Comparative effects of antiglaucoma drugs on voltage-dependent calcium channels

Melena, José; Stanton, David; Osborne, Neville N.

doi:10.1007/s004170100312

Cited by 45 publications

(31 citation statements)

References 58 publications

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“…The results would raise a question of whether inhibition of voltage-dependent Ca 2+ channels by β-antagonists described previously (12,32) is involved in this protective effect. These channels are endogenously expressed in Xenopus oocytes, but the amount of expression of Ca 2+ channels is relatively low, producing small currents ranging only from 20 -50 nA (40,41).…”

Section: +mentioning

confidence: 82%

“…If this is the case, the blocking effects of betaxolol to not only NMDA receptors but also Ca 2+ and Na + channels are unlikely to be produced. As described previously, however, it seems likely that β-antagonists may reach high enough concentrations to directly affect NMDA-receptor function by repeated topical application because lipophilic drugs, such as ophthalmic β-antagonists, could accumulate in the lipid bilayer, which also raises the possibility that drug concentrations could reach hundred times higher levels in retina compared to the aqueous surroundings (32,34). Therefore, repeated topical applications of Table 1.…”

Section: Discussionmentioning

confidence: 98%

“…The direct effects of timolol and betaxolol on NMDAreceptor function were obtained at concentrations from 10 to 100 µM, at which the direct effects of betaxolol on voltage-dependent Na + and Ca 2+ channels have also been reported (12,31,32). In terms of betaxolol, however, topical application of 25 µg / ml suspension for 28 -30 days to monkeys and human eyes resulted in the local concentration reaching approximately 0.1 to 0.4 µM in retina and optic nerve head, an estimation based on the assumption that betaxolol is evenly distributed throughout the retina (33).…”

Section: Discussionmentioning

confidence: 99%

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Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

et al. 2008

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Abstract. In the present study, we investigated the direct effects of antiglaucoma drugs (timolol, betaxolol, pilocarpine, and latanoprost) on N-methyl-D-aspartate (NMDA)-receptor function using a Xenopus oocytes expression system and electrophysiological techniques. In oocytes expressing wild-type NMDA (NR1a / NR2A) receptors, timolol and betaxolol significantly inhibited glutamate-evoked currents, whereas less inhibition was obtained with pilocarpine, and latanoprost had few effects. Moreover, the effect of timolol and betaxolol was noncompetitive with respect to glutamate. Mutations that changed Asn616 of the NR1a subunit, a critical residue for Mg 2+ blocking of NMDA receptors, to Arg (N616R) or Gln (N616Q) almost eliminated the inhibitory effects of timolol and betaxolol, as well as the blocking effect of Mg 2+. Experiments were also carried out to examine the protective effects of timolol and betaxolol against death of oocytes expressing NMDA receptors. During incubation of oocytes, especially in Mg 2+ -free medium, cell death was induced by addition of glutamate because of the continuous activation of the NMDA receptors expressed. Timolol and betaxolol significantly improved oocyte viability when they were added during the incubation period. These results suggest that timolol and betaxolol may have an additional role that they directly inhibit NMDA-receptor function, possibly via N616 of the NR1a subunit.

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Section: +mentioning

confidence: 82%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

et al. 2008

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“…Betaxolol is already known to inhibit the latter (Melena et al, 1999(Melena et al, , 2001Hirooka et al, 2000); however, it's effects on NMDA receptors has yet to be established. Electrophysiological studies on lower vertebrates showed that betaxolol can inhibit the voltage-gated Na ϩ and Ca 2ϩ currents of ganglion cells (Gross et al, 2000;Hirooka et al, 2000).…”

mentioning

confidence: 99%

Inner retinal neurons display differential responses to N‐methyl‐D‐aspartate receptor activation

