To evaluate the influence of salt sensitivity on the blood pressure response to oral indomethacin treatment, we studied 35 hospitalized essential hypertensive patients (24 men and 11 women, aged from 40 to 55 years). During a normal NaCl intake (120 mmol Na+per day), patients were assigned to receive in a randomized double-blind fashion either 200 mg indomethacin (25 patients) or placebo (10 patients) for 5 days. Two weeks after the interruption of indomethacin treatment, during which the normal NaCl intake was continued, salt sensitivity was assessed by giving each patient a high (220 mmol Na+per day for 10 days) and then a low (20 mmol Na+per day for 10 days) NaCl diet Blood pressure changes were evaluated, and the measurement taken at the end of the 2 weeks under normal sodium intake was considered baseline blood pressure. Patients were classified as salt sensitive when a diastolic blood pressure change of 10 mm Hg or more occurred after both low and high periods of sodium intake. In salt-resistant patients treated with indomethacin (n=12, nine men and three women, mean age 50.5±3.7 years), neither blood pressure (systolic blood pressure from 150.8±11.2 to 154.6±9.3 mm Hg, NS; diastolic blood pressure from 99.3±2.1 to 101.1±4.4 mm Hg, NS) nor the urinary Na+excretion (from 108.1±20.9 to 97.9±9.1 mmol/24 hr, NS) was significantly affected by the drug. On the contrary, when compared with patients receiving placebo (five men and five women, mean age 44.4±4.1 years), salt-sensitive hypertensive patients (n=13, 10 men and three women, mean age 47.9±6.5 years) showed significantly higher levels (p<0.004) of diastolic blood pressure after indomethacin therapy. According to these data, compared with pretreatment values blood pressure significantly increased in salt-sensitive patients after indomethacin treatment (systolic blood pressure from 156.9±9.7 to 163.5±10.8 mm Hg,p<0.001; diastolic blood pressure from 98.5±2.1 to 105.7±5.7 mm Hg,p<0.006) despite a marked plasma renin activity (from 0.18±0.14 to 0.10±0.09 ng/L per second,p<0.02) and aldosterone (from 390.5±154.9 to 299.3±169.5 pmol/L,p<0.002) decrease. Salt-sensitive patients also showed a significant indomethacin- related decrease of urinary Na+excretion (from 108.1±11.6 to 90.9±10.1 mmol/24 hr,p<0.04). Our results indicate that the blood pressure response to indomethacin depends on salt sensitivity in human essential hypertensive patients. The increase of blood pressure, observed in salt-sensitive hypertensive patients, is followed by a significant reduction in urinary Na+excretion. This finding suggests that the indomethacin-induced decrease in Na+excretion is responsible for the blood pressure increase showed by salt-sensitive patients after oral indomethacin treatment.