The antihypertensive efficacy of hydrochlorothiazide is not prostacyclin dependent. We tested the hypothesis that vascular prostacyclin synthesis is stimulated by hydrochlorothiazide and could account for some of the drug's antihypertensive effect. We studied 13 patients with mild essential hypertension in a randomized, double-blind design to assess the effects of indomethacin on hydrochlorothiazide's ability to lower blood pressure, alter body weight, stimulate plasma renin activity, and modulate vascular prostacyclin biosynthesis as assessed by the urinary excretion of the major enzymatically produced metabolite of prostacyclin, 2,3-dinor-6-keto-prostaglandin F1 alpha (PGF1 alpha), measured by GC/MS. Administration of hydrochlorothiazide, 50 mg daily for 2 weeks, was associated with a significant decrease in both systolic and diastolic blood pressure in both supine (systolic, 148 +/- 3 to 136 +/- 3 mm Hg; diastolic, 97 +/- 2 to 94 +/- 3 mm Hg) and upright (systolic, 151 +/- 4 to 131 +/- 2 mm Hg; diastolic, 103 +/- 2 to 97 +/- 3 mm Hg) positions. Hydrochlorothiazide administration resulted in a 1 kg weight loss and stimulation of plasma renin activity from 1.7 +/- 0.4 to 5.3 +/- 1.1 ng angiotensin I/ml/hr. However, the urinary excretion of 2,3-dinor-6-keto-PGF1 alpha was unchanged after administration of hydrochlorothiazide (86 +/- 13/ng/gm creatinine during placebo, 74 +/- 13 ng/gm during week 1 of hydrochlorothiazide, and 70 +/- 9 ng/gm during week 2 of the drug). Administration of indomethacin, 50 mg twice a day, resulted in greater than 60% inhibition of 2,3-dinor-6-keto-PGF1 alpha excretion but did not affect the antihypertensive response to hydrochlorothiazide. Indomethacin did not oppose the diuretic effect of hydrochlorothiazide as assessed by weight loss but did attenuate the rise in plasma renin activity. Our data demonstrate that the blood pressure-lowering effect of a thiazide diuretic does not require enhanced prostacyclin synthesis and the cyclooxygenase inhibitor indomethacin does not antagonize the antihypertensive efficacy of hydrochlorothiazide. 