Hirooka K, Kelly M E, Baldridge W H, Barnes S
Department of Physiology & Biophysics, Dalhousie University, Halifax, Nova Scotia, Canada.
Exp Eye Res. 2000 May;70(5):611-21. doi: 10.1006/exer.2000.0822.
Betaxolol, a beta 1-selective adrenoceptor antagonist, is widely used in the treatment of glaucoma. In addition to its ocular hypotensive effects, betaxolol has been suggested to act as a retinal neuroprotective agent (Osborne et al., 1997). To investigate possible mechanisms underlying the neuroprotective effects, we tested the actions of betaxolol on ion channels and calcium signaling in isolated retinal ganglion cells. Betaxolol (50 microM) reduced 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 microM) and timolol (50 microM) had no inhibitory actions on HVA Ca channel currents. The L-type Ca channel antagonist, nisoldipine, blocked the HVA Ca channel current partially and the remaining current was not inhibited by betaxolol. Outward current was inhibited in the presence of betaxolol. Both iberiotoxin (IBTX; 10 nM), a selective inhibitor of large-conductance Ca-activated K channels, and Cd2+ (100 microM), which suppresses Ca-activated K channels subsequent to its block of Ca channels, reduced outward current and the remaining current was not blocked significantly with betaxolol. In the presence of betaxolol, Na channel currents were reduced by about 20%, as were currents evoked by glutamate (10 mM) and GABA (1 mM). Current clamp recordings from isolated ganglion cells showed that betaxolol had several effects on excitability: spike height decreased, repetitive spike activity was suppressed, spike width increased and hyperpolarization following spikes was reduced. Calcium imaging in isolated rat retinal ganglion cells revealed that betaxolol inhibited glutamate-induced increases in [Ca2+]i. These results suggest that betaxolol has 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+ influx. The subsequent reduction in [Ca2+]i may contribute to the apparent neuroprotective actions of betaxolol in promoting ganglion cell survival following ischemic insult, as may occur in glaucoma and retinal disease.
倍他洛尔是一种β1选择性肾上腺素能受体拮抗剂，广泛用于青光眼的治疗。除了其降眼压作用外，倍他洛尔还被认为可作为一种视网膜神经保护剂（奥斯本等人，1997年）。为了研究神经保护作用潜在的可能机制，我们测试了倍他洛尔对分离的视网膜神经节细胞中离子通道和钙信号的作用。倍他洛尔（50微摩尔）使从虎螈视网膜分离的神经节细胞中高压激活（HVA）钙通道电流降低了约20%。相比之下，β1肾上腺素能受体拮抗剂普萘洛尔（10微摩尔）和噻吗洛尔（50微摩尔）对HVA钙通道电流没有抑制作用。L型钙通道拮抗剂尼索地平部分阻断了HVA钙通道电流，剩余电流不受倍他洛尔抑制。在倍他洛尔存在的情况下外向电流受到抑制。大电导钙激活钾通道的选择性抑制剂iberiotoxin（IBTX；10纳摩尔）和在阻断钙通道后抑制钙激活钾通道的Cd2+（100微摩尔）均降低了外向电流，剩余电流不受倍他洛尔显著阻断。在倍他洛尔存在的情况下，钠通道电流降低了约20%，谷氨酸（10毫摩尔）和GABA（1毫摩尔）诱发的电流也降低了约20%。对分离的神经节细胞进行电流钳记录显示，倍他洛尔对兴奋性有多种影响：动作电位高度降低，重复动作电位活动受到抑制，动作电位宽度增加，动作电位后的超极化减弱。对分离的大鼠视网膜神经节细胞进行钙成像显示，倍他洛尔抑制了谷氨酸诱导的细胞内钙离子浓度（[Ca2+]i）升高。这些结果表明倍他洛尔对神经节细胞离子通道有多种抑制作用，因此，该药物的一个净作用是减少钙离子内流。随后细胞内钙离子浓度（[Ca2+]i）的降低可能有助于倍他洛尔在促进神经节细胞在缺血性损伤后存活方面的明显神经保护作用，青光眼和视网膜疾病中可能会发生这种缺血性损伤。
