endothelin-1 and Optic-Neuropathy--Ischemic

Non-arteritic anterior ischemic optic neuropathy (NAION) is a common cause of acute optic neuropathy in the elderly. The role of the genetic polymorphisms of Atonal Homolog 7 (ATOH7), Endothelin-1 (ET-1) and Angiotensin Converting Enzyme (ACE) in NAION and the combined effects of the gene-gene and gene-medical comorbidities on NAION were not clear. We conducted a perspective, case-control study. 71 NAION patients and 142 age and sex-matched healthy controls were enrolled. Single nucleotide polymorphisms of ATOH7 (rs1900004), ET-1 (rs5370) and ACE (rs1799752) were identified by polymerase chain reaction (PCR) method and all PCR products were screened with Sanger sequencing. The prevalence of genetic factors in NAION patients were compared to normal people, and assessed in conditional logistic regression models. The modified effects of gene-gene or gene-medical comorbidities on NAION development were assessed with a multiplicative model. A significant high risk was found in the T allele of ATOH7 in NAION, with an odds ratio (OR) of 1.55 (P = 0.04). Conditional logistic regression analysis, including diabetes and hypertension, revealed that ATOH7 TT genotype carriers conferred a significantly increased risk of NAION (TT/CC + CT, OR = 3.32, 95% confidence interval (CI) = 1.16-9.53, P = 0.03). Interaction analysis showed that ET-1 (P = 0.01), ACE (P = 0.046) and hypertension (P = 0.02) have modified effects on NAION development. Our results showed that the polymorphism of optic disc associated gene-ATOH7 conferred a significant risk of NAION. Combination of ATOH7 and ET-1, ATOH7 and ACE, as well as ATOH7 and hypertension, increased the susceptibility of NAION. Our data may be useful for NAION predicting.

Topics: Aged; Alleles; Basic Helix-Loop-Helix Transcription Factors; Case-Control Studies; Endothelin-1; Female; Genotype; Humans; Hypertension; Logistic Models; Male; Middle Aged; Odds Ratio; Optic Neuropathy, Ischemic; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Single Nucleotide

To examine the relationship between nonarteritic anterior ischemic optic neuropathy (NAION) and genetic polymorphisms of enzymes influencing endothelial function.. The subjects were 34 patients with NAION (mean age, 62.4 years old; 59% male) and 102 controls (mean age, 63.8 years old; 66% male). Genetic polymorphisms were investigated in three candidate genes associated with endothelial function: endothelin-1 (ET-1), angiotensin-converting enzyme (ACE), and methylenetetrahydrofolate reductase (MTHFR). The genotype distributions in the patients with NAION were compared with those in the controls.. There were no significant differences in the genotype distributions of the ACE I/D and MTHFR C677T polymorphisms between the NAION and control groups (p=0.261 and p=0.354, respectively), whereas the genotype distribution of the G/T (Lys198Asn) polymorphism of the ET-1 gene varied significantly between the groups (p=0.009). After adjusting for covariates, individuals with the TT genotype of the Lys198Asn polymorphism were more likely to develop NAION compared with those with the GG genotype (odds ratio=4.43, 95% confidence interval 1.33-14.73, p=0.015).. We found an increased prevalence of a G/T polymorphism of the ET-1 gene in patients with NAION. Our data suggest that this polymorphism may be an important risk factor in developing NAION in the Japanese population.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Case-Control Studies; Endothelin-1; Endothelium, Vascular; Female; Gene Frequency; Genotype; Humans; INDEL Mutation; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Optic Neuropathy, Ischemic; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Risk Factors

To investigate the effects of microvascular compromise on the expression of oxidative proteins in the optic nerve head.. Endothelin-1 (0.1 μg/day) was delivered to the perineural region of the anterior optic nerve by osmotically driven minipumps for two, four, and eight weeks in ten rabbits, respectively. As a control, a balanced salt solution was delivered for two and eight weeks in five rabbits, respectively. Expression of oxyproteins in the cornea, vitreous, retina, and optic nerve head for each time period was determined using the OxyBlot protein oxidation detection kit. Retina was stained with H&E and TUNEL for histological examination.. There was a significant increase in the expression of oxyproteins in the optic nerve head after two weeks of endothelin-1 administration (p < 0.001, Mann Whitney U test). In contrast, there was no expression of oxyproteins in the cornea, retina, or vitreous. The number of cells in the retinal ganglion cell layer, inner nuclear layer, and outer nuclear layer decreased remarkably with time in the endothelin-1-treated group. Furthermore, the inner and outer nuclear layers, as well as the inner and outer plexiform layers, became thinner over time.. Administration of endothelin-1 to the microvasculature of the optic nerve leads to increased expression of oxyproteins in the optic nerve head and loss of retinal ganglion cells.

