endothelin-1 and Glaucoma--Open-Angle

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

Normal tension glaucoma is a form of primary open angle glaucoma where the intraocular pressure remains within the normal range. In this case the main challenge is to establish the correct diagnosis. The clinical evaluation of a patient suspected of a normal tension glaucoma must answer two questions: 1) is the intraocular pressure normal and 2) is it a glaucomatous optic neuropathy or another type of optic neuropathy?

Topics: Biomarkers; Diagnosis, Differential; Endothelin-1; Evidence-Based Medicine; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Practice Guidelines as Topic; Risk Factors; Tonometry, Ocular; Visual Acuity; Visual Field Tests

During the last decade, the presumed etiology of glaucoma has moved from a pure pressure concept to a combined mechanical and vascular theory. Evidence of a localized vascular insufficiency leading to perfusion deficits of ocular structures, including the optic nerve head, the retina, the choroid, and the retrobulbar vessels, is now clear. This article evaluates the role of vasospasm as the primary cause of such a vascular failure. The role of both ocular and systemic vasospasms and their clinical correlations are discussed. At a cellular level, the function of the modulating role of the vascular endothelium is reviewed. Evidence of abnormalities of the vascular endothelium and its vasoactive peptides as a conduit for vasospasm is mounting. Herein lies exciting prospects for potential pharmacologic targets in future glaucoma management.

Topics: Blood Flow Velocity; Endothelin-1; Endothelium, Vascular; Eye; Glaucoma, Open-Angle; Humans; Nitric Oxide; Ophthalmic Artery; Vasoconstriction

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

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

In patients with glaucoma, one of the main initiating mechanisms that triggers the chain of events is disruption of the universal mechanism for regulating vascular tone due to endothelial dysfunction (ED). The main manifestation of ED is an imbalance of vasoconstrictor and vasodilator endothelial mediators, which inconsistency triggers the mechanisms of adaptive distress leading to the progression of morphological destruction, dyslipidemia, acceleration of atherogenesis, development of hemodynamic and hydrodynamic disorders. The drug Mexidol has a wide range of pharmacological activity and affects the main pathogenetic links of primary open-angle glaucoma (POAG).. The study analyzes the vascular remodulation, antioxidant and antihypoxic effects of the drug Mexidol in patients with PAOG.. The study included 78 patients with POAG of the early (. The following changes are observed in patients of the main group using Mexidol: the index of oscillatory potentials significantly increases, peak latency decreases, perimeter indices show positive trends, vascular endothelial function improves according to reactive hyperemia test, concentration of vasoconstrictor mediator ET-1 in blood plasma decreases and of nitrite (NO. The drug Mexidol proved to be an effective endothelial protector, a powerful antioxidant and antihypoxant, contributed to deceleration of atherogenesis in patients with POAG.. У пациентов с глаукомой одним из основных инициирующих механизмов, запускающих цепь событий, является нарушение универсального механизма регулирования сосудистого тонуса вследствие эндотелиальной дисфункции (ЭД). Основным проявлением ЭД служит дисбаланс вазоконстрикторных и вазодилататорных эндотелиальных медиаторов, рассогласованность которых запускает механизмы адаптационного дистресса, ведущего к прогрессированию морфологической деструкции, дислипидемии, ацеклерации атерогенеза, развитию гемодинамических и гидродинамических нарушений. Препарат Мексидол имеет широкий спектр фармакологической активности, действующий на основные патогенетические звенья первичной открытоугольной глаукомы (ПОУГ).. Изучить вазоремодулирующее, антиоксидантное и антигипоксантное действие препарата Мексидол у пациентов с ПОУГ.. В исследование включено 78 пациентов с ПОУГ начальной стадии (. На фоне применения препарата Мексидол у пациентов основной группы значимо повышается индекс осцилляторных потенциалов, снижается межпиковая латентность, наблюдаются положительная динамика периметрических индексов, улучшение функции эндотелия сосудов в пробе с реактивной гиперемией, уменьшение концентрации в плазме крови медиатора-констриктора ЕТ-1, умеренный рост нитрита (NO. Препарат Мексидол проявил себя как эффективный эндотелиопротектор, мощный антиоксидант и антигипоксант, способствовал снижению факторов ацеклерации атерогенеза у пациентов с ПОУГ.

Topics: Aged; Antioxidants; Cholesterol; Endothelin-1; Glaucoma, Open-Angle; Humans; Hyperemia; Nitrites

This study aimed to evaluate the potential risk factors for postoperative late low intraocular pressure (IOP) in patients with primary open-angle glaucoma (POAG) after trabeculectomy.. Adult patients who were diagnosed with POAG and scheduled to undergo primary unilateral trabeculectomy in our hospital were consecutively included. Blood samples before the surgery and aqueous humor samples during the surgery of each participant were collected. Patient demographics, preoperative assessments, and laboratory tests were compared in patients with or without late low IOP. The risk factors for late low IOP were evaluated using logistic regression modeling. The predictive value of endothelin-1 (ET-1) in aqueous humor for late low IOP was evaluated by receiver operating characteristic curve analysis.. Thirty-nine of 222 enrolled patients were cases of late low IOP with an incidence of 17.6% (39/222). The multivariate logistic regression analysis indicated that ET-1 concentration in aqueous humor was the only independent risk factor for late low IOP after trabeculectomy (odds ratio, 0.89; 95% confidence interval, 0.79-0.98; P=0.021). Receiver operating characteristic curve analysis showed that ET-1 concentration in aqueous humor was a predictor for late low IOP after trabeculectomy with an area under the curve of 0.639, a specificity of 84.62%, and a sensitivity of 39.89%, respectively (P=0.006).. Our study indicated that ET-1 concentration in aqueous humor was an independent risk factor for late low IOP in patients with POAG after trabeculectomy.

