Cellular Basis for Bimatoprost Effects on Human Conventional Outflow

Vision loss associated with glaucoma is treatable if intraocular pressure (IOP) is lowered sufficiently and maintained over time.1 Because of safety issues, frequency of the dosing regimen, and their efficacy as ocular antihypertensive agents, prostaglandin (PG)-F2α mimetics have quickly become the medical treatment of choice for managing IOP in glaucoma patients.2 PG-F2α drugs lower intraocular pressure by 25% to 30% after 1 week of once-a-day administration without the significant ocular and systemic side effects experienced more frequently with other topical medications.3 Moreover, PGs as a class are much better than other topical glaucoma drugs at controlling diurnal IOP fluctuations, which appear to increase the progression of visual field defects.4,5 Early studies on aqueous humor dynamics in monkeys demonstrated that latanoprost, the prototypical FP receptor agonist, lowered IOP exclusively by increasing uveoscleral outflow.6–8 Since these initial reports, recent studies indicate that PGs exert a pronounced effect on pressure-dependent (trabecular/conventional) outflow in human volunteers9,10 and in perfused human anterior segments.11,12 Although the four PGs currently approved as ocular antihypertensive agents (unoprostone, latanoprost, travoprost, and bimatoprost) do not appear to increase conventional outflow in monkeys, a newer, more potent analog (tafluprost) does, increasing conventional outflow by 33%.13 Thus, a class of drugs originally thought to lower IOP solely by effects on uveoscleral outflow clearly impacts conventional outflow. The chief cellular mechanisms by which PGs exert their effects on uveoscleral outflow appear to be a result of extracellular matrix remodeling between longitudinal ciliary muscle fiber bundles. Alteration in matrix metalloproteinase secretion and opening of flow pathways increase uveoscleral outflow over time.14–19 Interestingly, modified flow pathways in chronically treated monkey eyes are lined by endothelial cells, apparently a result of new, organized outflow channel formation between muscle bundles.20 In contrast, the mechanism by which PGs increase conventional outflow in humans is not well understood. Human trabecular meshwork cells express PG-FP receptors,21 and activation of FP receptors in perfused human anterior segments results in both acute (hours) and chronic (days) modulation of outflow facility.11,12 The chronic change appears to correspond to the extracellular matrix remodeling observed in the trabecular meshwork (TM) of monkeys treated with PGs for 1 year20 and the altered matrix metalloproteinase secretion detected in cultured human TM cells.17 The acute increase in outflow facility is consistent with decreased contractility of cultured bovine TM cells.22 Given that previous studies of PG effects on contractility were performed using bovine TM cells and given that Schlemm's canal (SC) cells were not examined, the purpose of the present study was to test the response of PGs on both cell types that populate the human conventional outflow pathway. Using cellular dielectric spectroscopy, we found that bimatoprost significantly increased impedance (an indicator of cell relaxation) of primary cultures of human TM and SC cell monolayers in a receptor-specific manner, suggesting that both cell types mediate effects of PGs on conventional outflow facility.