Topics: Animals; Disease Models, Animal; Endothelin-1; Male; Optic Disk; Optic Neuropathy, Ischemic; Oxidative Stress; Rabbits; Reactive Oxygen Species

Approximately 15-20% of patients with giant-cell arteritis (GCA) develop ischaemic complications often preceded by transient ischaemia. The expression of the endothelin (ET) system in GCA lesions was investigated to assess its relationship with the development of ischaemic complications.. Plasma ET-1 was quantified by immunoassay in 61 patients with biopsy-confirmed GCA and 16 healthy donors. ET-1, endothelin-converting enzyme (ECE-1) and endothelin receptor (ET(A)R and ET(B)R) messenger RNA were measured by real-time quantitative reverse transcriptase-PCR in temporal arteries from 35 of these patients and 19 control arteries. Proteins were measured by immunoassay and Western blot.. ET-1 concentration was increased at the protein level in temporal artery samples from GCA patients compared with controls (0.98 (SEM 0.32) vs 0.28 (SEM 0.098) fmol/mg, p = 0.028). ECE-1, ET(A)R and ET(B)R/actin ratios (Western blot) were also significantly higher in GCA patients. Intriguingly, mRNA expression of ET-1, ECE-1 and both receptors was significantly reduced in GCA lesions compared with control arteries. When investigating mechanisms underlying these results, platelet-derived growth factor and IL-1beta, present in GCA lesions, were found to downregulate ET-1 mRNA in cultured human temporal artery-derived smooth muscle cells. Glucocorticoid treatment for 8 days did not result in significantly decreased endothelin tissue concentration (0.87 (SEM 0.2) vs 0.52 (SEM 0.08); p = 0.6). Plasma endothelin concentrations were higher in patients with ischaemic complications (1.049 (SEM 0.48) vs 1.205 (SEM 0.63) pg/ml, p = 0.032).. The endothelin system is increased at the protein level in GCA lesions creating a microenvironment prone to the development of ischaemic complications. Recovery induced by glucocorticoids is delayed, indicating persistent exposure to endothelin during initial treatment.

Topics: Aged; Aged, 80 and over; Aspartic Acid Endopeptidases; Brain Ischemia; Cells, Cultured; Down-Regulation; Endothelin-1; Endothelin-Converting Enzymes; Female; Gene Expression Regulation; Giant Cell Arteritis; Glucocorticoids; Humans; Interleukin-1beta; Male; Metalloendopeptidases; Middle Aged; Muscle, Smooth, Vascular; Optic Neuropathy, Ischemic; Platelet-Derived Growth Factor; Receptors, Endothelin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Temporal Arteries

To investigate changes of plasma endothelin-1 (ET-1) concentration in photodynamic induced rat anterior ischemic optic neuropathy model (rAION) and evaluate the effects of compound anisodine hydrobromide (CA).. Eighty-five Sprague-Dawley (SD) male rats were randomly divided into a blank control group of 10 rats and a model group of 75 rats. rAION model was established in the model group by photodynamic induction. The model group was divided into a rAION simple group of 25 rats, a CA intervention group of 25 rats, and a normal saline (NS) control group of 25 rats. Beginning from the day that the rAION model was established, temporal subcutaneous injections (once daily for 3 days) of CA and NS were performed in the CA and the NS groups, respectively. The plasma ET-1 concentrations were detected by radioimmunoassay and analyzed at 1, 3, 5, 7 and 14 days.. The means plasma ET-1 concentration of rAION simple group is (114.9±17.6) ng/L, higher than that of the control group (69.4±9.1) ng/L (t=14.92, P<0.01). In the rAION model group, the plasma ET-1 concentrations 1 to 5 days after the model was established were higher than that of 7 to 14 days. During observational periods, on the 1st, 5th, 7th and 14th day, there was no significant difference between the CA and NS groups (t=0.58, 2.07, 0.81 and 0.93, P>0.05), but on the 3rd day the level of plasma ET-1 concentration in the CA group was significantly lower than that of the NS group (t=4.72, P<0.05).. Increase of plasma ET-1 concentrations may play an important role in the pathogenesis of photodynamic induced rAION model. CA can decrease the plasma ET-1 concentrations in rAION rats.

