Effect of Amiloride to Retinal Toxicity Induced by Tissue Plasminogen Activator

Tissue plasminogen activator (tPA), an effective thrombolytic agent, is commercially available for the treatment of vitreous hemorrhage, subfoveal hemorrhage, suprachoroidal hemorrhage, and retinal vascular occlusive disease in the field of ophthalmology [1,2]. In particular, intravitreal or subretinal injections of tPA have been used when performing surgery for submacular hemorrhages or subfoveal choroidal neovascularization [3-8]. Dose-dependent retinal toxicity has been reported with the injection of intravitreal tPA; this toxicity has been reported to be due to the L-arginine vehicle rather than the tPA itself [9]. The retinal toxicity of L-arginine has been reported to increase nitric oxide (NO) in cells [10]. NO activates guanylate cyclase in the photoreceptor layer of the retina to produce more cyclic guanosine monophosphate (cyclic-GMP) [11]. In the rd/rd mouse, photoreceptor degeneration is due to a mutation of the rod-specific enzyme cyclic-GMP phosphodiesterase, resulting in permanently open cyclic-GMP-gated cation channels in the rod outer segment membrane, allowing Na+ and Ca2+ ions to enter the cell and leading to possibly toxic levels of Ca2+ [12]. Therefore, the increase in NO that is caused by L-arginine leads to the accumulation of cyclic-GMP, thus leading to toxicity. Amiloride has an inhibitory function on the Na+/H+ exchanger in the apical plasma membrane of the distal nephron and the cyclic-GMP gated channel of the outer membrane of retinal photoreceptor cells [13]. Therefore, inhibition of the cyclic-GMP gated channels of retinal cells may result in a decrease in intracellular Ca2+, which then leads to increased retinal cell survival after tPA-induced toxicity. The purpose of this study was to examine the effect of amiloride on cellular toxicity caused by tPA-arginine in mouse primary retinal cells.