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

1 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. 2 Betaxolol inhibited specific [H-3]-batrachotoxinin-A 20-alpha-benzoate ([H-3]-BTX-B) binding to neurotoxin site 2 in a concentration-dependent manner with an IC50 value of 9.8 mu M. Comparison of all the beta-adrenoceptor antagonists tested revealed a potency order of propranolol > betaxolol approximate to levobetaxolol > levobunolol approximate to carteolol greater than or equal to timolol > atenolol. 3 None of the drugs caused a significant inhibition of [H-3]-saxitoxin binding to neurotoxin receptor site 1, even at concentrations as high as 250 mu M. 4 Saturation experiments showed that betaxolol increased the K-D of [H-3]-BTX-B binding but had no effect on the B-max. The association kinetics of [H-3]-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 [H-3]-BTX-B binding by betaxolol. 5 Betaxolol inhibited veratridine-stimulated Na+ influx in rat cortical synaptosomes with an IC50 value of 28.3 mu M. Carteolol, levobunolol, timolol and atenolol were significantly less effective than betaxolol at reducing veratridine-evoked Na+ influx. 6 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.