Living monkeys were perfused via the anterior chamber by the two step constant pressure technique with the sulfhydryl (SH)-reactive diuretic, ethacrynic acid (ECA) at dosages from 0.1 to 1.0 mM. Above 0.37 mM a reproducible increase in outflow facility (C) was observed. At 0.5 mM C increased 115% with ECA compared to a 22% increase in control eyes (n = 9; P less than 0.01). In three monkeys simultaneous perfusion of ECA with cysteine in 10% excess prevented this effect. In enucleated calf eyes at dosages ranging from 0.1 to 0.5 mM ECA a similar increase in outflow facility was demonstrated. Simultaneous perfusion of 0.1 mM ECA with 0.5 mM cysteine blocked this increase in facility. At high dosages (6 mM) of ECA a decrease in C of 35% was observed (P less than 0.01, n = 8). Electron microscopic studies of the perfused monkey eyes did not readily explain the observed facility effects of ECA, except for the occurrence of a small number of breaks in the inner wall endothelium of Schlemm's canal. The juxtacanalicular meshwork appeared normal. Moderate to profound trabecular endothelial cell swelling was observed with ECA alone and with simultaneous cysteine. Morphologic studies performed 4 and 11 weeks after repetitive acute exposure to ECA indicated that the tissues of the outflow pathway appeared normal. The importance of this work is that it points to a new class of drugs that may be used someday to treat glaucoma.(ABSTRACT TRUNCATED AT 250 WORDS)