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Jason Y H Chang, C Ross Ethier, W Daniel Stamer, Darryl R Overby; Differential effects of nitric oxide synthase inhibitors on conventional outflow facility in mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2886.
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© ARVO (1962-2015); The Authors (2016-present)
Excess nitric oxide (NO) increases conventional outflow facility and lowers intraocular pressure (IOP) in wild-type mice (Chang et al., ARVO 2013) and transgenic mice that over-express endothelial NO synthase (eNOS; Stamer et al., IOVS 2011). To uncover the specific NO synthase influencing conventional outflow, we examined the effect of two different nitric oxide synthase (NOS) inhibitors on conventional outflow facility in wild-type mice.
Enucleated eyes from C57BL/6 mice (retired breeders, 7+ month old females) were perfused with a computerized syringe pump at 4, 8, 15 and 20 mmHg at 35°C in a bath of isotonic saline. Paired eyes were perfused with Dulbecco’s phosphate buffered saline + 5.5mM glucose (DBG) supplemented with or without NOS inhibitors, either (a) L-NG-Nitroarginine methyl ester (pan-NOS inhibitor, 100µM L-NAME; N = 6 pairs) or (b) Cavtratin (eNOS-specific inhibitor, 50µM; N = 5 pairs). Eyes were perfused either immediately after enucleation or after 4 hours storage at 4°C, with the treatments assigned randomly. Conventional outflow facility (C) was calculated as the slope of the linear regression through the flow rate-pressure data.
L-NAME treated eyes showed a slight increase in C which did not reach statistical significance (0.0289±0.0054 vs. 0.0241±0.0050 µL/min/mmHg; mean±SD, p = 0.12), whereas the eNOS-specific inhibitor (Cavtratin) showed a 27% reduction in C (0.0203±0.0091 vs. 0.0276±0.0131 µL/min/mmHg; p < 0.05). As a control, eyes were treated with the NO donor, SNAP (100µM), resulting in a 62% increase in outflow facility.
Selective inhibition of eNOS by Cavtratin decreases conventional outflow facility in mice, suggesting that endogenous eNOS activity may modulate conventional outflow by maintaining basal NO tone. The absence of a facility effect with the broad spectrum NOS inhibitor L-NAME may be attributable to off-target effects (e.g., muscarinic antagonist) as previously described (Heyne et al., IOVS 2013). Future studies should examine the dose-dependent effect of L-NAME on facility to resolve this discrepancy.
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