Topics: Adult; Aged; Aqueous Humor; Endothelin-1; Female; Follow-Up Studies; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypotension; Postoperative Complications; Postoperative Period; Prognosis; Prospective Studies; Trabeculectomy

To explore the correlations of the tissue inhibitor of metalloproteinase-2 (TIMP2) and TIMP3 gene polymorphisms with primary open-angle glaucoma (POAG).. 295 POAG patients were recruited as the observation group and 200 healthy people as the control group. The general clinical information, medical history (hypertension, diabetes and hyperlipemia) and family history were collected. The vascular endothelium and hemorheology indexes in each group were detected. Moreover, the polymorphisms of TIMP2 rs796391657 and TIMP3 rs8136803 were detected via TaqMan-MGB probe assay.. The observation group exhibited higher prevalence rates of diabetes, hyperlipemia and family history than those of the control group (p<0.05), and there were no differences in age, sex and hypertension prevalence rate between the two groups (p>0.05). The observation group had a lower nitric oxide (NO) level, but higher levels of endothelin-1 (ET-1), plasma viscosity (PV), hematocrit (HCT) and fibrinogen (FIB) than those of the control group (p<0.05). The distribution of the three genotypes and alleles of TIMP2 rs796391657 varied a lot between the two groups (p<0.05). The frequency of genotype CC was markedly higher than that of genotype TT; however, C allele had a higher frequency than T allele. Similarly, the three genotypes and alleles of TIMP3 rs8136803 were differentially distributed in the two groups (p<0.05). The frequency of genotype GG was higher than that of genotype TT, while the frequency of G allele was higher than that of T allele.. The TIMP2 and TIMP3 gene polymorphisms are correlated with POAG.

Topics: Alleles; Case-Control Studies; Endothelin-1; Female; Fibrinogen; Gene Frequency; Genotype; Glaucoma, Open-Angle; Hematocrit; Humans; Male; Middle Aged; Nitric Oxide; Polymorphism, Single Nucleotide; Tissue Inhibitor of Metalloproteinase-2; Tissue Inhibitor of Metalloproteinase-3

The purpose was to measure the retinal venous pressure (RVP) in both eyes of primary open-angle glaucoma (POAG) patients before and 3 weeks after treatment with low-dosed Nifedipine.. This retrospective study included 20 POAG patients who were treated with Nifedipine (5 mg daily) and 20 untreated control POAG patients. In both the treated and untreated control group, a distinction was made between those patients who had the Flammer-Syndrome (FS) and those who did not. The RVP was measured in all patients bilaterally at baseline and 3 weeks later by means of contact lens ophthalmodynamometry and the RVP measurements of the treated POAG patients were compared to the RVPs of the untreated POAG controls. Ophthalmodynamometry is done by applying an increasing force on the eye via a contact lens. The minimum force required to induce a venous pulsation is called the ophthalmodynamometric force (ODF). The RVP is defined and calculated as the sum of ODF and intraocular pressure (IOP) [RVP = ODF + IOP].. The RVP decreased significantly after 3 weeks in both eyes of patients treated with low-dosed Nifedipine compared to the untreated group (mean decrease of 12.5 mmHg (SD 12.5), P < 0.001). A larger response to therapy was found in patients with the FS compared to patients lacking the FS (mean decrease of 16.07 vs. 7.28 mmHg, confidence Interval (CI): 5.2 to 9.3 vs. 12.3 to 19.7; P < 0.001). No significant differences were accounted for in the IOP's of the patients after treatment. In the untreated control group, no significant differences were accounted for either in the RVP or the IOP after 3 weeks.. Treatment with low-dosed Nifedipine decreases RVP in both eyes of glaucoma patients, particularly in those with the Flammer-Syndrome. This effect may be due to the partial inhibition of Endothelin-1 (ET-1) by Nifedipine.

Topics: Administration, Oral; Aged; Blood Flow Velocity; Blood Pressure; Calcium Channel Blockers; Endothelin-1; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Nifedipine; Ophthalmodynamometry; Regional Blood Flow; Retinal Diseases; Retinal Vein; Retrospective Studies; Tonometry, Ocular; Venous Pressure

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

To assess the relationship between endothelial dysfunction, endothelin 1 (ET-1) plasma levels and subclinical inflammation in primary open angle glaucoma (POAG) patients.. We enrolled 40 POAG patients with progressive visual field damage, although well controlled intraocular pressure (IOP) and compared to age and sex matched healthxy subjects. Each patient underwent an ophthalmological examination, a standard achromatic perimetry (SAP), blood sampling to assess ET-1 plasma levels, an objective assessment of cellularity within the anterior chamber (FLARE) and measurement of flow mediated dilation (FMD) with high resolution 2-dimensional ultrasonographic imaging of the brachial artery.. At baseline, POAG patients, compared to healthy controls, showed an increase of ET-1 plasma levels: 2.83 ± 0.28 pg/ml vs. 1.75 ± 0.25 pg/ml (p<0.001), lower FMD values 4.46 ± 1.28% vs. 13.18 ± 2.80% (p<0.001) and increased FLARE values 9.98 ± 0.97 photons/ms vs. 5.87 ± 0.64 photons/ms (p<0.001). A follow up after 1 year revealed a further increase of ET-1 plasma levels (to 3.68 ± 0.60; p<0.001) and decrease of FMD (3.52 ± 1.28; p>0.001).. The increase of ET-1 in POAG patients is related to vascular dysfunction (r=0.942; p=0.001) and vascular dysfunction is related to sub-clinical intraocular inflammation (r=0.968; p=0.001). Thus ET-1 and vascular dysfunction related to sub-clinical inflammation may play a key role in determining a progressive visual field damage in POAG patients who present a well-controlled IOP.

