Neuroprotective effect and intraocular penetration of nipradilol, a beta-blocker with nitric oxide donative action.
OBJECTIVE
To investigate the effect of nipradilol, an alpha(1),beta-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, [(14)C]-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 application.
Department of Pharmacology, Tokyo Research Laboratories, Kowa Company, Ltd., 2-17-43 Noguchi-cho, Higashimurayama, Tokyo 189-0022, Japan. kmizuno@kowa.co.jp
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Mizuno
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Koide
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Yoshimura
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Araie
D000317:Adrenergic alpha-Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001813:Blood-Retinal Barrier / Q000187:drug effects; D002452:Cell Count; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000493:pharmacokinetics*; D009599:Nitroprusside / Q000494:pharmacology; D011412:Propanolamines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012161:Retinal Artery / Q000187:drug effects; D013999:Timolol / Q000494:pharmacology; D014661:Vasoconstriction
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D004338:Drug Combinations; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D011412:Propanolamines; D011799:Quinazolines; D009599:Nitroprusside; D009569:Nitric Oxide; D016202:N-Methylaspartate; D013999:Timolol; C018176:bunazosin; C036089:nipradilol