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Aim: To evaluate the association of glycated haemoglobin (HbA1c) and serum glucose with intraocular pressure (IOP) in a large UK general population., Materials and Methods: Participants were selected from the UK Biobank, excluding those with eye conditions that may affect IOP. IOP was measured using an ocular response analyser. Goldmann-correlated IOP (IOPg) and corneal-compensated IOP (IOPcc) were outcomes of interest, and ocular hypertension was defined as left-eye IOPg or IOPcc > 21 mmHg. HbA1c and random (non-fasting) serum glucose were the exposures of interest. Multivariate restricted cubic spline models, as well as linear regression, were applied to explore the associations of interest., Results: Among 68 806 participants (46.5% male), the mean age was 56.7 years. The mean (standard deviation) for IOPg was 15.7 (3.6) mmHg and 15.9 (3.6) mmHg for IOPcc. Occular hypertension was prevalent in 8055 participants (11.7%) and 4178 participants (6.1%) had diabetes. Those with diabetes had higher IOP and a higher prevalence of ocular hypertension. After adjustment for demographic and clinical variables, HbA1c was positively associated with IOP in participants with diabetes, but not in those without diabetes. For every 10-mmol/mol increase in HbA1c, IOPg increased by 0.20 mmHg (95% confidence interval [CI] 0.12, 0.28) and IOPcc by 0.15 mmHg (95% CI 0.07, 0.23); the odds of ocular hypertension was increased by 6% (95% CI 1.00, 1.13) in participants with diabetes. A borderline positive association between serum glucose and IOP was found only in participants without diabetes., Conclusions: Impaired glycaemic control was associated with elevated IOP and a possible risk of ocular hypertension among participants with diabetes but of normal ocular health., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Primary open-angle glaucoma (POAG) is subdivided depending on eye pressure. Patients with normal-tension glaucoma (NTG) have never had high intraocular pressure (IOP) measured while patients with ocular hypertension (OHT) have high eye pressure but no signs of glaucoma. Although IOP is considered to be a risk factor for all glaucoma patients, it is reasonable to assume that other risk factors such as inflammation play a role. We aimed to characterize the proteome and cytokine profile during hypoxia in plasma from patients with NTG (n = 10), OHT (n = 10), and controls (n = 10). Participants were exposed to hypoxia for two hours, followed by 30 min of normoxia. Samples were taken before ("baseline"), during ("hypoxia"), and after hypoxia ("recovery"). Proteomics based on liquid chromatography coupled with mass spectrometry (LC-MS) was performed. Cytokines were measured by Luminex assays. Bioinformatic analyses indicated the involvement of complement and coagulation cascades in NTG and OHT. Regulation of high-density lipoprotein 3 (HDL3) apolipoproteins suggested that changes in cholesterol metabolism are related to OHT. Hypoxia decreased the level of tumor necrosis factor-α (TNF-α) in OHT patients compared to controls. Circulating levels of interleukin-1β (IL-1β) and C-reactive protein (CRP) were decreased in NTG patients compared to controls during hypoxia. After recovery, plasma interleukin-6 (IL-6) was upregulated in patients with NTG and OHT. Current results indicate an enhanced systemic immune response in patients with NTG and OHT, which correlates with pathogenic events in glaucoma. Apolipoproteins may have anti-inflammatory effects, enabling OHT patients to withstand inflammation and development of glaucoma despite high IOP., (© 2024. The Author(s).)

