administration is associated with enhanced prostacyclin production in this patient group but (2) the antihypertensive action of enalapril is not critically dependent on prostacyclin, since blockade of prostacyclin production with a cyclooxygenase inhibitor does not blunt the antihypertensive effect of the drug.