Topics: Animals; Disease Models, Animal; Endothelin-1; Male; Optic Neuropathy, Ischemic; Photochemotherapy; Rats; Rats, Sprague-Dawley; Scopolamine Derivatives; Solanaceous Alkaloids

To determine whether subconjunctival injection of unoprostone isopropyl alters changes in the topography and blood flow of the optic disc induced by endothelin 1 (ET-1) in rabbits.. From April 1, 2005, to April 28, 2006, we injected ET-1 (20 pmol) intravitreally into rabbits twice per week for 4 weeks. The observation period was 8 weeks. The first group received an intravitreal injection of ET-1 followed by a subconjunctival injection of unoprostone (0.12%, 50 microL). The second group received the same amount of ET-1 followed by a subconjunctival injection of the vehicle of unoprostone. The third group received the intravitreal vehicle of ET-1. The blood flow and topography of the optic nerve head (ONH) were measured by laser speckle flowgraphy and confocal scanning ophthalmoscopy, respectively. The number of cells in the retinal ganglion cell layer and inner nuclear layer was determined histologically.. We found that ET-1 decreased the ONH blood flow, decreased the cells in the ganglion cell layer and inner nuclear layer, enlarged the cup area of the ONH, and reduced the rim area of the ONH. When unoprostone was given with ET-1, no such changes occurred.. Unoprostone can suppress the effects of ET-1 on the circulation and topography of the ONH.. Unoprostone could be a candidate for treating eyes with ischemic ONH.

Topics: Animals; Antihypertensive Agents; Blood Flow Velocity; Cell Count; Chromatography, High Pressure Liquid; Dinoprost; Endothelin-1; Injections; Intraocular Pressure; Laser-Doppler Flowmetry; Lasers; Male; Ophthalmoscopy; Optic Disk; Optic Neuropathy, Ischemic; Rabbits; Regional Blood Flow; Retinal Ganglion Cells; Retinal Vessels; Tandem Mass Spectrometry; Tonometry, Ocular; Vitreous Body

Topics: Aged; Aged, 80 and over; Endothelin-1; Female; Humans; Male; Middle Aged; Optic Neuropathy, Ischemic; Radioimmunoassay; Risk Factors

Repeated intravitreal injections of endothelin-1 (ET-1) lead to alterations in the visually evoked potentials (VEPs) and loss of retinal ganglion cells (RGCs) in rabbits. The purpose of this study was to determine whether kallidinogenase can offset the alterations induced by ET-1.. ET-1 (2.5 x 10(-7) M, 20 microL) was injected into the vitreous of the right eye of rabbits (ET-1-treated eyes, n = 30) twice a week for 4 weeks. The vehicle for ET-1 was injected into the left eye on the same schedule (vehicle treated eyes, n = 30). During this 4 weeks period, kallidinogenase (1.0 unit/kg/day, kallidinogenase-treated group) or saline (saline-injected control group) was continuously delivered intravenously by an implanted osmotic pump. VEPs were recorded before, and 2 weeks and 4 weeks after, the first ET-1 injection, and all rabbits were sacrificed at 4 weeks. The number of RGC cells was counted in hematoxylin- and eosin-stained retinal sections. In the analyses, the ET-1 induced alterations were normalized to the values in the vehicle treated control eyes, i.e., kallidinogenase (K) + ET-1/K+ vehicle or saline (S) +ET-1/S + vehicle. Retinal sections were also examined by immunohistochemistry with antibodies to single-stranded DNA (ssDNA) or to glial fibrillary acidic protein (GFAP). The effect of kallidinogenase on the ONH blood flow was determined by a hydrogen gas clearance flowmeter.. The significant prolongation of the relative VEP implicit times (ITs) 4 weeks after the ET-1 injection (P < 0.01, paired t test; post-ET-1 vs. pre-ET-1) was significantly decreased by kallidinogenase (P < 0.001, t test, K + ET-1/K+ vehicle vs. S +ET-1/S + vehicle). The relative number of RGCs was decreased in the saline-injected group, and this decrease was also decreased by kallidinogenase (P < 0.05, t test, K + ET-1/K+ vehicle vs. S +ET-1/S + vehicle). ssDNA staining showed fewer apoptotic cells in the retina of kallidinogenase-treated rabbits. Intravitreal injection of ET-1 also decreased the blood flow in the optic nerve head and increased the GFAP immunostaining and axonal degeneration. These changes were also counteracted by kallidinogenase.. These results indicate that kallidinogenase can counter the effects of ET-1 and should be considered for the treatment of ischemic retinal and optic nerve disorders related to abnormal ET-1 production.