Topics: Adult; Brachial Artery; Case-Control Studies; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Follow-Up Studies; Glaucoma, Open-Angle; Humans; Inflammation; Intraocular Pressure; Male; Middle Aged; Ultrasonography; Vasodilation; Visual Field Tests; Visual Fields

Endothelin-1 (ET-1) has been found in elevated concentrations in the aqueous humor of glaucoma patients. Indirect evidence from animal studies suggests that ET-1 might directly influence intraocular pressure (IOP). The aim of this study was to determine whether ET-1 concentrations in aqueous humor of cataract and glaucoma patients correlate with IOP.. Aqueous humor and blood samples from patients with either cataract (control, n = 38), primary open angle glaucoma (POAG, n = 35), or pseudoexfoliation glaucoma (PEXG, n = 21), without other ocular or systemic disease, were collected during routine cataract surgery or trabeculectomy. ET-1 concentration was determined by an ET-1 ELISA kit. IOP was measured preoperatively by standard Goldmann applanation tonometry. All statistical analysis was performed using commercial predictive analytics software.. Both IOP and ET-1 concentration in aqueous humor were significantly increased in POAG (23.4 ± 6.8 mm Hg, 5.9 ± 2.9 pg/mL) and PEXG (24.3 ± 8.8 mm Hg, 7.7 ± 2.1 pg/mL) compared with control (15.0 ± 2.9 mm Hg, 4.3 ± 2.4 pg/mL). No difference was detected for plasma ET-1 concentrations. IOP and ET-1 in the aqueous humor were significantly correlated (R = 0.394, R² = 0.155, P < 0.001), although no correlation was found between IOP and ET-1 in blood plasma or between ET-1 in aqueous humor and ET-1 in plasma.. In this study, a small but highly significant correlation between IOP and the ET-1 concentration in the aqueous humor was found. Although no causative relationship can be deduced from this, ocular ET-1 effects on IOP control may merit further investigation.

Topics: Aged; Aqueous Humor; Cataract; Cataract Extraction; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Exfoliation Syndrome; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Predictive Value of Tests; Trabeculectomy

To investigate the levels of endothelin-1 (ET-1) and nitric oxide (NO) in the aqueous humor and plasma of human eyes with different types of glaucoma: primary open-angle glaucoma (POAG) and chronic closed-angle glaucoma (CCAG).. Patients were classified into 3 groups: group I comprised 35 patients with POAG, group II comprised 25 patients with CCAG, and 30 patients with senile cataract (group III) were used as a control group. Aqueous humor and corresponding plasma were analyzed for ET-1 and NO concentrations by enzyme-linked immunosorbent assay. A Bonferroni correction for multiple comparisons was performed.. There was no significant difference in plasma levels of either ET-1 or NO metabolites between the groups studied. ET-1 and NO were significantly elevated in the aqueous humor of patients with CCAG and POAG compared to the corresponding value in patients with cataract (p < 0.001). ET-1 and NO concentrations in the aqueous humor were more marked in CCAG than in POAG. NO levels were correlated with ET-1 in the aqueous humor of patients with glaucoma (p < 0.001).. Increased concentrations of ET-1 and NO in aqueous humor may be useful with POAG and CCAG. In addition, ET-1 and NO may have useful metabolite levels in the aqueous humor of POAG and CCAG patients as a result of glaucoma damage and may not be a cause of it.

Topics: Aged; Aqueous Humor; Chronic Disease; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Glaucoma, Angle-Closure; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Nitric Oxide; Radioimmunoassay

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

Primary open angle glaucoma (POAG) is a progressive optic neuropathy, characterized, in part by extensive extra cellular matrix remodeling and collapse of the lamina cribrosa (LC). Endothelin-1 (ET-1), a potent vasoactive peptide and its receptors, endothelin receptor A (ET(A)) and endothelin receptor B (ET(B)), have been implicated in glaucomatous optic neuropathy. In this study we examined the expression of ET-1 and its receptors in GFAP negative LC cells. RT-PCR analysis revealed that LC cells express both ET(A), ET(B) receptors and prepro- ET-1, the primary gene transcript of ET-1. A dose-dependent increase in intra-cellular calcium concentrations was observed in the presence of 1, 10 and 100nM ET-1. Increased intracellular calcium concentrations were blocked by the ET(A) selective antagonist BQ610 but not by the ET(B) specific antagonist BQ788. Desensitization to ET(A)-mediated increase in intracellular calcium was observed in LC cells following pre-treatment with ET-1 for 24h. Western blot analysis of LC cells treated with ET-1 for 24h revealed a decreased expression of ET(A) receptor protein at 1, 10 and 100nM concentrations, while a dose dependent increase in the ET(B) receptor was observed with a significant increase at 100nM. Quantitative PCR showed a dose-dependent decrease in ET(A) receptor mRNA levels and an increase in the mRNA levels of ET(B) receptors. A Griess colorimetric assay was used to measure the NO released from LC cells and ET-1 induced a dose-dependent increase in NO release which was significant at 100nM concentration. ET-1 induced NO release was significantly blocked by BQ788, an ET(B) selective antagonist, and as well as BQ610, an ET(A) selective antagonist. These results suggested that human lamina cribrosa cells expressed functional ET(A) and ET(B) receptors and their expression and function was altered in response to prolong exposure to ET-1. This may have an implication in the normal physiology of LC cells and in POAG subjects where elevated levels of ET-1 could impact LC function.

