endothelin-1 and Optic-Nerve-Diseases

It has become increasingly clear that astrocytes may play an important role in the genesis of glaucoma. Astrogliosis occurs in response to ocular stress or the presence of noxious stimuli. Agents that appear to stimulate reactive gliosis are becoming increasingly clear. One class of agents that is emerging is the endothelins (ETs; specifically, ET-1). In this review we examine the interactions of ET-1 with astrocytes and provide examples where ET-1 appears to contribute to activation of astrocytes and play a role in the neurodegenerative effects that accompany such reactivation resulting in astrogliosis. These actions are presented in the context of glaucoma although information is also presented with respect to ET-1's role in the central nervous system and brain. While much has been learned with respect to ET-1/astrocyte interactions, there are still a number of questions concerning the potential therapeutic implications of these findings. Hopefully this review will stimulate others to examine this potential.

Topics: Animals; Astrocytes; Endothelin-1; Glaucoma; Gliosis; Humans; Optic Nerve Diseases

The primary open-angle glaucoma (POAG) is an optic neuropathy which is influenced by a number of different risk factors. Some of them can induce the transcriptional factor NF-kappaB, a nuclear protein which binds to specific areas of the DNA to stimulate different genes. NF-kappaB can be activated by increased intraocular pressure, increased age, vascular diseases and by oxidative stress. In the case of POAG NF-kappaB might be overstimulated with the induction of uncontrolled biochemical reactions. Treatment strategies for reducing NF-kappaB are to reduce intraocular pressure as well as therapies with statins, omega-3-fatty acids and alpha-lipoic acid. This model is a hypothesis and is intended to provide a basis for further discussions and basic research.

Topics: Age Factors; Aged; Endothelin-1; Glaucoma, Open-Angle; Humans; Intraocular Pressure; NF-kappa B; Optic Nerve Diseases; Oxidative Stress; Risk Factors; Trabecular Meshwork; Transcriptional Activation

Glaucoma, one of the leading causes of blindness in the world, is characterized by progressive visual field loss and distinctive excavation of the optic nerve head. Although elevated intraocular pressure is the major risk factor, there is increasing evidence that the pathogenesis of glaucoma is also linked to altered ocular blood flow. This review summarizes the recent publications relevant to blood flow in glaucoma.. Several studies indicate that a perfusion instability, rather than a steady reduction of ocular blood flow, might contribute to glaucomatous optic neuropathy. The main cause of the instability is a disturbed autoregulation in the context of a general vascular dysregulation. The underlying mechanism of such a vascular dysregulation is not known. A dysfunction of both the autonomic nervous system and vascular endothelial cells is discussed.. The mechanical and vascular theories are not mutually exclusive; on the contrary, a vascular dysregulation increases the susceptibility to intraocular pressure. Therapeutically, therefore, both an intraocular pressure reduction and an improvement of the ocular blood flow might be considered.

Topics: Animals; Biomarkers; Blood Flow Velocity; Blood Pressure; Endothelin-1; Eye; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Laser-Doppler Flowmetry; Ophthalmic Artery; Optic Nerve Diseases; Regional Blood Flow; Ultrasonography, Doppler, Color; Vasoconstriction; Visual Fields

Vasospasm can have many different causes and can occur in a variety of diseases as well as in otherwise healthy subjects. We distinguish between primary vasospastic syndrome and secondary vasospasm. The term "vasospastic syndrome" summarizes the symptoms of patients having such a spasm to stimuli like cold or emotional stress. Patients with primary vasospastic syndrome tend to suffer from cold hands, low blood pressure, migraine and silent myocardial ischemia. The ocular vasospastic syndrome is clearly associated, among other manifestations, with glaucomatous optic neuropathy and non arteritic anterior ischemic optic neuropathy. The ocular vasospasm leads to a compromised autoregulation, and therefore sensitizes the eye to intraocular pressure or to a decrease in blood pressure. A variation in ocular perfusion may lead to an increase in free oxygen radicals and in glutamate. This may finally induce apoptosis cascade in retinal ganglion cells. Valuable diagnostic tools are nailfold capillary microscopy and angiography, but probably the best indicator is an increased plasma level of endothelin-1. The role of calcium channel blockers, magnesium, endothelin and glutamate antagonists are discussed.

