The Pharmacology of Aqueous Humor Outflow

In all individuals, the pathways which the aqueous humor (the colorless fluid which nourishes the front part of the eye) takes to leave the eye offer some resistance to the outflow of aqueous humor. This results in the intraocular pressure (IOP) being greater than the venous pressure. If this were not the case, the cornea would lose its convex shape, and thus, its important refractive role in focusing images on the retina. In primary open angle glaucoma (POAG), the resistance to fluid flow through the outflow tissues is much greater than in normal eyes. This results in an abnormally elevated IOP which can cause irreversible damage of the retina and optic nerve, leading to blindness. POAG has been difficult to study because the outflow tissues are minute and because there is no animal model. It is not known what factors cause the out flow tissues to become more resistant to fluid flow. To date, no clear reason for this increased resistance has been discovered in glaucomatous eyes either microscopically or biochemically. Furthermore, the determinants of outflow resistance in normal eyes are not well understood. In order to understand the cause of POAG, it is necessary to understand what the cells that line the aqueous outflow pathways “do”. One way of trying to decide what the cells “do” is to understand how various drugs affect their function. Ophthalmologists take advantage of the observation that certain classes of drugs lower outflow resistance (and, therefore, IOP). These drugs are used to treat POAG. However, very little is currently known about how they change the resistance. Recent advances in technology hold promise for finding the cause and a cure for POAG. One of these technological breakthroughs involves the organ culture of human eyes. This is a unique preparation in which short and long-term effects of drugs can be studied in human tissue (this is an important advantage, because animals do not get POAG). Since surprisingly little is known about the pharmacology of aqueous outflow resistance in human eyes, this model promises to advance our understanding of how resistance can be altered. Proposed studies will test the broad hypothesis that vasoactive drugs (i.e. drugs which alter the diameter and/or leakiness of blood vessels) will change the resistance to fluid outflow in the human eye, using the organ culture model. This hypothesis is based on previous observations in this system with epinephrine (a vasoactive drug), and on results obtained with vasoactive drugs in the monkey eye in vivo.

2nd Year

In glaucoma, the tissues involved in draining aqueous humor from the eye become more resistive to fluid flow. Therefore, the intraocular pressure (IOP) builds up due to this increased resistance to outflow of aqueous humor. Blindness eventually occurs, as the delicate nerves in the retina become damaged due to the increased eye pressure. Although it has been known for a number of years that glaucoma is due to this increase in resistance, it is still not clear how the resistance builds up. One of the reasons that there is a lack of information about how this happens is that very little is known about how the flow of aqueous humor out of the eye is regulated in normal tissue. The aim of our research is to better understand how the trabecular meshwork (the tissue responsible for the abnormal resistance to aqueous outflow in glaucoma) eliminates aqueous humor from the eye. One way to do this is to study the effects of various drugs and hormones on aqueous humor outflow in a newly developed in vitro human eye perfusion system. The project which AHAF is making possible is the study of the effects of various vasoactive substances on outflow resistance in the human eye in vitro. To date, we have identified several hormones which may play a regulatory role in aqueous outflow dynamics. With further physiological and biochemical studies we will better understand how the aqueous outflow system can be modified with various hormones. This may lead to better treatments of glaucoma and may help us to better understand how the abnormal resistance builds up in glaucoma.