Purpose: To compare the plasma levels of hydrogen sulfide (H 2 S), homocysteine (Hcy), and L-cysteine (Cys) among primary open-angle glaucoma (POAG), normal tension glaucoma (NTG), ocular hypertension (OHT), and normal individuals. To explore associated factors and evaluate their diagnostic abilities in glaucoma. Methods: POAG, NTG, OHT, and normal subjects were recruited from Ruijin Hospital between December 2016 and December 2018. All subjects underwent thorough ophthalmological examinations, and fasting venous blood was taken to determine the concentrations of H 2 S, Hcy, and Cys. Results: Forty-two POAG, 20 NTG, 52 OHT, and 78 controls were enrolled. The H 2 S levels in POAG group were significantly lower than those in OHT group ( P  = 0.036) and normal group ( P  < 0.001), while the Hcy and Cys levels in POAG and NTG groups were significantly higher ( P  = 0.007-0.043). The concentrations of H 2 S, Hcy, and Cys in glaucoma patients with different stages were not significantly different (all P  > 0.05). POAG patients with longer duration of diagnosis had lower concentrations ( P  = 0.026, P  = 0.001, P  < 0.001), but no significant differences in NTG patients (all P  > 0.05). The Hcy and Cys levels in NTG patients showed negative but weak correlations with mean deviation ( r  = -0.450, P  = 0.047; r  = -0.478, P  = 0.033). All these concentrations showed significant but poor diagnostic values in POAG-Normal group [area under curve (AUC) = 0.642-0.721, P  < 0.05]. The H 2 S level showed poor diagnostic power in POAG-OHT group (AUC = 0.657, P  < 0.01). Conclusion: Decreased levels of H 2 S and increased levels of Hcy and Cys may be associated with glaucoma, especially in POAG. However, the H 2 S/Hcy metabolic pathway is not sufficiently sensitive to be used as a reliable biomarker in glaucoma.

Purpose: The aim of this study was to evaluate thiol/disulfide homeostasis and ischemia-modified albumin levels with primary open-angle glaucoma, ocular hypertension, and control group; also to interpret the correlation between these biochemical parameters and retinal nerve fiber layer analysis., Material and Methods: In a prospective cross-sectional study, 30 primary open-angle glaucoma cases, 30 ocular hypertension cases, and 30 control subjects were included in the study. Native thiol, total thiol, and disulfide measurements and disulfide/native thiol, disulfide/total thiol, and native thiol/total thiol ratios were evaluated as thiol-disulfide homeostasis. Albumin and ischemia-modified albumin parameters were also evaluated. All cases underwent detailed ophthalmologic examination including visual acuity, retinal nerve fiber layer via optical coherence tomography, intraocular pressure, and central corneal thickness measurements and visual field analysis by 24-2 Swedish Interactive Threshold Algorithm (SITA) Standard visual field test., Results: Primary open-angle glaucoma group had significantly higher ischemia-modified albumin values than ocular hypertension and control group (p < 0.001). Native thiol and total thiol values of control group were statistically higher than those of primary open-angle glaucoma and ocular hypertension groups. The correlation between the temporal retinal nerve fiber layer value and ischemia-modified albumin, disulfide/native thiol, and disulfide/total thiol values of the primary open-angle glaucoma patients included in the study was moderate correlation in negative direction (r = -0.46, r = -0.39, r = -0.39, respectively), whereas there was a statistically significant moderate correlation in positive direction between the native thiol/total thiol values (r = 0.39) (p < 0.05)., Conclusion: These findings have reinforced the role of oxidative stress in the etiopathogenesis of primary open-angle glaucoma, suggesting that the thinning retinal nerve fiber layer may be associated with oxidative stress in favor of prooxidant shift.

A clinical method for characterizing the state of micro-vasculature vasomotion is demonstrated, based on observing in capillaries the dynamics of autologously re-injected erythrocytes containing ICG dye. Since a manifestation of vasomotion is transient erythrocyte pausing, vasomotion state within a field of capillaries is characterized by an histogram plot of the number of paused erythrocytes as a function of pause duration during a fixed period of observation, then the ratio of long-pausing to short-pausing erythrocytes was calculated. The method was first applied to the posterior pole retinal vasculatures of anesthetized-monkey eyes, and normal vasomotion state during air-breathing was compared to the state induced by O 2 -breathing, known to cause mild arteriolar vasoconstriction in the mature eye. Subsequently, the effects of other antagonists to normal arteriolarvasotonia state (long-standing experimentally-induced ocular hypertension and branch-vein occlusion, as well as tissue edema) were similarly characterized and the results compared to those obtained during baseline air-breathing. The feasibility of applying the histogram characterization of vasomotion state to human eyes and skin was also preliminarily explored., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aim of this study was to investigate the association between postprandial glucose and intraocular pressure in a relatively healthy population. We examined 1,439 adults getting a health check-up in a health promotion center at Tri-Service General Hospital (TSGH) in Taiwan between 2012 and 2013. All participants underwent examinations to measure metabolic variables and intraocular pressure. Multiple linear regression analyses were performed to assess the relationship between postprandial glucose and intraocular pressure. The levels of postprandial glucose were divided into quartiles with subjects in the lowest quartile being regarded as the reference group to perform quartile-based analysis. Covariate adjustment was designed for three models for further analysis. Subjects with higher quartiles of postprandial glucose level had a higher systolic blood pressure, a greater waist circumference and an elevated fasting glucose level (all p < 0.001). The β coefficient with adjusted covariates showed a significant positive association between postprandial glucose and intraocular pressure. The trends of intraocular pressure across increasing quartiles of postprandial glucose were statistically significant (all p for trend < 0.001). Thus, higher levels of postprandial glucose positively correlated with elevated intraocular pressure., Competing Interests: The authors have declared that no competing interests exist.

