July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Genetic deletion of NOS3 gene in CAV1-/- mice decreases drug sensitivity to nitric oxide donor and nitric oxide synthase inhibitor
Author Affiliations & Notes
  • Yuan Lei
    Eye and ENT hospital of Fudan University, Shanghai, China
  • Maomao Song
    Eye and ENT hospital of Fudan University, Shanghai, China
  • Jihong Wu
    Eye and ENT hospital of Fudan University, Shanghai, China
  • Xing-Huai Sun
    Eye and ENT hospital of Fudan University, Shanghai, China
  • Footnotes
    Commercial Relationships   Yuan Lei, None; Maomao Song, None; Jihong Wu, None; Xing-Huai Sun, None
  • Footnotes
    Support  Funding: National Science Foundation China (81371015),
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 1651. doi:
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      Yuan Lei, Maomao Song, Jihong Wu, Xing-Huai Sun; Genetic deletion of NOS3 gene in CAV1-/- mice decreases drug sensitivity to nitric oxide donor and nitric oxide synthase inhibitor. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1651.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Genetic double knockout (DKO) of nitric oxide synthase 3 (NOS3) and caveolin 1 (CAV1) restores aqueous humor outflow function in mice. However, the intraocular pressure (IOP) of these mice were shown to be unresponsive to the conventional effective dose of NO donor and NOS inhibitor. The aim of the study is to investigate the pharmacologic consequence in detail.

Methods : The dose-response of three animal models was compared in this study including DKO, CAV1 KO and wild-type (WT) male mice of 8-10 weeks old. A range of concentrations of NO donor sodium nitroprusside (SNP, 10 – 40 mg) or NOS inhibitor L-NG-nitroarginine methyl ester (L-NAME, 10-200 mM) were topically applied to one eye at 0, 0.5, 1, and 1.5h while the contralateral eye was treated with vehicle. IOP was measured in both eyes before drug treatment and one hour after the last drug treatment by tonometry. cGMP activity in the outflow tissue containing trabecular meshwork (TM) and Schlemm's canal (SC) and possibly some iris root was analyzed by ELISA. IOP data was analyzed by two-way analysis of variance (ANOVA) followed by LSD test for multiple comparisons.

Results : In DKO mice SNP concentration of up to 30 mg/mL did not significantly change IOP (n=6, p>0.05). Higher concentration (40 mg/mL) SNP significantly reduced IOP by 1.2 fold (n=4, p<0.05). In WT and CAV1 KO mice, the same concentration of SNP (20, 30, 40 mg/mL) significantly lowered IOP (n=6 for each group, p<0.05). 10 mg/mL SNP did not affect IOP in any of the three mouse strains (n=6, p>0.05). Similarly, 100 mM L-NAME did not significantly affect IOP in DKO mice (n=15, p>0.05), but 200 mM L-NAME produced a significant increase in IOP in drug-treated eyes compared with vehicle control eyes (n=4, p<0.05). In contrast, 100 mM L-NAME significantly increased IOP in WT and CAV1KO mice (n=6, p<0.05). 10 mM L-NAME did not significantly affect IOP in any of the mice strain. cGMP activity was lower in DKO mice compared with WT and CAV1 KO mice (n=6, p<0.05).

Conclusions : Genetic deletion of NOS3 in CAV1 deficient mice resulted in reduced sensitivity to NO donor and NOS inhibitor which may due to compromised cGMP activity in the TM/SC outflow tissue.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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