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Yuan Lei, Xuejin Zhang, Jihong Wu, Xing-Huai Sun; Aqueous humour outflow physiology in NOS3 knockout mice. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4849.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the role of endothelial nitric oxide synthase (NOS) on conventional outflow function using NOS3 knockout (KO) mice.
IOP was measured in both NOS3 KO and wild type (WT) mice by rebound tonometry. Outflow facility was measured by perfusing enucleated mouse eyes (NOS3 KO versus WT) at multiple pressure steps between 8 and 30 mmHg. A subset of eyes embedded in paraffin was sectioned and stained using haemotoxylin and eosin (H&E) for histology. Mock aqueous humour or mock aqueous humour + the nitric oxide (NO) donors nitroprusside dihydrate (SNP, 1 uM) or S-Nitroso-N-Acetyl-D,L-Penicillamine (SNAP, 100 uM) was perfused into enucleated eyes. SNP (4x2uL drops, total dose 160 ug) and SNAP (4x2uL drops, total dose 160 ug) was administered topically at 0, 1, 2, and 3 hours while the contralateral eyes served as vehicle controls. IOP was measured in both eyes before drug treatment and 1 hour after the last drug treatment.
IOP was higher (18.2 ± 3.9 vs. 13.9 ± 2.5 mm Hg; mean ± SD, P<0.05) in KO mice, and pressure-dependent conventional drainage was significantly lower (0.0058 ± 0.0010 uL/min/mmHg, mean ± SEM, n=21) compared with WT mice (0.0087 ± 0.0013, uL/min/mmHg, n=23, p<0.05). No obvious morphological difference in iridiocorneal angle tissues was observed in H&E stained mouse eye sections. SNP and SNAP significantly increased pressure-dependent drainage in KO animals from 0.0062 ± 0.0009 to 0.01465 ± 0.0050 uL/min/mmHg (mean ± SEM, n=12, p<0.05), and from 0.0067 ± 0.0015 to 0.0223 ± 0.0044 uL/min/mmHg (mean ± SEM, n=12, p<0.05), respectively. In WT mice, SNP and SNAP caused a significant increase in pressure dependent drainage (n=12, p<0.05) to a similar degree to KO mice. Topical application of SNP significantly reduced IOP in WT and KO mice by 31% and 30% respectively (n=12, p<0.05), but SNAP did not change IOP significantly (n=12).
NOS3 KO mice have elevated IOP which is likely the result of reduced pressure-dependent drainage. These findings are consistent with human data showing polymorphisms in NOS3 gene associate with ocular hypertension and the development of glaucoma.
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