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Alexandra Boussommier Calleja, Jacques Bertrand, David Woodward, C. Ross Ethier, W. Daniel Stamer, Darryl R. Overby; Pharmacological Manipulation of Conventional Outflow Facility in Mouse Eyes. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3259.
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© ARVO (1962-2015); The Authors (2016-present)
Mouse models are useful for glaucoma research, but it is unclear whether intraocular pressure (IOP) regulation in mice operates through mechanisms similar to those in humans. Our goal was to determine whether G-protein coupled receptors that modulate conventional outflow facility in human eyes exert similar effects in C57BL/6 mice. We examined compounds that decrease (sphingosine 1-phosphate; S1P) or increase (3,7-dithia PGE1, an EP4 agonist) conventional outflow facility in human eyes by 36% or 69%, respectively (Stamer et al., Exp. Eye Res., 2009;89:980, Millard et al., IOVS, 2011;52:3506).
A computerized perfusion system was used to measure conventional outflow facility in enucleated ex vivo C57BL/6 mouse eyes. Eyes were cannulated with a 33G needle and perfused with a computer-controlled syringe pump at 4, 8, 15 and 25 mmHg, with conventional facility defined as the slope of the least-squares linear regression through the flow rate-pressure data. One eye of each pair was perfused with Dulbecco’s phosphate buffered saline + 5.5 mM glucose (DBG) containing 5 µM S1P + 2 mg/mL bovine serum albumin (BSA; N=8 eyes) or 10 nM 3,7-dithia PGE1 (N=7), while contralateral eyes were perfused with DBG + BSA (N=6) or DBG alone (N=6). Eyes with unsteady facility tracings were excluded. Paired eyes were perfused sequentially, either immediately after enucleation or after 3 hrs storage at 4°C, with the treated eye randomly assigned. An additional 5 pairs were perfused with DBG alone as a control group to examine the effect of the 3 hrs delay.
Conventional outflow facility in DBG-perfused eyes was 0.0073±0.0048 µL/min/mmHg (mean±SD; N=5 eyes). S1P decreased conventional facility by 41.7±32.8% compared to contralateral controls (p=0.023). The EP4 agonist, 3,7-dithia PGE1 increased facility by 110±42.8% (p=0.0002). No facility difference was observed in eyes perfused after 3 hrs storage compared to contralateral eyes perfused immediately after enucleation (2.1±27.5%; p=0.65; N=5 pairs).
The effects of the receptor-mediated compounds S1P and 3,7-dithia PGE1 on conventional outflow facility are similar in C57BL/6 mouse and human eyes, suggesting that mice are promising models for studying pharmacological IOP regulation in humans, and may be useful for investigating the pharmacology of outflow resistance generation relevant to glaucoma.
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