Effects of phosphodiesterase type 5 inhibitor sildenafil on retinal function in isolated superfused retina.

After the oral ingestion of sildenafil, visual abnormalities have been reported constantly. The mechanism of these adverse events has been presumed to be a result of the interaction of sildenafil with the retinal phosphodiesterase (PDE) type 6. To investigate the physiological basis of the effects of sildenafil on retinal function, bovine retinas were isolated and perfused with an oxygen pre-equilibrated standard solution. The electroretinogram (ERG) was recorded as a transretinal potential using silver/silver-chloride electrodes. After reaching stable ERG amplitudes, sildenafil was added to the nurient solution at different concentrations, and its effect on the a- and b-wave amplitude was studied separately. The 0.1 microM and higher concentrations of sildenafil reduced the b-wave amplitude, while a reduction of the a-wave amplitude was observed at an elevated threshold of 0.3 microM. The changes of the ERG amplitudes were fully reversible for the b-wave at a concentration of 0.1 microM and for the a-wave at 0.3 microM sildenafil. At higher concentrations, sildenafil was found to be only partially reversible within recovery time. In conclusion, besides an inhibitory influence on photoreceptors, sildenafil performs additional effects on the postsynaptic neuronal network. Higher concentrations of sildenafil were found to have a potential for retinal degeneration, suggesting that further trials should be designed to evaluate the long-term effects of sildenafil. The physiological consequences of an abuse or long-term, daily use of sildenafil are not clear.

Effects of daunorubicin and CD95L on retinal function in superfused vertebrate retina.

Alternative treatments of proliferative vitreoretinopathy (PVR) are needed. The intravitreal application of daunorubicin combined with CD95 ligand (CD95L) could provide a new therapeutic strategy. The effects of this application on bovine retinal function were investigated. Bovine retina preparations were perfused with a standard solution preequilibrated with oxygen. The b-wave and, after the addition of aspartate, the photoreceptor potential P III of the electroretinogram (ERG) were recorded using Ag/AgCl electrodes. Stable ERG amplitudes were recorded, then daunorubicin was added to the solution for 45 minutes, also with the addition of CD95L antibody. Subsequently, the preparation was reperfused with the standard solution for 100 minutes, to allow for recovery. The reduction in b-wave amplitude was reversible and not significantly changed by the addition of 0.25 microg/mL CD95L antibody to 13 microM of daunorubicin. The reduction of the b-wave amplitude was significantly changed and only partly reversible within the recovery time using 40 microM and 80 microM of daunorubicin. The photoreceptor potential P III amplitude was not significantly changed for up to 80 microM of daunorubicin. The ERG showed toxic effects of daunorubicin above a concentration of 13 microM used therapeutically in humans. The combination with CD95L did not increase retinal toxicity. It is, therefore, concluded that daunorubicin may be applied intraocularly, combined with CD95L, without interfering with retinal function.

A Ni(2+)-sensitive component of the ERG b-wave from the isolated bovine retina is related to E-type voltage-gated Ca(2+) channels.

BACKGROUND: Voltage-dependent Ca(2+) channels trigger and control important cellular processes like neurotransmitter release and secretion, long-term potentiation, and gene expression in excitable cells. During retinal signal perception and processing, presynaptic Ca(2+) channels facilitate neurotransmitter release in photoreceptors and bipolar neurons, at nonspiking synapses which generate graded potentials. METHODS: The nature of voltage-gated Ca(2+) channels involved in retinal signal transduction is investigated in the present report by recording the electroretinogram (ERG) from the isolated and perfused bovine retina. Transcripts of the E/R- and T-type Ca(2+) channels are detected by RT-PCR. RESULTS: Using the Ca(2+) channel antagonists (+/-)-isradipine, NiCl(2), mibefradil, and SNX-482 results in either stimulatory or inhibitory effects on the ERG b-wave amplitude. On the transcript level, mRNA is detected for the E/R-type and a T-type voltage-gated Ca(2+) channel containing Ca(v)2.3 and Ca(v)3.1 as ion-conducting subunits, respectively. CONCLUSION: Blocking of the E/R-type Ca(2+) channels by NiCl(2) (10 microM) and SNX-482 (30 nM) contributes to the stimulatory effect, whereas antagonism of T-type as well as L-type Ca(2+) channels meditates the inhibitory action on the b-wave amplitude. Thus, a novel function for E/R-type voltage-gated Ca(2+) channels is probably associated with the visual signal transduction in the mammalian retina.