Aim: To conduct a comparative study of element concentrations in the aqueous humour of human eye and blood serum at various levels of intraocular pressure (IOP)., Material and Methods: The chemical composition of biological fluids was studied in two equal groups (33 patients/33 eyes each): group 1 - primary open-angle glaucoma (POAG) with decompensated IOP and group 2 - normal IOP (the controls). Sampling of the aqueous humour and blood was done during surgical procedures, namely, penetrating glaucoma surgery (group 1) and cataract phacoemulsification (group 2). Blood was taken from the cubital vein and centrifuged to obtain the supernatant for further analysis. The samples were studied with Zeiss EVO LS10 scanning electron microscope (SEM) equipped with Oxford X-Max50 energy dispersive spectrometer., Results: In both groups, regardless of the IOP level, Na and K concentrations were found to be constantly higher in the aqueous humour than the blood serum. The ratio of Na concentrations in the aqueous humour and serum (measured in mmol/l) was 1.51/1.30 at normal IOP and 1.49/1.31 at decompensated IOP. The ratio of K concentrations was 0.11/0.03 and 0.12/0.03, respectively. Concentrations of N and S in the aqueous humour were higher in the group with decompensated IOP., Conclusion: Regardless of the IOP level, Na and K concentrations were found to be constantly higher in the aqueous humour than the blood serum. IOP elevation was accompanied by an increase in N and S concentrations in the aqueous humour.

Background: Low levels of testosterone in men and changes in retinal microvascular calibre are both associated with hypertension and cardiovascular disease risk. Sex hormones are also associated with blood flow in microvascular beds which might be a key intermediate mechanism in the development of hypertension. Whether a direct association between endogenous testosterone and retinal microvascular calibre exists is currently unknown. We aimed to determine whether testosterone is independently associated with ocular perfusion via a possible association with retinal vascular calibre or whether it plays only a secondary role via its effect on blood pressure in a bi-ethnic male cohort., Probands and Methods: A total of 72 black and 81 white men (28-68 years of age) from the follow-up phase of the Sympathetic activity and Ambulatory Blood Pressure in Africans (SABPA) study were included in this sub-study. Ambulatory pulse pressure and intraocular perfusion pressures were obtained, while metabolic variables and testosterone were measured from fasting venous blood samples. Retinal vascular calibre was quantified from digital photographs using standardised protocols., Results: The black men revealed a poorer cardiometabolic profile and higher pulsatile pressure (>50 mm Hg), intraocular pressure and diastolic ocular perfusion pressure than the white men (p≤0.05). Only in the white men was free testosterone positively associated with retinal calibre, i.e. arterio-venular ratio and central retinal arterial calibre and inversely with central retinal venular calibre. These associations were not found in the black men, independent of whether pulse pressure and ocular perfusion pressure were part of the model., Conclusions: These results suggest an independent, protective effect of testosterone on the retinal vasculature where an apparent vasodilatory response in the retinal resistance microvessels was observed in white men.