Sun

Rait

Kalloniatis

2003

J of Comparative Neurology

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The N-methyl-D-aspartate (NMDA) responses of neurons from within the inner rabbit retina were mapped using a channel permeable cation, 1-amino-4-guanidobutane (agmatine, AGB). Serial sections were subsequently probed with immunoglobulins targeting AGB, glutamate, gamma-aminobutyric acid (GABA), and glycine to visualize the NMDA responses of neurochemical subpopulations of neurons. Most inner retinal subpopulations of neurons demonstrated an NMDA concentration-dependent increase in activation. This NMDA-induced activation displayed a distinct pattern, with the most sensitive class to least sensitive class ranking being GC > GABA cAC > GABA/Gly cAC > Gly cAC > GABA dAC (GC, ganglion cells; AC, amacrine cells; c, conventional; d, displaced; Gly, glycine). The variable NMDA response may reflect differences in NMDA receptor subunit disposition or differences in receptor density. In addition to the variable NMDA activation pattern, we found that virtually all ganglion cells (87%) showed NMDA-gated AGB entry, compared with only 58% of amacrine cells. We conclude that a large cohort of amacrine cells do not possess functional NMDA receptors. In addition to most ganglion cells being activated by NMDA, a large subpopulation displayed the highest sensitivity to NMDA application. The functional significance of this finding is that the ganglion cell population will be the first neuronal class to be susceptible to glutamate-induced neurotoxicity mediated through the NMDA receptor. The addition of betaxolol significantly reduced NMDA-mediated AGB entry into most neuronal groups (ganglion cells, GABA, and glycine amacrine cells), with the greatest effect being on ganglion cells. Betaxolol had no significant effect on NMDA-gated entry of AGB on the GABA/Gly amacrine cell population.

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“…We can not exclude the possibility that the selective b 1-adrenergic blocking property of betaxolol is may be related to this neuroprotective effect in this study. However, it is reported that a b -adrenergic receptor antagonist such as timolol has no neuroprotective effect on NMDA-induced retinal injury (35) and that betaxolol has a greater L-type blocking activity than other b -adrenergic receptor antagonist (36) and neuroprotective effect on the ischemiainduced retinal injury (12,13). These results suggested that betaxolol may function as a neuroprotective agent by reducing the excessive influx of calcium into the cell in some way (see the Introduction).…”

Section: Discussionmentioning

confidence: 99%

Effect of Betaxolol on Aspartate Aminotransferase Activity in Hypoxic Rat Retina In Vitro

Endo

Tomita

Ishiguro

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-We investigated the effect of betaxolol on the decrease of mitochondrial aspartate aminotransferase (mAAT) activity in rat retinas induced by hypoxia in vitro. It is reported that mAAT decreases in ischemic or hypoxic retina and that the decrease is caused by Ca 2+ -dependent proteases such as calpain. Betaxolol is a compound that has b1-adrenergic receptor blocking and voltage-dependent calcium channel blocking properties. The rat eye cups were maintained with Locke's solution saturated with 95% air -5% CO2. The eye cups were immersed in glucose-free Locke's solution saturated with 95% N2 / 5% CO2 (hypoxic solution). Ninety minutes of hypoxia caused a 20% decrease in mAAT activity. The eye cups incubated with the hypoxic solution containing 1 mM EGTA, 10 mM MK-801 or 100 mM betaxolol were protected from the decrease in mAAT activity, so that the residual mAAT activity was 50%, 45% or 40%, respectively, compared to the eye cups incubated in hypoxic solution alone, which had a 100% decrease in mAAT activity. In addition, co-incubation with EGTA and betaxolol had a greater protective effect against the mAAT decrease than a single application. This additive effect of betaxolol was dose-dependent. These results suggested that betaxolol had a protective effect against the decrease of mAAT caused by hypoxia and indicated that betaxolol might inhibit the Ca 2+ release from intracellular Ca 2+ stores.

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Comparative effects of antiglaucoma drugs on voltage-dependent calcium channels

Abstract: Of the antiglaucoma drugs investigated, betaxolol displays the greatest L-type VDCC-blocking activity and this may be of clinical relevance. Such a characteristic could account for some of its described ocular actions.

Cited by 45 publications

References 58 publications

Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

Direct Inhibition of N-Methyl-D-Aspartate (NMDA)-Receptor Function by Antiglaucomatous β-Antagonists

Inner retinal neurons display differential responses to N‐methyl‐D‐aspartate receptor activation

Effect of Betaxolol on Aspartate Aminotransferase Activity in Hypoxic Rat Retina In Vitro

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