A prospective, randomized, open-label, triple crossover comparison of the effects of indomethacin, misoprostol, or the combination, on renal function was performed to assess the ability of an oral prostaglandin E analogue, misoprostol, to minimize indomethacin-induced decline in renal function in middle-aged women. Twelve healthy women (mean age: 60.5 +/- 1.6 yr) with normal renal function (serum creatinine: 81 +/- 9 umol/L) were studied; six women were normotensive, and six women were hypertensive with their blood pressure controlled with 50-mg hydrochlorothiazide daily. All patients were placed on a 2-g sodium daily diet for 2 weeks before initiation of the study. The subjects were prospectively randomized to receive each of three 4-day treatments of indomethacin (25 mg q 6hr), misoprostol (200 mcg q 6hr), or the combination of drugs with a 4-day washout between each treatment period. Measurements of GFR (urine accumulation of 99mTc-DTPA) and RPF (serum disappearance 131I-Hippuran), and urine collections for electrolytes were obtained before the first treatment period and on the fourth day of each treatment period. Three of the six hypertensive patients and three of the six normotensive patients had a decrease (greater than 10%) in GFR associated with indomethacin therapy. When misoprostol was given with the indomethacin, four of these six patients did not experience a decline in GFR (baseline GFR for six patients: 75.4 +/- 6.6 mL/min/1.73m2, GFR after indomethacin: 57.8 +/- 9.5 mL/min/1.73m2, GFR with combination of indomethacin and misoprostol: 69.7 +/- 3.5 mL/min/1.73m2. RPF was not consistently altered by subacute/chronic dosing of indomethacin, misoprostol, or the combination of the drugs. The authors conclude that misoprostol ameliorates indomethacin-induced renal dysfunction in salt-restricted and diuretic-treated middle-aged women with normal serum creatinine.