Topics: Animals; Axons; Blood Flow Velocity; DNA, Single-Stranded; Electroretinography; Endothelin-1; Evoked Potentials, Visual; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections; Ischemia; Kallikreins; Male; Optic Disk; Optic Neuropathy, Ischemic; Rabbits; Regional Blood Flow; Retinal Ganglion Cells; Retinal Vessels; Vasodilator Agents; Vitreous Body

To investigate the neuroprotective effects of topically applied brimonidine tartrate 0.2% (BMD), an alpha(2)-receptor agonist, on the retinal ganglion cell (RGC) layer and inner nuclear layer (INL) of rabbit retina in endothelin-1 (ET-1)-induced optic nerve (ON) ischaemia model.. Osmotic minipumps were surgically implanted into one eye of 16 New Zealand Albino rabbits to deliver ET-1 at the constant rate of 0.5 microL/h for 2 weeks. Eyes were divided into four groups. ET-1 was given with (Group 3) and without topical BMD therapy (Group 1). Groups 2 and 4 were taken as controls. Rabbits were sacrificed at day 14. Morphological alterations, total cell number and proportion of cells undergoing apoptosis in INL and RGC layer were assessed by histopathological analysis to determine the survival of the cells of the INL and RGC layer.. Endothelin-1 led to severe reduction of cells in both the RGC layer and INL in Group 1 (P < 0.05). In Group 3, the total cell number and the proportion of cells undergoing apoptosis in the RGC layer were comparable with the control group (Group 4), whereas the former was found to be higher and the latter was found to be lower than those recorded for Group 1. However, the total cell number in the INL was found to be lower in Group 3 compared with that of Group 4, despite topical BMD therapy (P < 0.05).. Topically applied BMD seems to be neuroprotective and antiapoptotic in the ET-1-induced ON ischaemia model, especially for RGCs. BMD might be used as an adjuvant agent for its neuroprotective effects in hypoxic-ischaemic conditions such as diabetic retinopathy, normotensive glaucoma and other retinal vascular occlusive conditions which require further investigations.

Topics: Administration, Topical; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Animals; Apoptosis; Brimonidine Tartrate; Cell Count; Disease Models, Animal; Endothelin-1; Infusion Pumps, Implantable; Neuroprotective Agents; Optic Neuropathy, Ischemic; Quinoxalines; Rabbits; Retina; Retinal Ganglion Cells

The purpose of this study was to investigate the time course of the ocular hypoperfusion, retinal damage, and optic nerve damage induced by intravitreal injection of endothelin-1 (ET-1) in rabbits. ET-1, at 5 pmol (20 microL, twice a week for 2 or 4 weeks), was injected from the pars plana into the posterior vitreous of the right eye. Optic nerve head (ONH) blood flow and retinal artery diameter, together with the neurofilament light chain (NF-L) content, retinal morphology, and axon density of the optic nerve, were evaluated at 2, 4, and 8 weeks after the first injection of ET-1 (n=7 or 8). Tissue blood velocity in ONH was measured using a laser speckle method, and the diameter of major retinal arteries on the rim of the ONH was calculated from fundus photographs by a masked observer. Histological analysis and immunoblot evaluation of NF-L in the optic nerve were performed to evaluate optic nerve damage. At 2 weeks after the first ET-1 injection, tissue blood velocity was decreased by approximately 20% (versus the contralateral eye), and the diameter of retinal arteries had decreased by approximately 40%. These changes were sustained at the same level until 8 weeks after the first ET-1 injection. At 4 and 8 weeks after the first ET-1 injection, the amount of NF-L in the optic nerve was significantly less in the ET-1 treated eyes than in the contralateral eyes. At 8 weeks after the first ET-1 injection, a loss of myelinated axons and increases in gliosis and connective tissue were noted in the optic nerve of the treated eye, and the optic nerve-axon number had decreased significantly (each, versus the untreated eye). Retinal ganglion cells in the retina were not observed any damage at 2, 4, and 8 weeks after ET-1 injection. In conclusion, intravitreal injection of ET-1 induced chronic hypoperfusion in the ONH and retina, which presumably caused decreases in NF-L content and axon number in the optic nerve noted in the later part of the observation period.

