Betaxolol, a β 1 ‐adrenoceptor antagonist, reduces Na + influx into cortical synaptosomes by direct interaction with Na + channels: comparison with other β‐adrenoceptor antagonists

Betaxolol, a β 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 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 [ 3 H]‐batrachotoxinin‐A 20‐α‐benzoate ([ 3 H]‐BTX‐B) binding to neurotoxin site 2 in a concentration‐dependent manner with an IC 50 value of 9.8 μ M . 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 [ 3 H]‐saxitoxin binding to neurotoxin receptor site 1, even at concentrations as high as 250 μ M . 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 μ M . 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