Increase In B-wave Amplitude Research Articles

Natural history and biomarkers of KCNV2-associated retinopathy.

KCNV2-associated retinopathy is an autosomal recessive inherited retinal disease classically named cone dystrophy with supernormal rod response (CDSRR). This study aims to identify the best biomarker for evaluating the condition. A retrospective review of eight patients from seven families with genetically confirmed KCNV2-associated retinopathy was performed. The best corrected visual acuity (BCVA), full-field electroretinogram (ffERG), pattern ERG (pERG), fundus imaging: retinal photograph and fundus autofluorescence (FAF), and optical coherence tomography (OCT) were analysed. There was a disproportionate increase in b-wave amplitude with a relatively small light intensity increase, especially between the two dimmest stimuli of DA 0.002 and 0.01 (-2.7 and -2.0 log cd.s/m2). The a-wave amplitude was normal. The a-wave peak time was delayed in all stimuli. The b-wave peak time was delayed compared to normal, but the gap tightened as intensity increased. The b:a wave ratio was above or at the upper limit for the reference values. FAF bull's eye maculopathy pattern was prominent and variable foveal disruption on OCT was apparent in all patients. Legal blindness was reached before the age of 25. We identified three potential electrophysiology biomarkers to assist in evaluating future therapies: the disproportionate b-wave amplitude jump, delayed a-wave and b-wave peak time, and the higher than normal b:a wave ratio. Any of these biomarkers found with photoreceptor ellipsoid zone foveal-perifoveal disruption should prompt consideration for KCNV2 retinopathy. The BCVA natural history data suggests the probable optimum therapeutic window in the first three decades of life.

Hydrogen Peroxide Affects the Electroretinogram of Isolated Perfused Rat Retina

Purpose To evaluate the effects of H2O2 as an oxidant on the electroretinogram (ERG) in isolated rat retina. Methods Retinas were isolated from rat eyes and perfused with a nutrient solution. ERGs were recorded every 3 min. Once the signal was at a steady state, H2O2 was added to the perfusion solution. Results H2O2 caused instantaneous and transient changes in amplitudes and implicit times of the ERG, followed by changes in retinal survival curves. H2O2 0.2 mM produced a rapid increase in b-wave amplitude, followed by a return to the initial value and a survival curve above the control (without H2O2). A slight increase in a-wave was observed, followed by a decrease and a recovery above the control. The slow PIII decreased and then recovered to the initial value. H2O2 0.6 mM induced a small increase in b-wave amplitude, followed by a rapid decrease without recovery. The a-wave and slow PIII decreased rapidly without recovery. The implicit times of the a-wave and b-wave increased moderately with a low dose of H2O2, whereas they significantly increased with a high dose. Whatever the dose, the slow PIII implicit time increased significantly, followed by a return to the initial value. Barium increased the a-wave and b-wave, and then H2O2 reduced the two waves with a stronger effect on the a-wave. Aspartate and barium isolated the fast PIII, which decreased after H2O2 application. Conclusions H2O2 affects retinal function as shown by ERGs in isolated rat retina. The response differs with the dose of H2O2, suggesting that mechanisms underlying the action at low doses might be different from those at high doses. Our results also suggest an effect of H2O2 on ionic currents and/or neurotransmitter releases involved in the generation of the ERG and indicate a more pronounced effect on photoreceptors than on postsynaptic cells.

Increase in b-wave amplitude after light stimulation of the blind spot is positively correlated with the axial length of myopic individuals

Altered retinal dopamine and ON-pathway activity may underlie myopia development. It has been shown that the stimulation of the blind spot with short-wavelength light increases the electroretinogram (ERG) b-wave amplitude of myopic eyes and may engage the retinal dopaminergic system. This study evaluated the impact of various durations of blind spot stimulation on the electrophysiological response of the myopic retina and their relationship to axial length. Six myopic individuals underwent three short-wavelength blue light blind spot stimulation protocols (10 s, 1 min, 10 min) using a virtual reality headset. As a control condition, no stimulation was shown for 1 min. The b-wave amplitude of the photopic full-field ERG was measured at baseline and 10, 20, 30, 40, 50, and 60 min after each condition. A significant increase in b-wave amplitude was observed for all stimulation protocols compared to the control. The peak b-wave amplitude was observed 20 min after the 1-min stimulation protocol and 60 min after the 10-min stimulation protocol. A significant positive correlation was found between axial length of the eye and percent change in b-wave amplitude for the 10-min stimulation protocol. A rapid and a delayed b-wave time course responses were observed following 1 min and 10 min of blind spot stimulation, respectively. Overall, these results indicate that light stimulation of the blind spot for various durations elevates ON-bipolar cell activity in the retina and as such is assumed to reduce the myopic response. These findings could have implications for future myopia treatment.

