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Ken Mizuno, Takashi Koide, Mitsuo Yoshimura, Makoto Araie; Neuroprotective Effect and Intraocular Penetration of Nipradilol, a β-Blocker with Nitric Oxide Donative Action. Invest. Ophthalmol. Vis. Sci. 2001;42(3):688-694.
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purpose. To investigate the effect of nipradilol, an α1,β-blocker
with a nitric oxide donative action, on N-methyl-d-aspartate (NMDA)–induced retinal
damage in rats and to determine whether topically instilled nipradilol
penetrates the ipsilateral posterior retina–choroid at
pharmacologically active concentrations in rabbits.
methods. To determine effects on NMDA-induced damage, drugs were injected alone
or with NMDA into the vitreous of one eye, and cell loss in the
ganglion cell layer (GCL) and thinning of the retinal neural cell
layers were histologically evaluated. To evaluate posterior
penetration, first, [14C]-nipradilol was instilled, and
its tissue concentration was measured. Second, nipradilol or timolol
was instilled, and their effects on intravitreal injection of
endothelin-1–induced retinal artery contraction were compared, to
evaluate whether a pharmacologically active level of nipradilol
penetrates the inner limiting layer by topical application.
results. Intravitreous injection of NMDA reduced cell numbers in the GCL and the
thickness of the inner plexiform layer (IPL) to 50.4% ± 2.6% and
47.8% ± 4.9% (n = 8) of control, respectively.
Nipradilol alone had no effect. Coadministration of nipradilol with
NMDA reduced cell numbers in the GCL and IPL thickness to 67.8% ±
2.2% and 74.4% ± 5.2% of control, respectively
(P < 0.05–0.01). Sodium nitroprusside, but not
timolol or bunazosin, also significantly prevented the NMDA-induced
reduction of cell numbers in the GCL and IPL thickness. Radioactivity
of nipradilol was found in the ipsilateral posterior retina–choroid at
318.6 ± 42.9 ng/g (n = 4), which was
significantly higher than in the contralateral control (107.4 ±
21.8 ng/g). Topical application of nipradilol, but not timolol,
significantly suppressed the endothelin-1–induced contraction of the
retinal artery (83.95% ± 8.15% and 35.24% ± 5.62% of baseline
vessel diameter for nipradilol and timolol, respectively).
conclusions. Nipradilol suppressed the NMDA-induced retinal damage in rats for which
nitric oxide released from nipradilol may be responsible. Posterior
penetration studies suggested that an effective concentration of
nipradilol reached the posterior retina after topical
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