Purpose: Our previous studies suggested that CYP46A1 and 24S-hydroxycholesterol (24SOH) may be associated with glaucoma. Loss of CYP46A1-expressing retinal ganglion cells is involved in the activation of glia, and therefore possibly in the disbalance of cholesterol. In this context, the purpose of our present work was to emphasize the glial and longitudinal CYP46A1 expression after an interventional glaucoma-related stress triggered by elevated intraocular pressure (IOP)., Methods: Sprague-Dawley rats were submitted to laser photocoagulation of the trabecular meshwork, limbus and episcleral veins in one eye to induce elevated IOP. Rats were euthanized at days 3, 14, 30 and 60 (n = 10 per time-point), and 24SOH was measured in plasma and retina by gas chromatography-mass spectrometry. CYP46A1 was quantified by Western blotting. Glial activation was assessed by glial fibrillary acidic protein immunoreactivity in Western blots and retinal cryosections., Results: Sustained high IOP was observed in experimental eyes from day 1 to day 21. Plasma MCP-1 and ICAM-1, quantified using multiplex assay kits, were increased at day 3. Glial activation was observed bilaterally at all time-points, at lower levels in contralateral eyes than in experimental eyes. In experimental retinas, CYP46A1 expression showed a transient increase at day 3 and then returned to baseline. Plasma and retinal 24SOH peaked at day 14 and 30, respectively., Conclusions: These data show that CYP46A1 expression was induced early in response to retinal stress but remained constant at late time-points, reinforcing the constitutive role of CYP46A1 in maintaining cholesterol balance in neuronal tissues., (© 2012 The Authors. Acta Ophthalmologica © 2012 Acta Ophthalmologica Scandinavica Foundation.)

There are various reports of ocular abnormalities in metabolic disorders. This study was done with the aim to investigate the relationships between the amounts of serum calcium, phosphorus, and parathyroid hormone concentrations and ocular findings in patients undergoing hemodialysis. Fifty eight patients with end stage renal failure undergoing hemodialysis were randomly selected and enrolled in this prospective study. Demographic data, history of diabetes mellitus and hypertension, and duration of hemodialysis were recorded. Serum calcium, phosphorus, alkaline phosphatase (ALP), and parathyroid hormone (PTH) concentrations were measured. Also, blood urea nitrogen (BUN) and weight of the patient was measured just before and three minutes after the hemodialysis. Patients also underwent a complete ocular examination including visual acuity, intraocular pressure (IOP), biomicroscopic examination, and fundoscopy. In univariate analysis, adverse relationships were found between the ocular hypertension and ALP concentration (P = 0.017) and also between the visual acuity and phosphorus concentration (P = 0.033). However, in multivariate regression analysis and with regard to the patients' characteristics and medical history in a multivariate model, no relationships were found between ocular findings and serum calcium, phosphorus, ALP, and PTH concentrations. No relationships were found between the serum concentrations of calcium, phosphorus, ALP, and PTH and ocular findings in patients with end stage renal failure undergoing hemodialysis.

Unlabelled: Spasm of blood vessels supplying the optic nerve head is considered one of possible ischaemic mechanisms of glaucomatous optic neuropathy., Purpose: 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., Material and Methods: 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)., Results: 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., Conclusions: 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.

Aims: To examine whether the addition of dorzolamide to timolol monotherapy influences oxygen saturation in the human retina., Methods: Non-invasive spectrophotometric retinal oximetry was used to measure oxygen saturation in retinal vessels. Twenty patients with open-angle glaucoma (11) and ocular hypertension (9) were recruited. The patients were randomised into receiving timolol monotherapy or dorzolamide-timolol combination for an 8-month test period, followed by a second test period, before which the patients switched treatments. Oximetry measurements were performed at 2-month intervals during each period. Of the 20 patients, 13 followed the study protocol into the second test period, and 10 managed all study visits., Results: The oxygen saturation in retinal vessels was stable within the test periods. The mean arteriolar saturation was 96 (2)% (mean (SD)) during timolol monotherapy and 97 (2)% during dorzolamide-timolol combination therapy (p = 0.17, all patients pooled, n = 13). Corresponding values in venules were 66 (5)% during timolol monotherapy and 65 (6)% during dorzolamide-timolol therapy (p = 0.13). Patients who started on dorzolamide-timolol combination showed a significant reduction in arteriolar (98 (2)% to 95 (2)%, p<0.01) and venular saturation (69 (5)% to 66 (6)%, p<0.05) when changing to timolol monotherapy., Conclusion: Adding dorzolamide to timolol monotherapy has a minimal effect, but going from dorzolamide-timolol combination to timolol alone lowered arteriolar and venular oxygen saturation. The retinal oxygen saturation measurements show a high degree of stability over an extended period of time. Previous studies have suggested increased retinal and optic nerve blood flow with dorzolamide. Unchanged oxygen saturation and increased blood flow would indicate increased oxygen delivery to the retina.