Of men and mice: Human X-linked retinoschisis and fidelity in mouse modeling.

X-linked Retinoschisis (XLRS) is an early-onset transretinal dystrophy, often with a prominent macular component, that affects males and generally spares heterozygous females because of X-linked recessive inheritance. It results from loss-of-function RS1 gene mutations on the X-chromosome. XLRS causes bilateral reduced acuities from young age, and on clinical exam and by ocular coherence tomography (OCT) the neurosensory retina shows foveo-macular cystic schisis cavities in the outer plexiform (OPL) and inner nuclear layers (INL). XLRS manifests between infancy and school-age with variable phenotypic presentation and without reliable genotype-phenotype correlations. INL disorganization disrupts synaptic signal transmission from photoreceptors to ON-bipolar cells, and this reduces the electroretinogram (ERG) bipolar b-wave disproportionately to photoreceptor a-wave changes. RS1 gene expression is localized mainly to photoreceptors and INL bipolar neurons, and RS1 protein is thought to play a critical cell adhesion role during normal retinal development and later for maintenance of retinal structure. Several independent XLRS mouse models with mutant RS1 were created that recapitulate features of human XLRS disease, with OPL-INL schisis cavities, early onset and variable phenotype across mutant models, and reduced ERG b-wave to a-wave amplitude ratio. The faithful phenotype of the XLRS mouse has assisted in delineating the disease pathophysiology. Delivery to XLRS mouse retina of an AAV8-RS1 construct under control of the RS1 promoter restores the retinal structure and synaptic function (with increase of b-wave amplitude). It also ameliorates the schisis-induced inflammatory microglia phenotype toward a state of immune quiescence. The results imply that XLRS gene therapy could yield therapeutic benefit to preserve morphological and functional retina particularly when intervention is conducted at earlier ages before retinal degeneration becomes irreversible. A phase I/IIa single-center, open-label, three-dose-escalation clinical trial reported a suitable safety and tolerability profile of intravitreally administered AAV8-RS1 gene replacement therapy for XLRS participants. Dose-related ocular inflammation occurred after dosing, but this resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in dose-dependent fashion, but no antibodies were observed against the RS1 protein. Retinal cavities closed transiently in one participant. Technological innovations in methods of gene delivery and strategies to further reduce immune responses are expected to enhance the therapeutic efficacy of the vector and ultimate success of a gene therapy approach.

Low concentrations of ethanol but not of dimethyl sulfoxide (DMSO) impair reciprocal retinal signal transduction.

The model of the isolated and superfused retina provides the opportunity to test drugs and toxins. Some chemicals have to be applied using low concentrations of organic solvents as carriers. Recently, E-/R-type (Cav2.3) and T-type (Cav3.2) voltage-gated Ca(2+) channels were identified as participating in reciprocal inhibitory retinal signaling. Their participation is apparent, when low concentrations of NiCl2 (15 μM) are applied during superfusion leading to an increase of the ERG b-wave amplitude, which is explained by a reduction of amacrine GABA-release onto bipolar neurons. During these investigations, differences were observed for the solvent carrier used. Recording of the transretinal receptor potentials from the isolated bovine retina. The pretreatment of bovine retina with 0.01 % (v/v) dimethylsulfoxide did not impair the NiCl2-mediated increase of the b-wave amplitude, which was 1.31-fold ± 0.03 of initial value (n = 4). However, pretreatment of the retina with the same concentration of ethanol impaired reciprocal signaling (0.96-fold ± 0.05, n = 4). Further, the implicit time of the b-wave was increased, suggesting that ethanol itself but not DMSO may antagonize GABA-receptors. Ethanol itself but not DMSO may block GABA receptors and cause an amplitude increase by itself, so that reciprocal signaling is impaired.