Topics: Apoptosis; Calcium Channel Blockers; Diagnosis, Differential; Endothelin-1; Excitatory Amino Acid Antagonists; Eye; Eye Diseases; Free Radicals; Glutamic Acid; Humans; Optic Nerve Diseases; Syndrome; Vascular Diseases

Our recent study, which involved a randomized, placebo-controlled, double-masked 24-month trial (Ophthalmologica 2012;228:26-35), revealed that oral administration of black currant anthocyanins (BCACs) slowed down the visual field deterioration and elevation of ocular blood flow of open-angle glaucoma (OAG). To elucidate the underlying mechanisms of these BCAC-induced effects, as possible factors affecting glaucomatous optic neuropathy, changes of serum endothelin-1 (ET-1), nitric oxide (NO), and antioxidative activities were examined in the present study.. From among patients with OAG who participated in the randomized, placebo-controlled, double-masked trial, serum specimens were obtained from BCAC-treated (n=19) or placebo-treated (n=19) patients at baseline and every 6 months. Healthy volunteers (n=20) with age and gender matching the patients were used as a control. Serum ET-1 concentration, [NO2(-)] and [NO2(-) + NO3(-)] levels, advanced oxidation protein products (AOPP), and antioxidant activities were measured by using commercially available kits.. At the trial baseline, serum ET-1 concentrations were significantly lower in patients with OAG (BCACs, 3.18±1.06 pg/mL; placebo, 3.44±0.84 pg/mL) than those in healthy volunteers (4.38±1.03 pg/mL) (one-way analysis of variance and a Tukey's multiple comparison post hoc test, P<0.05). Upon administration of BCACs, serum ET-1 concentrations increased to the levels of those in healthy volunteers during the 24-month period. In contrast, those of placebo-treated patients remained at lower levels (3.82±1.14 pg/mL). While [NO2(-)] and [NO2(-)+NO3(-)] levels, AOPP, and antioxidative activities of patients from both the BCACs and placebo groups showed comparable levels to those of healthy subjects at baseline, no significant changes were observed during the observational period in either the BCAC or placebo groups.. Among the possible beneficial effects of BCACs toward visual field progression in patients with OAG, our present results suggest that BCACs caused normalization of serum ET-1 levels, and this may modulate ET-1-dependent regulation of the ocular blood hemodynamics.

Topics: Administration, Oral; Aged; Analysis of Variance; Anthocyanins; Antioxidants; Case-Control Studies; Double-Blind Method; Endothelin-1; Female; Glaucoma, Open-Angle; Humans; Male; Middle Aged; Nitric Oxide; Optic Nerve Diseases; Ribes; Treatment Outcome; Visual Fields

This prospective study aimed to compare vascular parameters (endothelin-1 [ET-1] blood levels, laser Doppler imaging [LDI] of distal phalanxes, and nailfold capillaroscopy) between open-angle glaucoma patients with low- and high-tension optic disc hemorrhages (LTDH and HTDH, respectively). The 33 enrolled patients (mean age, 62.3 ± 13 years) were classified as LTDH or HTDH if they presented at the time of DH detection an intraocular pressure (IOP) < 16 mmHg or ≥ 16 mmHg, respectively. Demographic and ophthalmological data, ET-1 concentrations, LDI (before and 1, 10, and 20 min after cold stimulation), and nailfold capillaroscopy findings were evaluated. The ET-1 blood level was 65% higher in the LTDH (2.27 ± 1.46 pg/ml) than in the HTDH (1.37 ± 0.57 pg/ml; p = 0.03) group. Moreover, there was a statistically significant negative correlation between ET-1 blood concentration and IOP at the time of DH detection (r = -0.45, p = 0.02). Blood flow measurements 10 and 20 min after cold stimulation were lower in the LTDH group than in the HTDH group (p < 0.01). Patients developing DH with lower IOPs have higher ET-1 blood levels and more peripheral vascular dysfunction as estimated by LDI than those with higher IOPs. These findings suggest that distinct underlying mechanisms may be involved in patients developing DH within different IOP ranges.