Topics: Animals; Axons; Blood Flow Velocity; Cell Count; Endothelin-1; Immunoblotting; Injections; Intraocular Pressure; Neurofilament Proteins; Optic Disk; Optic Neuropathy, Ischemic; Rabbits; Retina; Retinal Artery; Time Factors; Vitreous Body

The purpose of this study was to examine the effects of endothelin-1 (ET-1) on retrograde axonal transport in the rat optic nerve. Vehicle or ET-1 (0.2, 1, or 5 pmol/eye) were injected into the vitreous body in Sprague-Dawley rats. Retinal vessels were observed, using a fundus camera, before, and at 10 min, 3 days and 7 days after a single intravitreous injection. Two days after the injection, a neuronal tracer, fluoro gold, was administered via the superior colliculi to retrogradely label active retinal ganglion cells (RGCs). Five days after the tracer administration, retrogradely labeled RGCs were evaluated in the flat-mounted retina, and cross sections from each optic nerve were graded for injury by four independent, masked observers. ET-1 at 5 pmol/eye caused a significant constriction of retinal vessels (versus the vehicle-treated group) at 10 min after the injection. Intravitreous injection of ET-1 caused a dose-related decrease in the number of retrogradely labeled RGCs. Injection of 5 pmol/eye ET-1 led to a statistically significant decrease in the number of retrogradely labeled RGCs (versus the vehicle-treated group). ET-1 at 1 and 5 pmol/eye caused histological optic nerve damage (evaluated using a graded scale). The histological optic nerve damage correlated with the number of retrogradely labeled RGCs. In conclusion, a single intravitreous injection of ET-1 impaired retrograde axonal transport in the rat optic nerve and this impairment correlated with the histological optic nerve damage.

Topics: Animals; Axonal Transport; Axons; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Glaucoma, Open-Angle; Male; Optic Disk; Optic Neuropathy, Ischemic; Rats; Rats, Sprague-Dawley; Retinal Artery; Retinal Degeneration; Retinal Ganglion Cells; Stilbamidines; Vasoconstriction; Wallerian Degeneration

It is proposed that the anterior optic nerve is specifically susceptible to microcirculatory compromise contributing to the development of glaucomatous optic neuropathy.. Ischemic optic neuropathy was induced by delivering endothelin-1 (ET-1) to the retrobulbar space in one eye of 12 primates for 6 to 12 months. Regional ganglion cell axonal sizes and densities were compared with the normal, contralateral eyes.. Without changes of intraocular pressure, mean axonal density was significantly decreased in ET-1 eyes compared to controls (P = .03, paired t test). Two-way matched-pair analysis of variance showed a significant effect of ET-1 on overall axonal density (P < .0001). Among the animals with significant axonal loss, the mean axonal loss was 11.6%, and loss varied from 4% to 21%. Axonal loss was commonly localized within specific quadrants. Five animals were examined for preferential axonal size loss. As a group, there appears to be a tendency toward preferential large axonal loss, but the mean axonal loss of large and small axons did not meet significant differences (P = .1) However, examination of individual animals with significant loss shows significantly greater loss of large axons as compared to the small axons in three of the animals.. Chronic optic nerve ischemia causes demonstrable and localized damage of the optic nerve, without intraocular pressure elevation. There is preferential loss of large retinal ganglion cell axons in animals with significant axonal loss. Ischemia-induced focal axonal loss is similar to human glaucoma and may represent a differential regional vulnerability.