Focal Macular Electroretinograms after Intravitreal Injections of Bevacizumab for Age-Related Macular Degeneration

To evaluate the changes in the best-corrected visual acuity (BCVA), macular thickness, and focal macular electroretinograms (FMERGs) after three intravitreal injections of bevacizumab for a choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). The medical records of 18 eyes of 18 patients who had received three consecutive monthly intravitreal injections of bevacizumab were retrospectively studied. The BCVA, macular thickness determined by optical coherence tomography (OCT), and FMERGs were measured before the first injection, and 10 days after each of the intravitreal bevacizumab injections. The number of eyes with improvement in BCVA after the first injection was one (6%), after the second injection was four (22%), and after the third injection was five (28%). The number of eyes with reduction in macular thickness was 4 (33%), 8 (44%), and 10 (56%) after each of the three injections. The number of eyes with increase in b-wave amplitude of the FMERGs was 7 (38%), 6 (33%), and 10 (56%) after each of the three each injections. The mean macular thickness was significantly thinner after the first injection, and the mean BCVA was significantly improved after the second injection. The mean amplitude and implicit time of the b-wave of the FMERGs were significantly improved only after the third injection (P<0.05). All parameters improved but the best was after the third injection, indicating that three monthly intravitreous injections with bevacizumab may be an effective treatment regimen for AMD.

OXYGEN THERAPY FOR DIABETIC MACULAR ISCHEMIA

To evaluate the structural and functional effects of systemic oxygen therapy in patients with diabetic macular ischemia. This interventional case series was performed on 20 eyes from 13 consecutive diabetic patients with macular ischemia. For each patient, baseline optical coherence tomography and electroretinography were obtained before and after administration of 100% oxygen by face mask at a flow rate of 10 L/minute for 1 hour. Central macular thickness and b-wave amplitude were measured before and after oxygen therapy. The patients included 9 women and 4 men with mean (SD) age of 63.38 (7.34) years. Central macular thickness decreased from 358.55 ± 96.27 μm before to 326.55 ± 84.11 μm after the oxygen therapy (P < 0.001). A reduction of >10% was observed in 55% of the eyes. In dark-adapted combined response electroretinography, the amplitude of b-wave increased from 227.76 ± 105.66 μV before to 264.35 ± 128.48 μV after the oxygen therapy (P < 0.001), representing a 16% increase. More than a 10% increase in b-wave amplitude occurred in 60% of the eyes. Oxygen therapy seems to have beneficial effects on the structural and functional changes of the retina in patients with diabetic macular ischemia. It may decrease central macular thickness and improve electrophysiologic function of the retina.

Effects of Physical Effort on Neuroretinal Function in Athletes and Non-Athletes: An Electroretinographic Study

Physical exertion may disturb retinal function. We wondered whether different levels of physical performance could affect the plot of neuroretinal activity after dynamic exercise in healthy subjects. The aim of our study was to estimate the effect of increasing intensity physical exercise on retinal activity in 2 groups: athletes (n=10) and non-athletes (n=10). We analyzed the amplitude and implicit time of b-wave electroretinogram (ERG) responses for a photopic white 30-Hz flicker stimulus. Using a cycloergometer, 3 10-minute effort tests with increasing intensity were performed. Each participant was attributed an individual workload value (W) below his lactate threshold (40% VO2max), at his lactate threshold (65%-75% VO2max), and above his lactate threshold (80% VO2max). Five ERG recordings were taken: before the efforts (first), immediately after the 3 consecutive efforts (second to fourth), and 1 hour after the last effort (fifth). After the first effort, in both groups we observed a statistically significant increase in b-wave amplitude (p<0.05), and in non-athletes a decrease in implicit time of b-wave (p<0.05). After the last effort, we observed a decreased b-wave amplitude in non-athletes, whereas in athletes the amplitude remained at a high level. Physical effort significantly differentiated the plot of b-wave amplitude changes between athletes and non-athletes. These findings suggest that strenuous physical effort may disturb signal transfer in the inner retinal layer in non-athletic subjects. The ERGs may be used as a neurophysiologic indicator in defining the cardiovascular training status of an athlete.