Topics: Aged; Endothelin-1; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Low Tension Glaucoma; Middle Aged; Optic Disk; Optic Nerve Diseases; Prospective Studies; Retinal Hemorrhage; Visual Fields

We investigated the feasibility and efficacy of using a specific sphingosine 1-phosphate (S1P1) receptor agonist, CYM-5442, to slow or block retinal ganglion cell (RGC) loss in endothelin-1 (ET-1) induced RGC loss. A single intravitreal injection of ET-1 (20pmol/ul), a potent vasoactive peptide that produces retinal vessels vasoconstriction, was used to induce and characterize RGC-specific cell death. CYM-5442 (1 mgr/kg) or vehicle was administered intraperitoneally for five consecutive days after ET-1-induced RGC loss. The functional extent of RGC loss injury was evaluated with pattern visual evoked potentials (VEP) and electroretinography. RGCs and retinal nerve fiber layer (RNFL) thickness were assessed in vivo using optical coherence tomography and ex vivo using Brn3a immunohistochemistry in flat-mounted retinas. ET-1 caused significant RGC loss and function loss one week after intravitreal injection. VEP showed preserved visual function after CYM-5442 administration compared to vehicle-treated animals (11.95 ± 0.86 μV vs 3.47 ± 1.20 μV, n = 12) (p < 0.05). RNFL was significantly thicker in the CYM treated-animals compared to the vehicle (93.62 ± 3.22 μm vs 77.72 ± 0.35 μm, n = 12) (p < 0.05). Furthermore, Brn3a immunohistochemistry validated this observation, showing significantly higher RGCs numbers in CYM treated rats than in the vehicle group (76,540 ± 303 vs 52,426 ± 1,932 cells/retina, n = 9) (p = 0.05). CYM-5442 administration was associated with significant retinal cleaved caspase-3 deactivation, indicating reduced apoptotic levels. The results of the present study further demonstrate the important role of S1P1 receptor agonists to lessen intravitreal ET-1 induced RGC loss.

Topics: Animals; Disease Models, Animal; Electroretinography; Endothelin-1; Evoked Potentials, Visual; Feasibility Studies; Glaucoma; Immunohistochemistry; Indans; Intravitreal Injections; Ischemia; Nerve Fibers; Neuroprotective Agents; Optic Nerve Diseases; Oxadiazoles; Rats; Rats, Wistar; Receptors, Lysosphingolipid; Retinal Diseases; Retinal Ganglion Cells; Transcription Factor Brn-3A

Endothelin-1 (ET-1) has been suggested to play an important role in the pathogenesis of glaucoma. Herein, we studied whether increased levels of plasma ET-1 are associated with changes in the visual field and changes in optical coherence tomography (OCT)-measured retinal nerve fiber layer (RNFL) thickness in patients with different types of glaucoma.. : Plasma concentration of ET-1 was determined in 31 patients with primary open-angle glaucoma, 18 patients with normal tension glaucoma, 16 patients with primary angle-closure glaucoma, and in 37 normal controls. In all participants, visual field testing was performed and OCT was used to measure RNFL thickness. The correlation between mean ET-1 level and changes in the visual field (mean deviation, dB) and changes in OCT-measured RNFL thickness in 1 randomly selected eye from each patient in each group was then evaluated.. The ET-1 level was 3.27±1.25 pg/mL in the primary open-angle glaucoma group (-14.09±8.76 dB), 3.12±1.46 pg/mL in the normal tension glaucoma group (-8.87±6.15 dB), 2.58±.22pg/mL in the primary angle-closure glaucoma group (-14.55±10.2 dB), and 1.53±1.49 pg/mL in the control group. Although mean ET-1 levels were significantly higher in all 3 of the glaucoma groups than in the control group, there was no significant difference in ET-1 level among the 3 glaucoma groups. In addition, no significant correlation was found between levels of plasma ET-1 and structural or functional changes in patients with different types of glaucoma.. : There was no correlation between plasma levels of ET-1 and severity of glaucoma. The role ET-1 plays in the pathogenesis of glaucoma remains to be determined.

Topics: Cross-Sectional Studies; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Glaucoma, Angle-Closure; Glaucoma, Open-Angle; Gonioscopy; Humans; Intraocular Pressure; Low Tension Glaucoma; Male; Middle Aged; Nerve Fibers; Optic Nerve Diseases; Prospective Studies; Retinal Ganglion Cells; Tomography, Optical Coherence; Tonometry, Ocular; Vision Disorders; Visual Acuity; Visual Fields