Objective: To study the expression of glucocorticoid receptors (alpha and beta) in mononuclear cells of peripheral blood (PBMCs) in patients with glucocorticoid-induced ocular hypertension (GIOH) and the relationship between of the expression of GRalpha and GRbeta in PBMCs and its susceptibility to GIOH., Methods: Case control study. Thirty-two patients with anaphylactic conjunctivitis were enrolled in this study. All of whom were received topical application of 0.1% dexamethasone. The patients with the elevation of intraocular pressure (IOP) over 8 mm Hg(1 mm Hg = 0.133 kPa) or higher within two weeks were defined as GIOH and the others were considered as control group. There were no statistical difference in sex, average age, and baseline IOP between two groups. Each group consisted of sixteen patients. GRalpha and GRbeta mRNA (relative value) in PBMCs were detected with semi-quantitative reverse transcriptional polymerase chain reaction (RT-PCR), GRalpha and GRbeta protein (positive ratio) in PBMCs examined with fluorescent labelling flow cytometry., Results: The GRalpha mRNA/GAPDH ratio of GIOH group was significantly (t = 3.872, P < 0.05) higher than that of control group (1.152 +/- 0.057 vs 1.048 +/- 0.031). The GRbeta mRNA/GAPDH of GIOH group was lower than that of control group's (1.055 +/- 0.034 vs 1.063 +/- 0.035), but was not statistically different (t = 0.419, P > 0.05). GRalpha positive percentage was significantly (t = 8.513, P < 0.01) higher in PBMCs of GIOH group than that of the control group (93.10 +/- 7.35)% vs (46.00 +/- 13.11)%, whereas GRbeta positive percentage was significantly (t = 4.842 P < 0.01) lower in PBMCs of GIOH group than that in control group (12.50 +/- 4.18)% vs (23.83 +/- 3.92)%., Conclusions: The higher expression of GRalpha in PBMCs in patients may have an implication of susceptibility to GIOH and warrant further investigation.

Background: The aim of this study was to gain more information about the possible immunological mechanisms in glaucoma. We analyzed the complex autoantibody patterns against human optic nerve antigens in sera of patients with glaucoma and tried to identify important antigens., Methods: Sera of 133 patients were included: healthy control subjects (n = 44), primary open-angle glaucoma (n = 44), and normal tension glaucoma patients (n = 45). The sera were tested against Western blots of human optic nerve, and antibody bands were visualized with chloronaphthol. IgG antibody patterns were analyzed by multivariate statistical techniques, and the most significant antigens were identified by mass spectrometry (Maldi-TOFTOF)., Results: All subjects, even healthy ones, showed different and complex antibody patterns. Glaucoma groups showed specific up- and down-regulations of antibody reactivities compared to the control group. The multivariate analysis of discriminance found significant differences (P < 0.05) in IgG antibody profiles against human optic nerve antigens between both glaucoma groups and healthy subjects. The identified antigens include: myelin basic protein (up-regulated in the POAG group), glial fibrillary acidic protein (down-regulated in the glaucoma groups), and vimentin (down-regulated in the glaucoma groups in comparison to controls)., Conclusions: Using human optic nerve antigen, we were able to demonstrate that complex IgG autoantibody patterns exist in sera of patients with glaucoma. Large correlations between the given and our previous studies using bovine optic nerve antigens could be seen. Furthermore, anti-myelin basic protein antibodies, which can also be detected in patients with multiple sclerosis, were found in sera of glaucoma patients.

Purpose: To determine the systemic high-sensitivity C-reactive protein (hsCRP) level in patients with normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG)., Materials and Methods: With the exclusion of patients with cardiovascular and other systemic diseases, 40 patients with NTG, 40 with POAG, and 40 normal controls were enrolled in this study. Each patient underwent blood sampling for hsCRP, biochemistry, and lipid profile analysis., Results: Each group had similar demographic parameters including the age, sex, body mass index, heart rate, and blood pressure. There was no statistically significant difference in the hsCRP and biochemistry results between the 3 groups. The lipid profile exhibited a mild elevation in the patients with POAG., Conclusions: Our data revealed no difference in the hsCRP level between NTG, POAG, and normal controls after exclusion of patients with cardiovascular and other systemic diseases. Systemic vascular inflammation may not be a major cause in the pathogenesis of glaucoma in those without histories of cardiovascular diseases.