Antagonists of ionotropic γ‐aminobutyric acid receptors impair the NiCl2‐mediated stimulation of the electroretinogram b‐wave amplitude from the isolated superfused vertebrate retina

NiCl(2) (15 microM) stimulates the electroretinogram (ERG) b-wave amplitude of vertebrate retina up to 1.5-fold through its blocking of E/R-type voltage-gated Ca(2+) channels. Assuming that such an increase is mediated by blocking the release of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) via ionotropic GABA receptors, we tested the effect of both GABA itself and GABA-receptor antagonists such as (-)bicuculline (1.51-fold increase) and (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA; 1.46-fold increase) on the b-wave amplitude. Recording of the transretinal potentials from the isolated bovine retina. GABA (100 microM) reduced the b-wave amplitude only when NiCl(2) (15 microM) was applied first. Each antagonist applied on its own stimulated the b-wave amplitude only partially: subsequent NiCl(2) superfusion caused a small but additional increase, leading to a 1.69- and a 1.88-fold total increase of the amplitude by Ni(2+) plus (-)bicuculline or Ni(2+) plus TPMPA, respectively. Only the application of both antagonists in combination, before superfusing low NiCl(2) (15 microM), completely prevented subsequent stimulation by NiCl(2) with a similar 1.90-fold total increase of b-wave amplitude. Those retina segments that did not respond to NiCl(2) could not be stimulated by (-)bicuculline and vice versa. The stimulatory effect of NiCl(2) on the ERG b-wave amplitude is mainly, but not only, mediated by a NiCl(2)-sensitive, Ca(v)2.3-triggered GABA release acting through ionotropic GABA-A and GABA-C receptors.

Acid-Sensing Ion Channel 3 in Retinal Function and Survival

Changes in extracellular pH occur in the retina and directly affect retinal activity and phototransduction. The authors analyzed the expression in rodent retina of ASIC3, a sensor of extracellular acidosis, and used ASIC3 knockout mice to explore its role in retinal function and survival. The expression and the role of ASIC3 were examined by immunolocalization and by comparing retinas from wild-type and knockout mice at different ages through electroretinography, retinal histology (light and electron microscopy), expression of glial fibrillary acidic protein (GFAP), analysis of cell apoptosis (TUNEL assay), and patch-clamp recordings in primary cultures of retinal ganglion cells (RGCs). ASIC3 is present in the rod inner segment of photoreceptors and in horizontal and some amacrine cells. ASIC3 is also detected in RGCs but does not significantly contribute to ASIC currents recorded in cultured RGCs. At 2 to 3 months, knockout mice experience a 19% enhancement of scotopic electroretinogram a-wave amplitude and a concomitant increase of b-wave amplitude without alteration of retinal structure. Older (8-month-old) knockout mice have 69% and 64% reductions in scotopic a- and b-waves, respectively, and reductions in oscillatory potential amplitudes associated with complete disorganization of the retina and degenerating rod inner segments. GFAP and TUNEL staining performed at 8 and 12 months of age revealed an upregulation of GFAP expression in Müller cells and the presence of apoptotic cells in the inner and outer retina. Inactivation of ASIC3 enhances visual transduction at 2 to 3 months but induces late-onset rod photoreceptor death, suggesting an important role for ASIC3 in maintaining retinal integrity.

Cone phototransduction and growth of the ERG b-wave during light adaptation

The purpose of this study was to determine whether cone redepolarization accounts for the amplitude increase of the b-wave of the human electroretinogram (ERG) during light adaptation. The time course of the b-wave amplitude increase was compared to the time course of the change in the activation phase of cone phototransduction, as derived from a delayed Gaussian model applied to the leading edge of the ERG a-wave. ERG recordings were obtained from five visually normal subjects, alternately in the presence of the adapting field ( adapt-on condition) and 300 ms after its temporary extinction ( adapt-off condition). The proportional increase in amplitude was less for R mp3 (maximum amplitude of P3, the massed cone photoreceptor response) than for the b-wave for both adaptation conditions, and the time course of the amplitude increase for R mp3 was faster than that for the b-wave in the adapt-off condition. The results demonstrate that time-dependent changes in the activation phase of cone phototransduction have only a minimal role in governing the increase in the amplitude of the human cone-derived ERG b-wave during light adaptation. In addition, the systematic increase in b-wave amplitude and the decrease in b-wave implicit time in the adapt-off condition indicates that the ERG response measured shortly after adapting field offset does not necessarily represent the waveform of the dark-adapted cone ERG.

