Betaxolol, a β1‐adrenoceptor antagonist, reduces Na+ influx into cortical synaptosomes by direct interaction with Na+ channels: comparison with other β‐adrenoceptor antagonists

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Abstract
Betaxolol, a β1‐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 β‐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 [3H]‐batrachotoxinin‐A 20‐α‐benzoate ([3H]‐BTX‐B) binding to neurotoxin site 2 in a concentration‐dependent manner with an IC50 value of 9.8 μM. Comparison of all the β‐adrenoceptor antagonists tested revealed a potency order of propranolol>betaxolol∼levobetaxolol>levobunolol∼carteololtimolol>atenolol. None of the drugs caused a significant inhibition of [3H]‐saxitoxin binding to neurotoxin receptor site 1, even at concentrations as high as 250 μM. Saturation experiments showed that betaxolol increased the KD of [3H]‐BTX‐B binding but had no effect on the Bmax. The association kinetics of [3H]‐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 [3H]‐BTX‐B binding by betaxolol. Betaxolol inhibited veratridine‐stimulated Na+ influx in rat cortical synaptosomes with an IC50 value of 28.3 μM. 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. British Journal of Pharmacology (2000) 130, 759–766; doi:10.1038/sj.bjp.0703369