Topics: Aged; Aged, 80 and over; Astrocytes; Calcium; Dose-Response Relationship, Drug; Endothelin-1; Gene Expression Regulation; Glaucoma, Open-Angle; Glial Fibrillary Acidic Protein; Humans; Nitric Oxide; Optic Disk; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction

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

Vasospasm, resulting from a generalized dysfunction in the vascular endothelium, is implicated in the development of normal-pressure glaucoma (NPG). Impaired endothelium-derived nitric oxide activity and abnormalities of the endothelin system suggest systemic endothelial cell dysfunction in patients with NPG. Endothelin (ET)-1 vasoreactivity was assessed in the peripheral circulation of patients with NPG.. Forearm blood flow was measured using venous occlusion plethysmography in eight patients with untreated NPG and eight age- and sex-matched healthy volunteers during intra-arterial infusion of ET-1 (5 pmol/min) and, on a separate occasion, to BQ123, a selective endothelin-A receptor antagonist, (100 nmol/min). Blood pressure and heart rate were measured in the noninfused arm, and plasma ET-1 concentrations were measured using a radioimmunoassay.. Forearm blood flow fell during infusion of ET-1 (P<0.001 for both) to a similar extent in both groups (P=0.7; patients versus control subjects). In contrast, BQ123 increased forearm blood flow in both groups (P<0.001 for both), although the vasodilatation was lower in patients than in control subjects (P<0.001; patients versus control subjects). There was no difference in basal plasma ET-1 concentrations between the two groups (P=0.81; patients versus control subjects).. Despite normal responses to ET-1, patients with NPG have reduced vasodilatation in response to ETA-receptor antagonism. This could be due to attenuated ETA-receptor-mediated tone, increased ETB-receptor-mediated contraction or impaired ETB-receptor-mediated release of endothelial nitric oxide. These results are consistent with the authors' previous demonstration of systemic vascular dysfunction in patients with NPG.

Topics: Blood Flow Velocity; Blood Pressure; Endothelin A Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Female; Forearm; Glaucoma, Open-Angle; Heart Rate; Humans; Intraocular Pressure; Male; Middle Aged; Peptides, Cyclic; Radioimmunoassay; Vasodilation

To compare the plasma concentration of endothelin-1 (ET-1) among patients < 60 years of age with normal-tension glaucoma (NTG), primary open-angle glaucoma (POAG), and in age-matched normal participants.. Plasma concentration of ET-1 was determined in 30 NTG 18 POAG patients, and 19 age-matched normal participants using an enzyme immunoassay.. The ET-1 level was 1.49 +/- 0.51 pg/ml in the NTG patients (49.4 +/- 8.8 years), 1.58 +/- 0.64 pg/ml in the POAG patients (44.7 +/- 10.7 years), and 1.33 +/- 0.50 pg/ml in the normal participants (49.9 +/- 5.6 years). The ET-1 levels were not significantly different among the three groups, and no significant correlation with the extent of visual field damage, intraocular pressure (IOP), refraction, or age was seen in the glaucoma patients.. The plasma ET-1 level showed no difference among NTG patients, POAG patients, and normal participants < 60 years of age in the Japanese population.

Topics: Adult; Asian People; Endothelin-1; Female; Glaucoma, Open-Angle; Humans; Immunoenzyme Techniques; Intraocular Pressure; Male; Middle Aged

To compare the plasma levels of endothelin-1 (ET-1) between patients with primary open angle glaucoma with visual field progression despite normal or normalised intraocular pressure and patients with stabile visual fields in a retrospective study.. The progressive group consisted of 16 primary open angle glaucoma patients and the group with stable visual field consisted of 15 patients. After a 30 minute rest in a supine position, venous blood was obtained for ET-1 dosing. Difference in the plasma level of ET-1 between two groups was compared by means of analysis of covariance (ANCOVA), including age, sex, and mean arterial blood pressure as covariates.. ET-1 plasma levels were found to be significantly increased in patients with deteriorating (3.47 (SD 0.75) pg/ml) glaucoma when compared to those with stable (2.59 (SD 0.54) pg/ml) visual fields (p = 0.0007).. Glaucoma patients with visual field progression in spite of normal or normalised intraocular pressure have been found to have increased plasma endothelin-1 levels. It remains to be determined if this is a secondary phenomenon or whether it may have a role in the progression of glaucomatous damage.

Topics: Aged; Analysis of Variance; Blood Pressure; Endothelin-1; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Retrospective Studies; Visual Fields

Endothelin 1 (ET-1), a potent vasoconstrictor, may affect regulation of intraocular pressure and ocular vessel tone. Thus, ET-1 and its receptors may contribute to development of glaucoma. We investigated whether gene polymorphisms of ET-1 (EDN1) and its receptors ETA (EDNRA) and ETB (EDNRB) were associated with glaucoma phenotypes and clinical features.. We studied 224 normal Japanese controls and 426 open angle glaucoma (OAG) patients including 176 with primary open angle glaucoma (POAG) and 250 with normal tension glaucoma (NTG). Nine single nucleotide polymorphisms were detected among the participants using the Invader assay; four for EDN1 (T-1370G, +138/ex1 del/ins, G8002A, K198N), four for EDNRA (G-231A, H323H, C+70G, C+1222T), and one for EDNRB (L277L). Genotype distributions were compared between normal controls and OAG. Age at diagnosis, untreated maximum intraocular pressure (IOP), and visual field defects at diagnosis were examined for association with polymorphisms.. Of the 9 polymorphisms, genotype distributions showed no significant differences between OAG patients and controls adjusted by age. The GG genotype of EDNRA/C+70G was associated with worse visual field defects in NTG patients (p=0.014; Mann-Whitney U test, and p=0.027; logistic regression analysis).. The polymorphism of EDNRA/C+70G may be related to NTG risk factors.

