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CK Bahler, MP Fautsch, CR Hann, DH Johnson; H-7 Increases Outflow Facility in Human Cultured Anterior Segments . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1031.
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Purpose: To determine the effect of H-7 on outflow facility and histology in human cultured anterior segments. H-7, a serine-threonine kinase inhibitor, has been reported by Tian and Kaufman (Arch Ophth 1998) to weaken the cytoskeleton. Weakening the cytoskeleton may allow targeted disruption of the cells lining Schlemm's canal, because of the transmural pressure gradient they face as aqueous passes into the canal. Other meshwork cells are surrounded by aqueous and do not face a pressure gradient. Methods: Anterior segments of 8 pairs of human eyes were placed in perfusion organ culture. After stabilization of baseline intraocular pressure (IOP), sequential doses of H-7 (100 and 300 µM) were added to one eye, while the fellow eye received vehicle. Eyes were fixed and examined by light and electron microscopy. In an additional experiment, anterior segments of 4 pairs of human eyes were cultured and stable baseline IOP obtained. The meshwork was then removed and the anterior segment was placed back in culture and IOP measured. Results: H-7 increased outflow facility after both the 100 µM dose (43%, p=0.02, n=8) and the 300 µM dose (15%, p=0.05, n=7). Fellow control eyes increased only 2%. Eyes responded variably to H-7, ranging from no response to a three-fold increase in facility. Histologic observation revealed up to 50% loss of inner and outer wall canal cells in the experimental eyes. The extracellular matrix generally remained intact in these regions. Trabecular cells in other regions appeared normal. Control eyes had only scattered loss of canal cells. Lowest IOP in H-7 experimental eyes was 11.8 3.3 mm (pre-drug: 17.2 mm). In contrast, the eyes in which meshwork had been removed had lower final pressures: 3.0 mm 1.8 mm (p=0.002 vs H-7 eyes; pre-dissection IOP: 19.3 mm). Conclusion: H-7 increases outflow facility in the human eye, associated with loss of cells lining Schlemm's canal. After H-7, IOP did not drop to levels as low as when the meshwork was removed, suggesting the remaining extracellular matrix plays a role in regulating outflow facility.
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