Topics: Analysis of Variance; Animals; Axons; Drug Administration Schedule; Endothelin-1; Eye; Female; Glaucoma; Infusion Pumps; Intraocular Pressure; Macaca mulatta; Optic Nerve; Optic Neuropathy, Ischemic; Retinal Ganglion Cells

A redistribution of neurochemicals has been identified in the visual cortex of monkeys with laser-induced glaucoma. Examined were functional, structural, and neurochemical changes to the retina, optic nerve, and central visual system in a nonhuman primate model of optic nerve head (ONH) ischemia caused by sustained unilateral administration of endothelin (ET)-1 to the optic nerve.. ET-1 or sham control solution was delivered by osmotic minipump to the retrolaminar region of one optic nerve of rhesus monkeys (Macaca mulatta) for 1.5 years. ONH topography and blood flow velocity were serially studied with scanning laser tomography and laser Doppler flowmetry, respectively. Retinal and cortical electrophysiologic measurements from pattern-derived stimuli were obtained quarterly. Immunohistochemistry was used to identify the distribution of calbindin (CB) and c-Fos labeled neurons in the visual cortex areas V1 and V2, and lateral geniculate nucleus (LGN). Retinal ganglion cell counts and optic nerve axon density were determined by light microscopy.. No significant changes in retinal and ONH morphology, ONH blood flow velocity, and retinal and cortical pattern-derived functional activity were detected. Measurement of CB-positive cell density in V1 and V2 showed a significant decrease in CB labeling to the contralateral side of the ET-1-treated eye (P < 0.04). CB-positive cells were present in the magnocellular layers of the LGN with no differences noticed between the ET-1- and sham-treated eyes. c-Fos-labeled neurons were found in striate area V1 and extrastriateV2 of both groups. No c-Fos labeling was observed in the LGN.. Administering ET-1 to the orbital optic nerve alters neuronal metabolic activity in the visual cortex in rhesus monkeys. Metabolic activity reductions in the visual cortex precede the ability to detect functional and structural alterations in the retina, ONH, and visual cortex in this animal model.

Topics: Animals; Axons; Blood Flow Velocity; Calbindins; Cell Count; Disease Models, Animal; Electrophysiology; Endothelin-1; Geniculate Bodies; Immunohistochemistry; Infusion Pumps, Implantable; Laser-Doppler Flowmetry; Macaca mulatta; Optic Disk; Optic Nerve; Optic Neuropathy, Ischemic; Proto-Oncogene Proteins c-fos; Retina; Retinal Ganglion Cells; S100 Calcium Binding Protein G; Tonometry, Ocular; Visual Cortex

To evaluate the effects of chronic optic nerve ischemia in a nonhuman primate model and to evaluate the regional variability of axonal loss.. Unilateral ischemic optic neuropathy was induced by administration of endothelin-1 to the retrobulbar space via osmotic pumps in 12 primates for 6 to 12 months. The transversely cut sections were stained and divided into 16 regions. Average axonal density in each region was quantified and compared with the untreated contralateral control eyes.. Mean axonal density was 208 310/mm(2) and 220 661/mm(2) in treated and control eyes, respectively (P = .03, 1-tailed paired t test), for the entire group. Two-way analysis of variance showed a significant effect of endothelin-1 on overall axonal density for the experimental group (P<.001). Among the nerves with significant axonal loss, the mean axonal loss was 11.6% (4%-21%). Regional mapping of the damage showed the axonal loss varied in the damaged nerves; the damaged regions often clustered within specific quadrants.. Chronic ischemia induced by local administration of endothelin-1 causes significant loss of optic nerve axons with varying regional susceptibility. Clinical Relevance Localized damage occurs in other types of optic neuropathy, such as glaucoma, and may result from regional differences in anatomy, metabolism, or vasculature of the primate optic nerve.