Purpose: To determine if there is a difference in response of the adrenal gland to intramuscular adrenocorticotropic hormone (ACTH) between normals and ocular hypertensives (OHs) plus primary open-angle glaucomas (POAGs) without pigmented angles., Methods: Intramuscular ACTH was given to 29 normals and 24 OH plus POAG hospitalized in a Clinical Study Unit. Blood samples were obtained at baseline (0 hours) before administration of intramuscular ACTH and 4, 8, and 24 hours after administration of intramuscular ACTH for analysis of plasma cortisol/body mass index (BMI)., Results: The OH plus POAG group showed lower cortisol/BMI values compared with the normal group at 4, 8, and 24 hours with a significantly lower peak/BMI value (P=0.030). Multivariate analyses with the peak plasma cortisol/BMI level as the dependent variable showed that a lower peak plasma/BMI was associated with the OH plus POAG group. Also, a lower peak plasma cortisol/BMI level was associated with a lower 0-hour cortisol/BMI (Log)., Conclusions: Compared with normals, the OH plus POAG subjects showed lower plasma cortisol levels in response to intramuscular ACTH. This observation suggests adrenal suppression in the OH plus OAG group.

Background: The objective was to measure the plasma concentrations of thymulin and nerve growth factor (NGF) in a group of patients with primary open angle glaucoma (POAG) and compare them with age- and sex-matched normal controls., Methods: Twenty-eight patients newly diagnosed with POAG who were not undergoing treatment were compared with the same number of age- and sex-matched healthy controls. Blood samples were drawn into heparinized tubes and plasma samples were collected for the determination of the concentrations of thymulin and NGF, using specific enzyme-linked immunosorbent assay (ELISA). The Student's t test was used to perform the necessary statistical analysis of the results., Results: Seventeen women and 11 men were enrolled in each of the two groups (study and control), with a mean age of 63.7 (SD 10.3) years in the former and 63.3 (SD 9.6) years in the latter. There was a highly significant (p<0.001) elevation in the thymulin levels in POAG patients compared with the control group. However, no significant difference was observed when comparing the plasma NGF levels., Conclusion: This is the first report to measure plasma thymulin levels in glaucoma patients. The significant results point the possible role of this immunomodulator in the pathogenesis of primary open angle glaucoma. The potential role of NGF seems to be less likely. These findings warrant further investigation.

Purpose: To determine if there is a difference in response to metyrapone, which blocks the conversion of 11-deoxycortisol to cortisol in the adrenal gland between normals and ocular hypertensives (OH) plus primary open-angle glaucomas (POAG) without pigmented angles., Methods: Intravenous metyrapone was given to 20 normals and 15 ocular hypertensives plus primary open-angle glaucomas without pigmented angles. Blood samples were obtained at 4, 6, and 8 hours after administration of intravenous metyrapone for analyses of 11-deoxycortisol and cortisol., Results: The ocular hypertensives plus primary open-angle glaucoma group showed significantly lower cortisol values compared with the normal group at 6 hours (P = 0.002) but not at 4 or 8 hours. There were no significant differences between the two groups for 11-deoxycortisol values at 4, 6, or 8 hours. The percent decrease of plasma cortisol from baseline was significantly greater for the ocular hypertensives plus open-angle glaucoma group compared with the normals at 4 hours (P = 0.010) and 6 hours (P = 0.0004). Significant negative correlations were observed for the total group of subjects between levels of plasma cortisol at 6 hours and intraocular pressure, worse eye (P = 0.029), percent area of cupping, worse eye (P = 0.045), pallor, worse eye (P = 0.001), and visual field loss, worse eye (P = 0.048), so that the less the plasma cortisol, the greater the abnormality of the glaucomatous parameters. Multivariate analyses with the 6-hour plasma cortisol level as the dependent variable showed that the only significant (P = 0.0004) independent variable was the percent area of pallor, worse eye, associated with a smaller level of plasma cortisol at 6 hours. Similarly, the multiple regression models using the percent change from baseline of the 6-hour plasma cortisol value showed a significant association of larger percent decreases of plasma cortisol in the ocular hypertensives plus open-angle glaucoma compared with the normals., Conclusions: The ocular hypertensives plus primary open-angle glaucoma subjects show greater adrenal inhibition to metyrapone in the synthesis of cortisol from 11-deoxycortisol compared with normals. This observation suggests an adrenal abnormality in the ocular hypertensive plus primary open-angle glaucoma subjects.