Topics: Aged; Endothelin-1; Female; Genotype; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Polymorphism, Genetic; Receptor, Endothelin A; Receptor, Endothelin B; Risk Factors; Vision Disorders; Visual Fields

There is evidence to suggest that vasospasm and vascular dysregulation play a role in the etiology of glaucoma. This effect may be particularly relevant in patients with glaucoma who have a history of migraine or vasospastic tendencies. This study was conducted to investigate the role of genes with products that regulate blood flow to ocular tissues. The candidate genes were the two isoforms of nitric oxide synthase (NOS), NOS3 and -2A, and endothelin (ET)-l. The frequency of the T786C mutation in NOS3 was also examined.. DNA was obtained from 58 patients with primary open-angle glaucoma (POAG), 76 with normal tension glaucoma (NTG), and 38 control subjects. Polymerase chain reactions (PCR) were used to compare the frequency of the alleles between the subjects with glaucoma and the control subjects and the subjects with glaucoma with vasospasm or migraine. The PCR product was sequenced to identify the frequency of the T786C mutation.. The distribution of the NOS3 repeat alleles in subjects with glaucoma and control subjects just failed to reach statistical significance (P = 0.06). The distribution in subjects with NTG or POAG did not differ significantly. A significant difference was found (P < 0.001) in the distribution of allele frequencies of the NOS3 marker in subjects who had glaucoma with migraine versus control subjects. There were no differences in the distribution of the NOS2A or ET-1 markers between the subjects with glaucoma and the control subjects.. This study provides evidence of an association between the NOS3 gene and subjects with glaucoma who have a history of migraine. Unlike in other studies, no evidence was found of an association between ET-1 and glaucoma.

Topics: Aged; Endothelin-1; Female; Gene Frequency; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Migraine Disorders; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Polymerase Chain Reaction

To investigate the source of ocular blood flow alterations in glaucoma.. In 56 patients with open angle glaucoma, blood flow parameters were obtained from both eyes in the ophthalmic and central retinal artery by means of colour Doppler imaging, as well as in the choroidal circulation and the neuroretinal rim of the optic nerve by means of laser Doppler flowmetry. Based on these haemodynamic parameters, a cluster analysis (two groups) was performed and differences with regard to risk factors were assessed between clusters.. Ocular blood flow data in the two clusters indicated that the two groups (cluster 1 = 26 patient with higher blood flow values; cluster 2 = 30 patients with lower blood flow values) differed mainly in choroidal and optic nerve blood flow. No differences in sex distribution, propensity to have normal tension glaucoma, age, endothelin-1 plasma levels, visual field damage, intraocular pressure, or systemic blood pressure parameters were observed between the two clusters. However, 12 patients (46%) from the cluster with high ocular blood flow values showed a vasospastic response in nailfold capillaroscopy, while such a response was observed in 24 patients (80%) of the cluster with low ocular blood flow values. This difference in vasospastic propensity was statistically significant (p = 0.0121).. Ocular blood flow alterations in glaucoma patients seem, at least partly, to be related to a systemic vascular dysregulation.

Topics: Aged; Aged, 80 and over; Blood Flow Velocity; Blood Pressure; Choroid; Endothelin-1; Eye; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Laser-Doppler Flowmetry; Male; Middle Aged; Ophthalmic Artery; Optic Nerve; Regional Blood Flow; Retinal Artery; Vasoconstriction; Visual Fields

Vasospasm has been associated with glaucoma, but its mechanisms have not been elucidated. The present study was designed to evaluate the role of endothelin (ET)-1, a potent endogenous vasoconstrictor, in the genesis of vasospasm in glaucoma.. Our sample contained patients with open-angle glaucoma (n = 43) and subjects with normal nonglaucomatous eyes and without acral vasospasm (n = 27). After the eligibility visit, all subjects underwent a provocative cooling test, consisting of wearing for 30 minutes a head-vest cooling garment containing coolant fluid. Blood was collected before and after cooling, and plasma ET-1 was determined by immunoassay. In addition, visual fields and retinal blood flow, measured with a confocal scanning laser and Doppler flowmeter, were measured before and after cooling. Peripheral finger flow, skin temperature, and blood pressure were monitored during the experiment. A recovery visit was performed within 1 month, when visual field and retinal blood flow measurements were repeated.. Baseline plasma ET-1 levels were similar between patients with glaucoma and control subjects (mean +/- SD: 2.81 +/- 1.29 and 2.56 +/- 1.36 pg/mL, respectively, P = 0.465). Patients with glaucoma, however, had a significant increase in plasma ET-1 after cooling (mean +/- SD increase of 34% +/- 52%, P = 0.001), not observed in control subjects (mean +/- SD increase of 7% +/- 43%, P = 0.750). No significant change in visual fields or retinal blood flow was observed after cooling in either group. Patients with glaucoma who had evidence of acral vasospasm, however, were more likely to show deterioration in visual fields after cooling than patients without acral vasospasm (P = 0.007).. Patients with glaucoma have an abnormal increase in plasma ET-1 after the body cools. It is possible that at least in some patients, increased levels of ET-1 in response to vasospastic stimuli may be involved in the pathogenesis of glaucomatous damage.

