Advances in Glaucoma Treatment and Management: Outflow Drugs

I ntraocular pressure (IOP) rises when the balance between aqueous humor formation and outflow resistance is compromised.In a normal eye, ciliary muscle (CM) and trabecular meshwork (TM) contraction and relaxation function in synchrony to provide fine control of outflow.Recent investigations of the role of endothelial nitric oxide synthase (eNOS) 1 suggest TM mechanosensitivity as a homeostatic mechanism mediated in part by NO to maintain normal outflow facility and IOP.The active role of TM contraction and relaxation in the regulation of IOP is also likely to be mediated in part by the actomyosin contractility/cytoskeleton/cell-cell and cell-matrix adhesion system.The cytoskeleton and contractility mechanisms may be the efferent "execution" arm of the reflexive and regulatory mechanism; their arrangement governs the final facility.The eNOS/NO system appears to be a signal/transduction arm that mediates response to the stressors.It is generally agreed that the greatest resistance to outflow resides in the juxtacanalicular region and inner wall of Schlemm's canal (SC)-areas that are directly affected by contractile changes in the CM and TM. 2 The CM plays a major role, but the TM has its own active contractile/relaxant role executed efferently by the system noted above, modulated afferently by the various sensors in the CM tendons, the CM apex, and the TM, mediated by CTGF 3,4 and NOS/NO, 1 among others, and further modulated by TGF␤2 and consequent downstream mediators and their effects on the ECM and other tissues.The interactions of this system are just now being appreciated.Understanding how this system functions is critical for determining how to effectively and efficiently manipulate elements of the system to therapeutic effect.The molecular pathways that modulate uveoscleral and trabecular outflow are complex.Advances in identifying the most salient therapeutic elements in such complicated systems are best catalyzed in small, focused meetings.These are a valuable complement to the larger research meetings, and more are needed.