Recombinant adeno-associated virus type 2-mediated gene delivery into the Rpe65-/- knockout mouse eye results in limited rescue

BackgroundLeber's congenital amaurosis (LCA) is a severe form of retinal dystrophy. Mutations in the RPE65 gene, which is abundantly expressed in retinal pigment epithelial (RPE) cells, account for approximately 10–15% of LCA cases. In this study we used the high turnover, and rapid breeding and maturation time of the Rpe65-/- knockout mice to assess the efficacy of using rAAV-mediated gene therapy to replace the disrupted RPE65 gene. The potential for rAAV-mediated gene treatment of LCA was then analyzed by determining the pattern of RPE65 expression, the physiological and histological effects that it produced, and any improvement in visual function.MethodsrAAV.RPE65 was injected into the subretinal space of Rpe65-/- knockout mice and control mice. Histological and immunohistological analyses were performed to evaluate any rescue of photoreceptors and to determine longevity and pattern of transgene expression. Electron microscopy was used to examine ultrastructural changes, and electroretinography was used to measure changes in visual function following rAAV.RPE65 injection.ResultsrAAV-mediated RPE65 expression was detected for up to 18 months post injection. The delivery of rAAV.RPE65 to Rpe65-/- mouse retinas resulted in a transient improvement in the maximum b-wave amplitude under both scotopic and photopic conditions (76% and 59% increase above uninjected controls, respectively) but no changes were observed in a-wave amplitude. However, this increase in b-wave amplitude was not accompanied by any slow down in photoreceptor degeneration or apoptotic cell death. Delivery of rAAV.RPE65 also resulted in a decrease in retinyl ester lipid droplets and an increase in short wavelength cone opsin-positive cells, suggesting that the recovery of RPE65 expression has long-term benefits for retinal health.ConclusionThis work demonstrated the potential benefits of using the Rpe65-/- mice to study the effects and mechanism of rAAV.RPE65-mediated gene delivery into the retina. Although the functional recovery in this model was not as robust as in the dog model, these experiments provided important clues about the long-term physiological benefits of restoration of RPE65 expression in the retina.

Improvement of neuronal visual responses in the superior colliculus in Prph2Rd2/Rd2 mice following gene therapy

Inherited retinal degenerations are a major cause of blindness for which there are currently no effective therapies. Significant progress concerning in vivo gene transfer has allowed retardation of degeneration or retinal functional improvement in different animal models. To date, there has been no evaluation of the impact of these treatments on higher visual function, a critical step for validating gene therapy treatment strategies.Here, we have used adeno-associated (AAV2)-mediated gene transfer of Prph2 in the Prph2Rd2/Rd2 mouse model. We then assessed higher visual function by recording from central visually responsive neurons in the superior colliculus and improvements were correlated in individual animals with retinal function (ERG) and histological and biochemical changes. Although gene replacement therapy only partially restores photoreceptor morphology, it results in a 300% increase of the visual cycle protein rhodopsin, leading to retinal function improvement (250% increase of b-wave amplitude) and significantly higher central visual responses (166% increase at 24 cd/m2). These findings suggest that gene replacement therapy leading to even relatively modest structural improvement may result in improved central visual function.

Long-term evaluation of retinal function in Prph2Rd2/Rd2 mice following AAV-mediated gene replacement therapy.