Topics: Adult; Aged; Aged, 80 and over; Blood Flow Velocity; Blood Pressure; Cold Temperature; Endothelin-1; Female; Fingers; Glaucoma, Open-Angle; Humans; Laser-Doppler Flowmetry; Male; Middle Aged; Retinal Vessels; Skin Temperature; Vasoconstriction; Visual Fields

Concentrations of aqueous humor endothelin (ET)-1 are increased in patients with primary open-angle glaucoma (POAG) as well as in animal models of glaucoma. Glucocorticoids have also been associated with glaucoma, in that topical administration of glucocorticoids can increase intraocular pressure by increasing outflow resistance in the trabecular meshwork (TM) in some individuals. Recent research has shown that dexamethasone (Dex), a synthetic glucocorticoid, can increase the release of ET-1 from human nonpigmented ciliary epithelial (HNPE) cells, a source of aqueous ET-1. In the present study, the downstream interaction of ET-1 with Dex in target TM cells, an action that may alter outflow resistance, was investigated.. A normal primary human TM (NTM) cell line and a TM cell line derived from a glaucomatous eye (GTM) were used. The cells were treated with vehicle or Dex. The mRNA levels of prepro-ET-1, endothelin receptor A (ET(A)), and endothelin receptor B (ET(B)) were measured by quantitative RT-PCR (QPCR). The protein expression of ET(A) and ET(B) receptors were investigated by Western blot analysis using polyclonal anti-ET(A) and anti-ET(B) antibodies, respectively, on plasma membrane fractions. Intracellular Ca(2+) ([Ca(2+)](i)) mobilization mediated by ET-1 was measured using the Fura-2 AM fluorescent probe technique as an index of ET receptor function. ET-1-stimulated nitric oxide (NO) release was measured using a Griess colorimetric NO synthase assay kit.. Both NTM and GTM cultured cells expressed prepro-ET-1 mRNA less abundantly than did HNPE cells, and Dex treatment had no effect on the mRNA expression of the ET-1 gene. TM cells expressed mRNA of ET(A) receptors as detected by QPCR, whereas the ET(B) message was not clearly delineated. Western blot analysis showed that both ET(A) and ET(B) receptor proteins were present. The ET(A) receptor was linked to calcium mobilization as ET-1 produced an increase in intracellular calcium release, and this increase was blocked with a selective ET(A) receptor antagonist. Dex failed to induce any change in the expression of the ET(A) receptor in both NTM and GTM cells, and this was supported by the absence of a Dex effect on the ET-1-induced calcium response. However, Dex treatment diminished ET(B) receptor protein expression and produced a decrease in ET-1-stimulated release of NO, a response mediated by ET(B) receptors in TM cells.. The Dex-induced increase in ET-1 released by HNPE cells coupled to the downstream Dex-induced specific suppression of ET(B) receptor protein expression and declines in ET-1-mediated increase in NO released by TM cells could increase contraction and decrease relaxation of the TM and contribute to the declines in conventional aqueous humor outflow and increases in intraocular pressure that occur with glucocorticoids.

Topics: Aged; Blotting, Western; Calcium; Cell Line; Cell Membrane; Dexamethasone; Endothelin-1; Fura-2; Glaucoma, Open-Angle; Glucocorticoids; Humans; Male; Nitric Oxide; Receptor, Endothelin A; Receptor, Endothelin B; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Trabecular Meshwork

The aim of the work was to define the relationships between the endothelin-1 level in blood serum of glaucoma patients concerning the visual field defects and the number of nerve fibers.. 24 women and 14 men, aged 38-74 year (mean 53.4 year) with primary open angle glaucoma, without any systemic diseases. The control group consisted of 20 healthy women and men, aged 34-70 year (mean 52.6 year). The endothelin-1 level was tested with the enzymo-immunologic method from the blood serum. The visual field defects were examined with the Humphrey static perimetry. The nerve fibers were analyzed with the Gdx apparatus.. Mean value of ET-1 in blood serum were similar in both examined groups, it was 0.51 in group of glaucoma patients and 0.54(fmol/l) in the control group. There were no significant correlations between ET-1 level, static perimetry, GDx parameters and age in the group of patients with POAG. The statistics significances were stated for ET-1 level and MD-parameter in static perimetry (p < 0.03) and ET-1 level with The Number--the GDx parameter (p < 0.03).. There was no significant level of ET-1 in blood serum in group of patients with POAG. There have not been stated any relationships between the static perimetry and GDx changes in patients with POAG to endothelin-1 level in blood serum. It is the preliminary communication.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Diagnostic Techniques, Ophthalmological; Endothelin-1; Female; Glaucoma, Open-Angle; Humans; Male; Middle Aged; Statistics, Nonparametric; Vision Disorders; Visual Field Tests; Visual Fields

Prostaglandin (PG) F(2alpha) and other Ca(2+)-mobilizing agonists, such as carbachol (CCh) and endothelin (ET)-1, induce an increase in uveoscleral outflow, in part through receptor-mediated mechanisms in the ciliary muscle. Because changes in uveoscleral outflow across the ciliary muscle could cause elevation of intraocular pressure (IOP) in patients with glaucoma, the present study was conducted to investigate the possibility that basal and agonist-induced second-messenger formation may be altered in glaucomatous human ciliary muscle (g-HCM) cells compared with normal (n)-HCM cells.. Normal and glaucomatous HCM cells were cultured from donor eyes, the cells were identified based on their positive immunostaining with smooth muscle-specific anti-alpha-actin (SM), anti-SM-myosin, and anti-desmin antibodies. Activation of phospholipase A(2) (PLA(2)) was measured by the release of [(3)H] arachidonic acid (AA) into the medium, accumulation of PGE(2) was measured by radioimmunoassay, [(3)H]myo-inositol phosphate production was measured by ion-exchange chromatography, and phospholipase C (PLC)-beta(1) expression was determined by immunoblot analysis with polyclonal antibodies specific for PLC-beta(1).. Homogenous primary cell cultures from normal and glaucomatous human ciliary muscle were established and characterized. The data obtained can be summarized as follows: Both n- and g-HCM cells exhibited similar morphologic characteristics and immunoreactivities. The effects of the agonists on AA release in both n- and g-HCM cells were in the following order: PGF(2alpha) > ET-1 > CCh; their effects on PGE(2) release were in the following order: PGF(2alpha) > CCh > ET-1; and their effects on inositol phosphate production were in the following order: CCh > ET-1 > PGF(2alpha). Both the basal- and stimulated release of AA were significantly higher in the g-HCM cells than in the n-HCM cells (for PGF(2alpha), 60% vs. 151%). The basal release of PGE(2) in g-HCM cells was two- to fivefold higher than that of n-HCM cells, and there are alterations in the effects of the agonists on PGE(2) release. Agonist-induced inositol phosphate production in g-HCM cells was considerably lower than that of n-HCM cells (CCh, 58% vs. 421%), and the amount of PLC-beta(1) expressed in g-HCM cells, compared with that in n-HCM cells, was markedly reduced (by 44%).. These data are the first to show that basal and agonist-induced AA release and inositol phosphate production as well as expression of PLC-beta(1) are altered in g-HCM cells compared with that of n-HCM cells. The molecular mechanisms underlying these alterations in g-HCM cells could include changes in sensitivity and number of receptors, overexpression of PLA(2) and the cyclooxygenases, and underexpression of PLC-beta(1). Alterations in these signaling pathways in g-HCM cells could contribute to changes in the uveoscleral outflow pathway, which may lead to an increase in IOP in patients with glaucoma. Comparative studies on the signaling pathways in g- and n-HCM cells can provide important information about the regulation of uveoscleral outflow and the pathologic course of glaucoma.

