title: Betaxolol, a beta(1)-adrenoceptor antagonist, reduces Na(+) influx into cortical synaptosomes by direct interaction with Na(+) channels: comparison with other beta-adrenoceptor antagonists.
abstract: Betaxolol, a beta(1)-adrenoceptor antagonist used for the treatment of glaucoma, is known to be neuroprotective in paradigms of ischaemia/excitotoxicity. In this study, we examined whether betaxolol and other beta-adrenoceptor antagonists interact directly with neurotoxin binding to sites 1 and 2 of the voltage-sensitive sodium channel (Na(+) channel) in rat cerebrocortical synaptosomes. Betaxolol inhibited specific [(3)H]-batrachotoxinin-A 20-alpha-benzoate ([(3)H]-BTX-B) binding to neurotoxin site 2 in a concentration-dependent manner with an IC(50) value of 9.8 microM. Comparison of all the beta-adrenoceptor antagonists tested revealed a potency order of propranolol>betaxolol approximately levobetaxolol>levobunolol approximately carteolol>/=timolol>atenolol. None of the drugs caused a significant inhibition of [(3)H]-saxitoxin binding to neurotoxin receptor site 1, even at concentrations as high as 250 microM. Saturation experiments showed that betaxolol increased the K(D) of [(3)H]-BTX-B binding but had no effect on the B(max). The association kinetics of [(3)H]-BTX-B were unaffected by betaxolol, but the drug significantly accelerated the dissociation rate of the radioligand. These findings argue for a competitive, indirect, allosteric mode of inhibition of [(3)H]-BTX-B binding by betaxolol. Betaxolol inhibited veratridine-stimulated Na(+) influx in rat cortical synaptosomes with an IC(50) value of 28. 3 microM. Carteolol, levobunolol, timolol and atenolol were significantly less effective than betaxolol at reducing veratridine-evoked Na(+) influx. The ability of betaxolol to interact with neurotoxin site 2 of the Na(+) channel and inhibit Na(+) influx may have a role in its neuroprotective action in paradigms of excitotoxicity/ischaemia and in its therapeutic effect in glaucoma.
authors.affiliation: Nuffield Laboratory of Ophthalmology, University of Oxford, Walton Street, Oxford OX2 6AW.
authors.forename: G
authors.initials: G
authors.lastname: Chidlow
authors.forename: J
authors.initials: J
authors.lastname: Melena
authors.forename: N N
authors.initials: NN
authors.lastname: Osborne
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001262:Atenolol / Q000494:pharmacology; D001496:Batrachotoxins / Q000378:metabolism; D015784:Betaxolol / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002354:Carteolol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D002040:Levobunolol / Q000494:pharmacology; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012530:Saxitoxin / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D012979:Sodium Radioisotopes; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D013999:Timolol / Q000494:pharmacology; D014316:Tritium
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D001496:Batrachotoxins; D015222:Sodium Channels; D012979:Sodium Radioisotopes; D014316:Tritium; D012530:Saxitoxin; D001262:Atenolol; C031775:batrachotoxinin A 20-alpha-benzoate; D013999:Timolol; D002354:Carteolol; D012964:Sodium; D011433:Propranolol; D002040:Levobunolol; D015784:Betaxolol