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S. Husain, C.E. Crosson; Acute Effects of Latanoprost on Intraocular Pressure in the Rat . Invest. Ophthalmol. Vis. Sci. 2006;47(13):219.
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To study the mechanisms involved in the acute effects of latanoprost on intraocular pressure (IOP) in the rat.
Wistar rats that were housed under standard laboratory conditions with a 12–hour light and 12–hour dark cycle were used in this study. IOP was measured in conscious rats in a masked fashion using a calibrated rebound TonoLab tonometer. After two baseline readings (–1 and 0), the drug or vehicle was applied topically (3–12 µL) to one eye. IOP was then measured at 1, 2, 3, 4, 5, 6, and 24 hours post–treatment. The secretion of matrix metalloproteinases (MMP) was determined by Western blot analysis using conditioned media from human ciliary muscle (HCM) cells, anti–MMP–1, and anti–MMP–2 antibodies.
Latanoprost (60 ng) administration produced a biphasic change in IOP: an initial rise in pressure (2.11 ±0.72 mmHg) peaking at two hours, followed by a prolonged hypotension with a peak reduction in IOP (5.22 ±0.74 mmHg) at 6 hours. Both the hyper and hypotensive actions of latanoprost were dose–related with EC50 values of 108 and 5.2 ng, respectively. This response was blocked by pretreatment with pilocarpine (4%) and the GM–6001, a broad range MMP inhibitor. In addition, the latanoprost–induced reduction in IOP was partially blocked by pretreatment with thalidomide, a tumor necrosis factor (TNF–α) biosynthesis inhibitor. In addition, TNF–α treatment increased the secretion of MMP–1 by 189 ±8% and MMP–2 by 165 ±37% from human ciliary muscle cells at 6 hours.
These results show that the IOP response to latanoprost in the rat eye is biphasic. The hypotensive response is similar to that of the human and primates. Therefore, a rat model can be used to evaluate the effects of anti–glaucoma drugs such as prostaglandins. Data also suggest that the latanoprost–induced reduction in IOP is mediated, in part, through TNF–α–dependent signaling pathways in which MMPs play a key role to increase uveoscleral outflow.
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