Topics: Actins; Aged; Aged, 80 and over; Arachidonic Acids; Blotting, Western; Calcium; Carbachol; Cells, Cultured; Ciliary Body; Desmin; Dinoprost; Dinoprostone; Endothelin-1; Fluorescent Antibody Technique, Indirect; Glaucoma, Open-Angle; Humans; Inositol Phosphates; Isoenzymes; Middle Aged; Muscle, Smooth; Myosins; Phospholipase C beta; Radioimmunoassay; Type C Phospholipases

Glaucoma is an optic nerve head neuropathy in which retinal ganglion cells are lost. A clear association exists between glaucoma and different risk factors, such as high intraocular pressure (IOP) or blood-flow dysregulation. Nitric oxide (NO) and endothelin, two recently identified cellular mediators, appear to be involved in the regulation of IOP as well as in the modulation of ocular blood flow. To some extent, NO is also involved in apoptosis, a mechanism of cell death that can lead to retinal ganglion cell loss in glaucoma. This article provides a short and simplified overview of the biochemistry of NO and endothelin and highlights the potential role of these two mediators in certain important aspects related to the pathogenesis of glaucoma.

Topics: Apoptosis; Arteries; Blood Flow Velocity; Chronic Disease; Endothelin-1; Eye; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Nitric Oxide; Retinal Ganglion Cells; Vasoconstriction

1. Endothelium-derived substances are important regulators of the microcirculation. Endothelium-derived nitric oxide (NO), which is catalysed by nitric oxide synthase (NOS), is a potent modulator of vascular tone in the human ophthalmic artery, which is normally in a state of constant vasodilation due to the actions of NO. Endothelin-1 (ET-1) produces vasoconstriction of the anterior optic nerve vasculature and may be associated with glaucomatous optic neuropathy. The aetiology of primary open-angle glaucoma (POAG) remains largely unknown. Thus, alterations in the regulatory sequences of the genes coding for endothelium-derived NOS (eNOS) and ET-1 may have important effects in the development of POAG and were looked for in the present study. 2. In 56 patients with familial POAG and in 100 control subjects with no family history of hypertension or POAG, we examined the 5' flanking sequences of the eNOS and ET-1 genes, which contain many positive and negative regulatory regions affecting gene transcription, using polymerase chain reaction-based single strand conformation polymorphism analysis, to search for alterations. No variant in the promoter region of the ET-1 gene was observed in familial POAG or controls. Using three primer sets spanning 706 b.p. of the eNOS gene, we observed alterations in 11 of 56 (20%) familial POAG members and in seven of 100 (7%) controls. Sequence analysis demonstrated a C/T substitution at the 5' sequence position nucleotide (nt) -690 from the transcription start site, which lies between the cAMP regulatory element (nt -726 to -732) and an activator protein-1 binding domain (nt -655 to -661). 3. In summary, genotypic and allelic frequency analysis found no association between alterations in the promoter region of the ET-1 gene and familial POAG. A variant in the promoter region of the eNOS gene was seen in a significant percentage of familial POAG patients. Future expression studies will determine whether this polymorphism results in altered eNOS gene expression.

Topics: Adult; Aged; Endothelin-1; Endothelium, Corneal; Glaucoma, Open-Angle; Humans; Middle Aged; Nitric Oxide Synthase; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Regulatory Sequences, Nucleic Acid; Sequence Analysis, DNA

The authors investigate cutaneous capillary blood flow using the cold pressor test and plasma endothelin-1 (ET-1) concentration in primary open-angle glaucoma (POAG) and capsular glaucoma (CG), and evaluate the connection between the two factors, which reflect vasoconstrictive mechanisms with a potential role in the pathogenesis of glaucoma.. The ET-1 concentration of venous blood plasma samples from 20 patients with POAG, 22 patients with CG, and 44 healthy volunteers was measured using a radioimmunoassay kit. On a separate occasion, the right hand was subjected to the cold pressor test (hand immersed in 4 degrees C water for 30 seconds, then in 30 degrees C water for 2 minutes), during which cutaneous capillary blood flow of the left middle finger was measured using a Periflux 4001 Master Laser Doppler Flowmeter (Perimed AB, Järfälla, Sweden).. In the CG group, baseline cutaneous capillary blood flow was significantly lower than either that of POAG (p = 0.001) or that of the healthy group (p = 0.046). In the CG group, time to maximal cold-induced flow reduction was significantly longer than in the POAG group (p = 0.028) or in the healthy group (p = 0.025). Also, recovery time was significantly longer in CG than in the healthy group (p = 0.008) and tended to be longer than in the POAG group. No statistically significant difference between the groups was found either in the frequency of increased vasospastic response (cold-induced flow reduction higher than 70% of the baseline value) or in ET-1 concentration. No correlation was seen between ET-1 concentration and the findings of the cold pressor test.. The results suggest that in CG, which is a systemic disease with vascular abnormalities, baseline cutaneous capillary perfusion and its response to cold and warmth are altered, without any alteration of plasma ET-1 level. The authors found that both plasma ET-1 level and the response to the cold pressor test are normal in patients with POAG. These findings suggest that regulation of cutaneous capillary perfusion and the concentration of plasma ET-1 are not related to each other in patients with glaucoma.