Background: A new long-acting (LA) formulation of carteolol 2% instilled once daily has been shown to provide a therapeutic effect similar to that of the regular formulation of carteolol 2% instilled twice daily. This study was designed to test whether the new formulation reduces the systemic delivery of carteolol., Methods: In this double-masked, randomised, intra-subject comparative study, 23 patients with bilateral primary open-angle glaucoma or bilateral ocular hypertension received sequentially, according to the randomised order of administration, each of the 2 following treatments: carteolol 2% LA once daily for 2 months and carteolol 2% regular twice daily for 2 months. Treatments were instilled in both eyes throughout the study period. At the end of each period of treatment, blood samples were taken immediately before the last morning instillation (residual time), then 30 min, 1 h, 2 h and 4 h after this instillation in order to measure the carteolol plasma concentrations., Results: The mean values of maximal plasma concentration (C(max)), residual level and area under the curve obtained following carteolol 2% LA treatment were significantly lower than the values obtained after carteolol 2% regular treatment (mean+/-SD): C(max) (ng/ml): 1.72+/-0.85 versus 3.64+/-3.65; residual level (ng/ml): 0.70+/-0.58 versus 1.80+/-0.84; area under the curve (ng/mlxh): 5.50+/-2.66 versus 10.27+/-5.46. Regarding safety, two drug-related, non-serious adverse events were reported in the LA group: one case of moderate, superficial, punctate keratitis and one case of "bitter taste in the throat." Both treatments appeared to be well tolerated., Conclusions: The data from this study showed that the systemic delivery of carteolol is lower for the once-daily LA formulation than for the regular twice-daily formulation. Consequently, long-acting carteolol eye-drops should reduce the risk of beta-blocking systemic side effects.

Objectives: The aims of the study were to assess the correlation between the plasma concentration of ophthalmic timolol and cardiovascular parameters, and the influence of timolol on advanced haemodynamic variables, such as stroke (SI), cardiac (CI) and systemic vascular resistance (SVRI) indices and arterial pulse wave velocity (PWV)., Methods: Twenty-five glaucoma or ocular hypertensive patients were treated with 0.5% aqueous and 0.1% hydrogel formulations of timolol using a randomised, double-masked, crossover, multicentre design. All the patients were subjected to passive head-up tilt, electrocardiography, exercise test and measurement of plasma concentration of timolol. In the analysis, the data on the two treatments were combined, and the Spearman correlation coefficients between the plasma level of timolol and physiological effects were calculated., Results: During the head-up tilt test before rising the bed up, the resting heart rate (HR; R=-0.52, P=0.001) and PWV (R=-0.34, P=0.04) were inversely correlated with timolol level. In the upright position, ophthalmic timolol effectively suppressed the rise in HR (R=-0.36, P=0.03). The SI did not change with timolol concentration, while CI diminished as timolol concentration rose (R=-0.39, P=0.02). The SVRI correlated with timolol concentration (R=0.38, P=0.02). In the exercise test, correlation between HR and plasma level of timolol steadily grew stronger as the load increased, reaching R=-0.60 (P<0.0001) at the maximum load. Systolic and diastolic arterial pressures were not associated with the timolol concentration., Conclusion: The plasma concentration of ophthalmic timolol correlates with several haemodynamic effects. As HR decreases, SVRI increases and blood pressure is kept unchanged.

Purpose: To determine if there were significant differences between the number of red blood cell ouabain binding sites in normals and untreated ocular hypertensives plus one open-angle glaucoma patient., Methods: We measured the binding of (3)H ouabain to erythrocyte membranes of 23 normals, 25 ocular hypertensives and one open-angle glaucoma. We also measured the levels of plasma cortisol and digoxin in these subjects. Characteristics of cupping of the optic disc and thickness of the retinal nerve fiber layer, as well as area of optic disc pallor of these subjects were measured by stereophotogrammetry and by computerized image analysis from single and stereo photographs., Results: The number of (3)H ouabain binding sites was observed to be significantly less in the ocular hypertensives and one glaucoma compared to the normals (p = 0.0009). In multi-variate analyses, to determine what other factors affected this difference, there was a significant negative association with mean intraocular pressure (p = 0.003) (average of both eyes) and total cup volume (average of both eyes) (p = 0.005), diagnosis of ocular hypertension and glaucoma (p = 0.0005) and male gender (p = 0.019). There was a significant positive association with plasma cortisol levels (p = 0.048), and diastolic blood pressure (p = 0.037)., Conclusions: The number of (3)H ouabain binding sites in red blood cells decreases significantly with increasing ocular pressure and increasing cup volume indicating the possible presence of an increased systemic endogenous digoxin-like inhibitor and/or difference in the isozymes of Na(+), K(+)-ATPase which may be associated with increased levels of plasma cortisol in ocular hypertensives and glaucomas.

