Suppressive actions of betaxolol on ionic currents in retinal ganglion cells may explain its neuroprotective effects

Betaxolol, a beta(1)-selective adrenoceptor antagonist, is widely used in t he treatment of glaucoma. In addition to its ocular hypotensive effects, be taxolol has been suggested to act as a retinal neuroprotective agent (Osbor ne et al., 1997), To investigate possible mechanisms underlying the neuropr otective effects, we tested the actions of betaxolol on ion channels and ca lcium signaling in isolated retinal ganglion cells. Betaxolol (50 mu M) red uced by about 20 % the high-voltage-activated (HVA) Ca channel currents in ganglion cells isolated from tiger salamander retina. In contrast, the beta (1)-adrenoceptor antagonists propranolol (10 mu M) and timolol (50 mu M) ha d no inhibitory actions on HVA Ca channel currents. The L-type Ca channel a ntagonist, nisoldipine, blocked the HVA Ca channel current partially and th e remaining current was not inhibited by betaxolol. Outward current was inh ibited in the presence of betaxolol. Both iberiotoxin (IBTX; 10 nM), a sele ctive inhibitor of large-conductance Ca-activated K channels, and Cd2+ (100 mu M), which suppresses Ca-activated IC channels subsequent to its block o f Ca channels, reduced outward current and the remaining current was not bl ocked significantly with betaxolol. In the presence of betaxolol, Na channe l currents were reduced by about 20 %, as were currents evoked by glutamate (10 mna) and GABA (1 mM). Current clamp recordings from isolated ganglion cells showed that betaxolol had several effects on excitability: spike heig ht decreased, repetitive spike activity was suppressed, spike width increas ed and hyperpolarization following spikes was reduced. Calcium imaging in i solated rat retinal ganglion cells revealed that betaxolol inhibited glutam ate-induced increases in [Ca2+](i). These results suggest that betaxolol ha s a diversity of suppressive actions on ganglion cell ion channels and that , as a consequence, one of the net actions of the drug is to reduce Ca2+ in flux. The subsequent reduction in [Ca2+](i) may contribute to the apparent neuroprotective actions of betaxolol in promoting ganglion cell survival fo llowing ischemic insult, as map occur in glaucoma and retinal disease. (C) 2000 Academic Press.