Development of readily applicable glaucoma new drugs for lowering intraocular pressure, improvement of ocular circulation, and neuronprotection

研究了一种选择性α - 1d肾上腺素能拮抗剂的降眼压作用。选择性α - 1d肾上腺素能拮抗剂对荷兰兔的水流出量增加有效，但对食蟹猴没有作用。这种药的效果在不同的物种之间似乎是不同的。研究了Na^+-HCO_3共转运体（NBG-1）在眼组织中的作用。采用肾型NEC-1和胰腺型NBC-1特异性抗体对人和大鼠眼组织进行免疫组织学分析。两种类型均在角膜上皮、晶状体上皮和小梁网中表达。提示NBC-1在房水流出调控中有一定作用。用大白兔研究视神经血流的自调节功能。视神经血流在急性眼压升高或降低时表现出自我调节。Ca^<2+>阻滞剂可减弱该功能，但一氧化氮合成酶抑制剂吲哚美辛和交感神经去支配均无减弱作用。采用大鼠实验性青光眼模型或视网膜神经节细胞损伤模型进行的体内实验表明，Ca^<2+>阻滞剂对海碱盐所致的视网膜神经节细胞损伤具有神经保护作用。用纯分离的大鼠视网膜神经节细胞和神经胶质细胞进行的实验表明，神经胶质细胞影响视网膜神经节细胞的存活。低氧应激和高压应激诱导神经胶质细胞产生一氧化氮，抑制神经营养因子的表达。

The intraocular pressure lowering effect of a selective alpha1D adrenergic antagonist was studied. The selective alpha1D adrenergic antagonist was effective in increasing aqueous outflow in Dutch rabbit but not in cynomolgus monkey. The effect of this drug seemed to be different among species.The role of Na^+-HCO_3 cotransporter (NBG-1) in ocular tissues was studied. Immunohistological analysis of human and rat ocular tissue was performed using specific anti-body of kidney-type NEC-1 and pancreas-type NBC-1. Both types were expressed in corneal epithelium, lens epithelium, and trabecular meshwork. NBC-1 was suggested to have some role in regulation of aqueous humor outflow.The autoregulation function of optic nerve blood flow was studied using white rabbits. The optic nerve blood flow showed autoregulation in response to acute intraocular pressure increase or reduction. The function was attenuated by a Ca^<2+> blocker but not by a nitric oxide synthetase inhibitor, indomethacin, nor sympathetic denervation.In vivo experiments using rat experimental glaucoma model or retinal ganglion cell damage model showed that a Ca^<2+> blocker had neuroprotective effect on the retinal ganglion cell damage caused by kainate.Experiments using purely isolated rat retinal ganglion cell and glial cells showed that glial cells influence the survival of retinal ganglion cells. Hypoxic stress and high pressure stress induce the production of nitric oxide and suppress the expression of neurotrophic factors in glial cells.