Topics: Animals; Axons; Cell Count; Chronic Disease; Disease Models, Animal; Endothelin-1; Female; Intraocular Pressure; Macaca mulatta; Optic Nerve; Optic Neuropathy, Ischemic

To investigate the vasoactive effect of bimatoprost (Lumigan), a new topical ocular hypotensive agent, in isolated porcine ciliary arteries.. Arteries were placed in a myograph system to measure isometric forces. Quiescent vessels as well as vessels pre-contracted with either 10 nM endothelin-1 or 100 mM potassium chloride (KCl) were exposed, in a cumulative manner, to increasing concentrations (0.1 nM - 0.1 mM) of bimatoprost (dissolved in ethanol). In quiescent vessels, results were expressed in percent of 100 mM KCl-induced contraction. In endothelin-1-pre-contracted vessels, results were expressed in percent of the maximal contraction induced by endothelin-1. In KCl-pre-contracted vessels, results were expressed in percent of the plateau contraction reached 30 minutes after 100 mM KCl application.. Bimatoprost induced a significant (p < 0.05 - 0.001) vasoconstriction at concentrations equal to or higher than 0.1 micro M in quiescent vessels (0.1 mM: 73 +/- 12 %). In KCl-pre-contracted vessels, at concentrations higher than 1 micro M, bimatoprost induced significant (p < 0.05 - 0.01) contractions (0.1 mM: 67 +/- 17 %). In endothelin-1-pre-contracted vessels, bimatoprost also induced significant (p < 0.05 - 0.001) contractions at concentrations above 10 micro M (0.1 mM: 17 +/- 8 %).. The present study indicates that bimatoprost appears to have, in vitro, some vasoactive properties in porcine ciliary arteries. The question whether Lumigan has an influence on ocular blood flow needs to be further investigated.

Topics: Amides; Animals; Antihypertensive Agents; Aqueous Humor; Bimatoprost; Cloprostenol; Culture Techniques; Dose-Response Relationship, Drug; Endothelin-1; Glaucoma; Intraocular Pressure; Lipids; Optic Neuropathy, Ischemic; Potassium Chloride; Prostaglandins F, Synthetic; Regional Blood Flow; Swine; Vasoconstriction

The purpose of this study was to evaluate the neuroprotective effect of memantine, a N-methyl-D-aspartate antagonist, in an experimental optic nerve ischemia. Endothelin-1 (ET-1) in a dosage of 0.1 microg/day was delivered to the perineural region of the anterior optic nerve by osmotically driven minipumps for 8 weeks in 10 rabbits. In 5 rabbits, 1 mg/kg memantine was administered concurrently by intramuscular injection once a daily. Morphologic optic nerve head changes were monitored with a confocal scanning laser ophthalmoscope. Multivariate statistical analysis showed a significant change in topometric parameters (cup area, cup depth and rim volume), indicating an increase in optic nerve head cupping and a decrease of neural rim volume in the ET-1 administered eyes (P < 0.0001). In rabbits where memantine was given concurrently with ET-1, no significant change in topometric parameters was observed after ET-1 administration (P = 0.78). The current results suggest that memantine has a neuroprotective effect in optic nerve ischemia. Memantine may potentially be useful in the management of various ischemic disorders of the optic nerve, including glaucoma.

Topics: Animals; Endothelin-1; Excitatory Amino Acid Antagonists; Male; Memantine; Models, Animal; Neuroprotective Agents; Optic Disk; Optic Nerve; Optic Neuropathy, Ischemic; Rabbits

To explore the possibility that an elevation of glutamate levels in the vitreous might be associated with the microvascular compromise of the optic nerve.. Endothelin-1, 0.1 microg/d (5 rabbits), or balanced salt solution (4 rabbits) was delivered to the perineural region of the anterior optic nerve by osmotically driven minipumps for 2 weeks. Vitreous specimens were obtained, and their amino acid contents were determined by high-performance liquid chromatography.. There was a statistically significant elevation in the mean +/- SEM vitreous concentrations of glutamate (264% +/-41%; P = .04), aspartate (269% +/-31%; P = .04), and glycine (232% +/-26%; P = .04) in the eyes subjected to endothelin-1 when compared with the fellow control eyes.. Administration of endothelin-1 to the microvasculature of the optic nerve leads to elevation of glutamate, aspartate, and glycine concentrations in the vitreous.. The increase of excitatory amino acids in the vitreous might be associated with various ischemic processes of the optic nerve, including glaucomatous optic neuropathy, and may play a role in the neuronal damage that is seen in these diseases.

Topics: Animals; Aspartic Acid; Chromatography, High Pressure Liquid; Disease Models, Animal; Endothelin-1; Glutamic Acid; Glycine; Infusion Pumps, Implantable; Male; Optic Nerve; Optic Neuropathy, Ischemic; Rabbits; Vitreous Body