Prph2(Rd2/Rd2) mice have a retinal degeneration due to a null mutation for the Prph2 gene which encodes a photoreceptor-specific glycoprotein, peripherin2, essential for outer-segment formation. We have previously shown improvement of photoreceptor function at a single time point following AAV-mediated gene replacement therapy. Here we quantify the functional rescue over a 15-week time course and present a detailed analysis of the improvement in retinal function. An AAV2 vector, AAV.rho.rds, carrying a peripherin2 c-DNA, was in injected subretinally into 10-day-old Prph2(Rd2/Rd2) mice. One group was injected at a single time point while in a second group the injections were repeated after 5 days. The effect of treatment was analysed histologically using electron microscopy and electroretinography (ERG) was used to assess functional changes. Treated mice were recorded at regular intervals over 15 weeks. Untreated contralateral eyes served as internal control. A significant increase in b-wave amplitude was first noted 3 weeks after treatment of 10-day-old Prph2(Rd2/Rd2) mice and persisted for up to 14 weeks. An increase in the area of retina exposed to vector resulted in a significant increase in both b-wave amplitude and persistence. In this study AAV-mediated gene replacement in Prph2(Rd2/Rd2) mice resulted in a significant functional improvement over a period of 14 weeks. These results support the utility of gene therapy approaches as treatment for photoreceptor dystrophies.

Visual function in regenerating teleost retina following cytotoxic lesioning.

Teleost fish retinas can regenerate in vivo in adulthood. Retinal and visual function was assessed in adult goldfish following comprehensive retinal destruction by intraocular injection of ouabain. Electroretinograms (ERGs) and the dorsal light reflex (DLR) were used to evaluate the return of visual function. ERGs were detectable in regenerating eyes 50 to 70 days following ouabain injection. Amplitudes of both a- and b-waves increased steadily through day 210 following ouabain treatment, at which time a-wave amplitude was 90% and b-wave amplitude approached 50% of the contralateral control eye. The progressive gain observed in the a-wave was attributed to photoreceptor regeneration. The increase in b-wave amplitude was attributed to an increase in the number of inner nuclear layer cells and the number and efficacy of neuronal connections to or within the inner retina. The photopic spectral sensitivity of the b-wave in regenerating retina closely matched the intrafish control retina, suggesting that the relative numbers of cone photoreceptors was normal in regeneration. The recovery of the DLR (indicated by improved postural balance during regeneration) paralleled electrophysiological gains during retinal regeneration. Fish displayed a marked longitudinal body imbalance toward the control eye following retinal destruction. Improvement in equilibrium was correlated with increasing b-wave amplitudes. When the b-wave reached 50% of control amplitude (30 weeks), normal posture was restored. The return of the ERG indicates that photoreceptors and their synaptic connections must be functional in regenerating retina. Failure of the retina to regenerate produced an abnormal DLR that persisted through 30 weeks and ERGs were not measurable. The return of normal equilibrium indicates that the regenerating retina can establish central connections to the brain, and that the regenerated connections can mediate functional visual behavior.

Glucocorticoids alter recovery processes in the rat retina.

The effect of glucocorticoids on the electroretinogram (ERG) b-wave was studied in freely moving rats. b-Waves were evoked by flashes delivered by a light emitting diode implanted under the skin above the left eye. I.v. corticosterone and dexamethasone injection induced a transient increase in b-wave amplitude at 90 min. Retinal oscillatory potentials (OPs) were similarly enhanced. Pretreatment with a glucocorticoid receptor antagonist (RU 38486) abolished both increases. These results suggest that enhancements in retinal potentials may be the result of a glucocorticoid-induced facilitation of the processes under way in normal Müller cells following retinal excitation.

Adrenergic effects on the corneal and intraretinal direct-current electroretinogram and on the standing potential of albino rabbit eyes.

