We have investigated the possibility that direct cellular effects may mediate the action of EPI to lower the IOP. To do this, cultured HTM and SCE cells were grown as monolayers over a millipore-filter support structure. The monolayers were exposed to various adrenergic agonists and antagonists while flow of the perfusate (DME + 5% FBS) was measured using a specially-designed computer-linked apparatus. Exposure of the cells to 10(-5) M EPI for around 2 hours led to a rapid twofold increase in HC which gradually declines over the next 12 hours. Continuous exposure of either cell type (ie, HTM or SCE cells) to EPI or ISO resulted in a four- to eightfold increase with a maximal effect measured around 10 hours and a half maximal effect at 2.5 hours. Administration of c-AMP alone gave similar responses. In agreement with clinical studies, timolol blocks EPI's effect completely while betaxolol acted as a partial antagonist. These findings suggest that the cellular changes and the increase in HC are mediated by a beta-2 receptor. There are many similarities between the responses observed using our in vitro system and the IOP-lowering response observed in vivo after the topical application of EPI (eg, concentration, time course, duration, and magnitude). The clinical implications of these preliminary results are discussed and it is proposed that the described in vitro system may be useful to select new adrenergic drugs for glaucoma therapy.