The regulation of trabecular meshwork and ciliary muscle contractility

Current models of aqueous humor outflow no longer treat trabecular meshwork (TM) as an inert tissue passively distended by the ciliary muscle (CM). In stead, ample evidence supports the theory that trabecular meshwork possesse s smooth muscle-like properties and is actively involved in the regulation of aqueous humor outflow and intraocular pressure. In this model. trabecula r meshwork and ciliary muscle appear as functional antagonists, with ciliar y muscle con traction leading to a distension of trabecular meshwork with s ubsequent reduction in outflow, and with trabecular meshwork contraction le ading to the opposite effect. Smooth-muscle relaxing substances would therefore appear to be ideal candid ates for glaucoma therapy with the dual goal of reducing intraocular pressu re via the trabecular meshwork and of improving vascular perfusion of the o ptic nerve head. However, for such substances to effectively lower intraocu lar pressure, the effect an the ciliary muscle would have to he minimal. Fo r this reason. more information is needed on the signalling processes invol ved in regulating trabecular meshwork and ciliary muscle contractility. This review attempts to outline current knowledge of signal transduction pa thways leading to relaxation and contraction of ciliary muscle and trabecul ar meshwork. Pathways can be classified as involving or not involving chang es of membrane voltage and of requiring or not requiring external calcium: possibly, other pathways exist. These different pathways involve different ion channels and isoforms of PKC and are expressed to a differing degree in ciliary miracle and trabecular meshwork, leading to differential responses when exposed to relaxing or contracting pharmacological agents. Some of th ese agents. like tyrosine kinase inhibitors and inhibitors of PKC, have bee n shown to relax ttrabecular meshwork while leaving ciliary muscle comparat ively unaffected. This profile makes these substances appear as ideal drugs for simultaneously improving ocular outflow and retinal circulation, param eters that determine the time course of Visual deterioration in glaucoma. ( C) 2000 Elsevier Science Ltd. All rights reserved.