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Elena Bastia, Francesco Impagnatiello, Daniela Miglietta, Barbara Giambene, Emanuela Masini, Nicoletta Almirante; Effects of diverse Nitric Oxide donation on ocular hemodynamic and intraocular pressure in normotensive rabbits. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4450.
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© ARVO (1962-2015); The Authors (2016-present)
There is evidence that nitric oxide (NO) is involved in the regulation of intraocular pressure (IOP) and ocular hemodynamics. We previously reported that NO donation incorporated into IOP lowering agents enhances IOP lowering activity and improves ocular perfusion of parent compounds. In an attempt to correlate IOP lowering properties with functional NO potency, we studied the effects on IOP and ocular hemodynamic of novel NO donors characterized by increasing NO donating capacity.
New Zealand White (NZW) rabbits were used. Novel NO donating compounds diversifying for one nitrate group (NCX 583) or two nitrate groups in vicinal (NCX 548) and distal (NCX 604) relationships were investigated. Isosorbide-5-mononitrate (ISMN) was used for comparison. The compounds were characterized with respect to their functional vascular effects as well as IOP lowering following topical dosing. NO-mediated vasorelaxant activity was tested in isolated norepinephrine (NE)-precontracted rabbit aortic rings. IOP was measured using a pneumatonomer prior to drug dosing and at 30, 60, 120, 180, 240 and 360 min thereafter. Ophthalmic artery hemodynamic was studied using Color Doppler Imaging.
Likewise ISMN (EC50=9.6±2.9µM) NCX 583, NCX 548 and NCX 604 showed vasorelaxant activity with an estimated potency of 2.5±0.6, 0.12±0.04 and 3.1±0.9 µM, respectively, thus indicating different NO release depending on the chemical nature of the compounds. NCX 583 (1%) and NCX 604 (1%) lowered IOP to similar extent as ISMN (1%) reaching 10% reduction of IOP from basal value within 30-60 min post dosing. In contrast, the vicinal dinitrate derivative, NCX 548 (1%) was the most active reaching a maximum of 25% reduction of IOP compared to vehicle. Similarly, compounds also lowered the resistivity index of the ophthalmic artery.
Data show that NO donation leads to IOP lowering and enhanced ocular perfusion. The magnitude of the effect appears to depend on the functional potency of the NO donors. Overall modulation of NO is a target of interest for the development of innovative IOP lowering agents
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