Topics: Biomarkers; Blood Pressure; Capillaries; Cold Temperature; Endothelin-1; Exfoliation Syndrome; Female; Follow-Up Studies; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Laser-Doppler Flowmetry; Male; Middle Aged; Radioimmunoassay; Regional Blood Flow; Skin; Vasoconstriction

Experimental evidence suggests a role of endothelin-1 (ET) in the regulation of intraocular pressure (IOP).. Therefore, in patients undergoing cataract surgery, ET-like immunoreactivity (ETIR) was measured by radioimmunoassay in pooled samples of aqueous humor of eyes with primary open-angle glaucoma (POAG) and normotensive eyes with cataract only.. ETIR was significantly (P < 0.05) higher in patients with cataract and POAG (20.5 +/- 1.8 pg/ml, n = 12; preoperative IOP 21.4 +/- 1.1 mmHg, n = 33) than in patients with cataract only (15.8 +/- 1.6 pg/ml, n = 15; preoperative IOP 16.0 +/- 0.6 mmHg, n = 77).. This finding may indicate a role of ET in POAG or ocular antihypertensive treatment, and its relevance should be further investigated.

Topics: Administration, Topical; Adrenergic beta-Antagonists; Aqueous Humor; Cataract; Cataract Extraction; Endothelin-1; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Ophthalmic Solutions; Radioimmunoassay

The potent vasoconstrictor peptide endothelin-1 has been shown to participate in the control of peripheral vascular tone and in the regulation of ocular perfusion. In glaucoma patients vasospasms and arterial hypotension have been identified as risk factors for the progression of glaucomatous damage, and the regulation of endothelin-1 release is disturbed in some of these patients. The aim of this study was to assess the relationship between resting blood pressure and cutaneous vascular responsiveness to endothelin-1 and phenylephrine in patients with glaucoma and in matched controls.. In 9 patients with primary open-angle glaucoma (POAG), 7 patients with normal tension glaucoma (NTG), and 16 age- and sex-matched controls, endothelin-1 and phenylephrine responses were assessed in the human forearm microcirculation using laser Doppler flowmetry during intra-arterial drug administration. Blood pressure was measured intra-arterially.. In contrast to alpha 1-adrenergic effects, endothelin-1 responses were inversely correlated to both systolic (r2 = 0.27, P = 0.05) and diastolic (r2 = 0.54, P = 0.001) blood pressure in glaucoma patients, whereas there was no such correlation in controls. Patients with lower blood pressure values were more sensitive to the vasoconstrictor effects of endothelin-1. Cutaneous responsiveness to endothelin-1 and phenylephrine was similar in glaucoma patients and in controls.. These results reveal that glaucoma patients appear to have peripheral microvascular abnormalities which are exhibited as altered responsiveness to endothelin-1. Thus, this study supports the hypothesis that endothelin-1-related microvascular dysfunction may be involved in the pathogenesis of glaucomatous damage.

Topics: Adult; Aged; Blood Pressure; Dose-Response Relationship, Drug; Endothelin-1; Female; Glaucoma, Open-Angle; Humans; Infusions, Intra-Arterial; Laser-Doppler Flowmetry; Male; Microcirculation; Middle Aged; Phenylephrine; Skin; Vasoconstriction; Vasoconstrictor Agents

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelin cells There are reports in the literature that ET-1 plasma levels are raised in low tension glaucoma (LTG). ET-1 plasma concentration and Color Doppler Imaging (CDI) evaluation in ophthalmic and posterior ciliary arteries were measured in 15 LTG patients and in 15 healthy subjects. The blood flow index recorded for the ophthalmic artery in normal subjects was a PSV of 36.646 +/- 6.611 cm/sec with RI of 0.717 +/- 0.019 while in the LTG patients it was 32.961 +/- 3.045 cm/sec (p < 0.003) with RI of 0.789 +/- 0.018 (p < 0.001). For the posterior ciliary arteries in the same two groups, we obtained a PSV of 13.878 +/- 4.149 cm/sec vs 8.720 +/- 1.645 cm/sec (p < 0.001) and an RI of 0.679 +/- 0.039 vs 0.722 +/- 0.024 (p < 0.001). The plasma ET-1 level in normal subjects was 1.720 +/- 0.174 pg while in LTG patients it was 2.947 +/- 0.217 pg (p < 0.001). On the basis of our experience, we think that GON and the visual field damage found in LTG can be attributed to an alteration in the endothelial self-regulating sections and consequent vascular insufficiency, particularly pronounced in the posterior ciliary arteries which, since it is these that provide the blood supply to the optic nerve head, leads to irreversible functional damage.

Topics: Aged; Biomarkers; Blood Flow Velocity; Ciliary Arteries; Endothelin-1; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ophthalmic Artery; Optic Disk; Ultrasonography, Doppler, Color; Visual Fields