Spasm of blood vessels supplying the optic nerve head is considered one of possible ischaemic mechanisms of glaucomatous optic neuropathy.. The aim of the study was to evaluate the role of two potent and long-acting vasoconstrictors: endothelin-1 (ET-1) and neuropetide Y (NPY) in the pathogenesis of glaucoma by: 1) measurement of plasma ET-1 and NPY concentrations in primary open-angle glaucoma (POAG) patients with high intraocular pressure (HTG patients) and with normal intraocular pressure (NTG patients) at baseline and following peripheral exposure to cold (cold-pressor test), 2) assessment whether changes, if any, in the plasma concentrations of both peptides following the cold-pressor test correlate with visual field defects.. The study was conducted in three groups of subjects: 1) HTG patients, 2) NTG patients and 3) controls. All subjects were young and free from any cardiovascular disorders. ET-1 and NPY concentrations in the plasma were measured by radioimmunoassay (ET-1: Amersham International UK, NPY: Peninsula Laboratories INC). The cold-pressor test was performed by immersing the whole hand in ice-cold water (4 degrees C) for 2 minutes. Visual fields were examined using standard automated perimetry (Octopus 101, G-2 programme, normal strategy).. In the NTG patients the mean baseline plasma ET-1 concentration was significantly lower and the mean baseline plasma NPY concentration significantly higher compared to controls. On the other hand, there were no statistically significant differences in the mean baseline peptide levels between the HTG patients and the control subjects. After the cold-pressor test the mean ET-1 concentrations considerably increased in the three groups. The highest increase was seen in the NTG group and it was statistically significant compared to the HTG group and controls. Following the cold-pressor test the mean NPY concentration was significantly decreased in the NTG group, but remained virtually unchanged in the HTG group and controls. In the NTG patients, significant increase in the mean ET-1 concentration and decrease in the mean NPY concentration seen after the cold-pressor test were accompanied by a significant decrease in the mean MS (mean retinal sensitivity) value in the second eye examined after the cold-pressor test, but no correlation was found between changes in the MS values and changes in the ET-1 and NPY concentrations. There were no significant changes in the mean MS values after cold-pressor test in the HTG patients and controls.. Our findings suggest abnormal neuro-endothelial mechanisms of vascular tone control in NTG patients, related to the effects of ET-1 and NPY, secondary to endothelial dysfunction and to dysregulation of the autonomic nervous system. These abnormalities may involve potentiation of the vasoconstrictive effects of both ET-1 and NPY leading to the optic nerve head ischaemia and subsequent development of visual field defects in the course of normal-tension glaucoma.

Topics: Adult; Blood Pressure; Choroid; Endothelin-1; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Neuropeptide Y; Ocular Hypertension; Optic Disk; Optic Nerve Diseases; Radioimmunoassay; Regional Blood Flow; Risk Factors; Vasoconstriction; Young Adult

The purpose of this study was to determine whether endothelin B (ETB) receptor levels in the optic nerve are related to retinal ganglion cell (RGC) loss in a model of chronic endothelin-1 (ET-1) induced optic neuropathy. RGCs of adult Brown Norway rats were first retrogradely labeled with fluorochrome from the superior colliculi. An osmotic minipump was surgically implanted 7 days later to deliver 10(-11) M (n = 9), 10(-9) M (n = 12) or 10(-7) M (n = 9) ET-1 to the retrobulbar optic nerve for 28 days. RGC survival was expressed as the ratio of RGC counts in experimental versus control eyes in wholemounted retinas. Optic nerves were used for either ETB western blot analysis (n = 24) or immunohistochemistry (n = 6) for ETB and glial fibrillary acidic protein (GFAP) to localize astrocytes. ETB expression was higher in the experimental nerve compared to the fellow untreated control nerve in 19 (79%) of the 24 animals with a mean increase of 16.7 +/- 4.5% in densitometric analyses of the immunoblots. Experimental nerves showed stronger labeling for both ETB and GFAP compared to control nerves. ETB-positive cells almost completely co-localized with GFAP-positive cells in both experimental and untreated control nerves, however, ETB expression was stronger in the astrocyte soma and proximal processes, while GFAP was expressed more strongly in the distal processes. There was a weak relationship between RGC loss and increase in ETB expression (r = -0.417, p = 0.076). There is an upregulation of ETB expression in optic nerve astrocytes in ET-1 induced chronic optic neuropathy causing RGC loss.