This study was undertaken to investigate further the responsiveness of the albino rabbit retinal pigment epithelium and the inner retina to adrenergic agents as reflected in changes of the direct-current electroretinogram and of the standing potential of the eye. After unilateral vitrectomy on albino rabbits, a continuous intraocular perfusion with a reference solution was established. The reference solution was then alternated with the test solution. The direct-current electroretinogram and the standing potential were recorded from both eyes with a scleral contact lens and a reference electrode connected to matched calomel half-cells. An in vivo experimental technique that allows intraocular perfusion of a test substance and simultaneous intraretinal microelectrode measurements was also used. The alpha-adrenergic agonist phenylephrine (0.04 microM, n = 8) produced a reversible increase in c-wave amplitude (48%, p < 0.001) and also a small increase in b-wave amplitude (12%, p < 0.002). There was no significant influence on the a-wave amplitude. The standing potential was elevated at 1694 +/- 362 microV (mean +/- SEM) (p < 0.002). The alpha 2-adrenergic agonist clonidine caused similar effects on the electroretinogram, although at a higher concentration (40 microM, n = 5), with an elevation of the c-wave (25%, p < 0.001) and a small b-wave increase (12% p < 0.002). No significant influence on the a-wave or on the standing potential was found. Intraretinal direct-current electroretinogram-recordings during intraocular perfusion with phenylephrine showed an increase in transepithelial potential (p < 0.004; n = 6), accompanied by a reduction of the slow PIII (p < 0.0035; n = 6). The c-wave increase resulting from alpha-adrenergic stimulation seems to be generated partly across the retinal pigment epithelium, with an increase in transepithelial potential, combined with a reduction of the slow PIII. The elevation of the b-wave amplitude, together with the influence on the slow PIII, suggests alpha-adrenergic effects also on the inner retina. The experimental technique used in this study with intraocular perfusion after vitrectomy and simultaneous intraretinal direct-current recordings seems to be a practicable method for studies of the influence of pharmacologic agents on the retina and the retinal pigment epithelium.

Properties of the human cone system electroretinogram during light adaptation

Changes in the response characteristics of the flash electroretinogram (ERG) of the human cone system were studied during the time course of adaptation to a cone-isolating ganzfeld background. During light adaptation, the amplitudes of the b- and i-waves increased, while the implicit time of the b-wave decreased. The amplitude of the a-wave and the implicit times of the a- and i-waves did not change systematically during light adaptation. Luminance-response functions for b-wave amplitude were obtained at discrete times following background onset and were analyzed using the hyperbolic equation R/R(max) = L(n)/(L(n) + K(n)). The increase in b-wave amplitude was characterized by increases in R(max), K, and n. The decrease in b-wave implicit time was of a similar magnitude at all flash luminances. The amplitude increase of the i-wave only occurred at moderate flash luminances. The results provide a basis for optimizing the clinical recording of cone-isolated single-flash ERGs.

The effects of beta-adrenergic agonists on cone systems in the cat eye.

The effects of the beta-adrenergic agonist nylidrin and the beta 2-adrenergic agonist clenbuterol on electroretinogram and optic nerve response were studied in the isolated and arterially perfused, light-adapted cat eye. Two cone mechanisms, short wavelength-sensitive and long wavelength-sensitive, were functionally separated by means of intense yellow adaptation. A reversible increase in b-wave amplitude in response to nylidrin or clenbuterol was observed for the cone systems. Both drugs also caused a reversible alteration in configuration of the optic nerve response, mainly a depression of the late components related in time to the changes in the electroretinogram. These observations suggest that beta-adrenergic mechanisms are involved in cone systems. The greater increase in b-wave amplitude on 558-nm stimulation and preliminary evidence for greater increase in sensitivity observed in the V-log I function compared with 439 nm further suggest that the short and long wavelength cone systems are affected differently by beta-adrenergic agonists.

Effects of beta-agonists on b- and c-waves implicit for adrenergic mechanisms in cat retina.

Nylidrin (buphenine) is a beta-adrenergic agonist known to dilate peripheral vessels and used therapeutically in retinal degeneration and glaucoma. We studied retinal function under beta-agonists in arterially perfused cat eyes and observed a dose-dependent, reversible increase in b-wave amplitude and a decrease in c-wave amplitude in concentrations from 4.5 to 120 microM. A half maximal response was obtained at 40 to 50 microM. The optic nerve response to light showed dose-dependent reversible changes under nylidrin. Standing potential, light peak, intraocular pressure, vascular resistance, and diameter of or retinal vessels showed no consistent changes under nylidrin. The effect were inhibited by each of the beta-blocking agents propranolol, ICI 118, and oxprenolol (in sequence of decreasing potency). Another potent beta 2-agonist, clenbuterol, was used to determine the extent to which the responses to nylidrin were due to beta-receptor-mediated action. Clenbuterol had similar effects on the b-wave and optic nerve response at slightly higher concentrations (30 200 microM) but more variable effects on the c-wave. The data are interpreted as functional evidence that beta-adrenergic mechanisms are involved in retinal signal processing. This concept is corroborated by identification of beta-adrenergic binding sites in cat retina (Bruinink et al., 1986).