Topics: Animals; Astrocytes; Cell Survival; Chronic Disease; Dose-Response Relationship, Drug; Endothelin-1; Glial Fibrillary Acidic Protein; Male; Microscopy, Confocal; Optic Nerve; Optic Nerve Diseases; Rats; Rats, Inbred BN; Receptor, Endothelin B; Retinal Ganglion Cells

To describe and evaluate a semiquantitative optic nerve grading scheme for assessing axonal loss in endothelin (ET)-1-induced chronic optic neuropathy.. Optic nerve cross-sections from both eyes of 39 Brown Norway rats unilaterally treated with various concentrations of ET-1 or physiological saline solution via a surgically implanted osmotic minipump were processed for light and transmission electron microscopy (TEM). The optic nerve damage grade, between 0 (no damage) and 10 (total damage), was based on the number of zones of approximately equal damage and the mean percentage of damage within each zone. Grading was performed under light microscopy by three observers and compared with axonal survival determined with TEM using two quantification methods: the sampling method, in which approximately 10% of the section was counted, and the full-count method, in which the whole section was counted (n = 12). Axonal survival was expressed as a ratio of axon counts in the experimental to control eye. Before these comparisons, the inter- and intraobserver agreement rates were determined in another group of 85 and 12 ET-1-treated animals, respectively.. The interobserver kappa was 0.66 (95% confidence interval [CI]: 0.58-0.74) for all eyes and 0.55 (95% CI: 0.43-0.67) for the experimental eyes only. The intraobserver kappa was 0.80, 0.81, and 0.80 for all 24 eyes and 0.60, 0.64, and 0.71 for experimental eyes only. The correlation between damage grade in the experimental eye and axonal survival using the TEM sampling method (Spearman's rho = -0.677 for all animals and -0.827 for the subset of animals with full counts only) was lower than that with the full-count method (Spearman's rho = -0.926). When axonal survival was less than 0.7, the sampling method always underestimated the extent of damage.. The grading scheme had good inter- and intraobserver agreement, and high correlation with the TEM methods. It is a practical and time-saving method, requiring less than 1 minute per nerve and is an alternative to sampling methods that can yield significant errors.

Topics: Animals; Axons; Cell Count; Cell Survival; Chronic Disease; Disease Models, Animal; Endothelin-1; Male; Observer Variation; Optic Nerve; Optic Nerve Diseases; Rats; Rats, Inbred BN; Retinal Ganglion Cells

To describe a model of chronic endothelin (ET)-1 administration to the optic nerve and evaluate its effect on retinal ganglion cell (RGC) and axon survival in rat.. Osmotic minipumps were surgically implanted in one eye of 113 Brown Norway rats to deliver 0.05, 0.10, 0.20, or 0.40 microg ET-1 per day (3.3, 6.7, 13.4, and 26.8 microM, respectively), or balanced salt solution (BSS) to the immediate retrobulbar optic nerve; the fellow untreated eye served as the control. Before pump implantation, RGCs were retrogradely labeled with fluorochrome. Animals were killed at 21, 42, or 84 days. RGC survival was expressed as the ratio of RGC counts in experimental versus control eyes in wholemounted retinas, whereas axon survival was expressed similarly from electron micrographs of the optic nerves. Serial optic disc changes were evaluated using scanning laser tomography. The effect of ET-1 (3 microL topical application of 10(-5) M) on blood flow in the surgically exposed optic nerve was measured using laser Doppler flowmetry in a separate group of five animals.. ET-1 led to a mean reduction in optic nerve blood flow of 68%. There were no significant differences in RGC survival among the four ET-1 doses used in this study. Pooled across all ET-1 doses, RGC survival decreased incrementally at 21, 42, and 84 days (P < 0.001; mean +/- SD, 0.77 +/- 0.25, 0.60 +/- 0.27, and 0.50 +/- 0.26, respectively) and was statistically significantly lower at each time point than in the BSS-treated animals. The axon survival data also showed a similar time-dependent loss. Only one of 21 animals showed significantly increased disc cupping, and there was no relationship between RGC survival and change in cupping. CONCLUSIONS. Chronic administration of ET-1 to the rat optic nerve results in a time-dependent loss of RGCs and their axons without apparent change in optic disc topography.

Topics: Animals; Axons; Cell Survival; Chronic Disease; Disease Models, Animal; Endothelin-1; Infusion Pumps, Implantable; Laser-Doppler Flowmetry; Male; Optic Disk; Optic Nerve Diseases; Rats; Rats, Inbred BN; Regional Blood Flow; Retinal Ganglion Cells