The aim of this study was to test whether immobilization and intravenous volume load as stressors influence the intraocular pressure in rabbits. Rabbits were immobilized for 1 h in a horizontally placed plastic tube with an internal diameter of 13.2 cm and a length of 33.2 cm. After immobilization, rabbits received rapid intravenous drip infusion of 5% glucose solution, 20 ml/kg of body weight, in 5 min. The intraocular pressure immediately after immobilization (11.2 +/- 3.0 mm Hg; mean and standard deviation) was significantly higher compared to control rabbits without immobilization (9.2 +/- 1.0 mm Hg, Student's t test, p = 0.0462). This difference became significantly larger when volume load was exerted on both groups of rabbits (22.7 +/- 5.6 versus 16.4 +/- 2.2 mm Hg, p = 0.0067). Serum levels of cortisol, adrenaline, and noradrenaline were significantly elevated after immobilization (p = 0.0002, p = 0.0271, p = 0.0296, respectively). Venous pressure of the ear tended to increase in rabbits immediately after immobilization (15.8 +/- 3.1 mm Hg) compared with control rabbits (8.5 +/- 2.3 mm Hg), and the difference became significant when volume load was exerted on both groups of rabbits (20.8 +/- 7.4 versus 9.2 +/- 4.8 mm Hg, p = 0.0211). In conclusion, we clearly demonstrated that physical stress due to immobilization, especially in combination with volume load, increased intraocular pressure in rabbits., (Copyright 2000 S. Karger AG, Basel)

Objectives: To examine whether an association exists between long-term use of topical timolol and blood lipids, including high-density lipoprotein cholesterol (HDL-C), cholesterol, and triglycerides, among participants of the Blue Mountains Eye Study., Methods: From 1992 through 1994, a detailed medical and eye examination was performed in 3,654 people aged 49 years or older, representing 82% of permanent residents in two postcode areas west of Sydney. Glaucoma and ocular hypertension were diagnosed, and an ophthalmic history was taken, including use of topical timolol. Fasting blood tests were performed in 89% of subjects. Lipid levels were compared in subjects using topical timolol for at least 1 year with those not using timolol, after excluding people using oral beta-blockers, topical beta1-selective agents, or oral lipid-lowering medications., Results: Analyses compared blood lipids of 63 people who had used topical timolol for at least 1 year with 2,597 nonusers. No statistically significant differences were found in any blood lipid mean levels between treated and untreated people, after multivariate adjustment. However, subgroup analyses of men and women separately showed that male timolol users had a mean value of HDL-C 0.13 mmol/L (11%) lower then the mean value of male nonusers, while female timolol users had a mean value of HDL-C 0.09 mmol/L (5%) higher than the mean for female nonusers. There were no statistically significant associations between timolol treatment duration and HDL-C or other lipid levels. Previously reported adverse effects of oral beta-blockers on blood lipid levels were confirmed., Conclusions: These population-based data suggest that long-term administration of topical timolol for glaucoma or ocular hypertension can cause adverse effects on HDL-C in men, but not in women. The magnitude of the effect in men was similar to that previously described in a number of short-term studies.

Purpose: To compare the effects of 0.5% timolol maleate, 2% carteolol, and 0.3% metipranolol on intraocular pressure (IOP) in 45 patients with primary open-angle glaucoma (POAG) and ocular hypertension. A secondary goal of this study was to evaluate the ocular and systemic side effects of these medications., Methods: Measurements of IOP were taken at baseline (pretreatment) and 2, 6, and 12 hours after instillation on treatment days 15, 30, 60, and 90. Mean sensitivity (MS) and mean defect (MD) values of perimetry before and after treatment and the effects of the three beta blockers on serum lipid profiles were determined. Ocular and systemic side effects were recorded., Results: The most prominent IOP lowering effect was noted with metipranolol at 2 and 6 hours on day 15, and with timolol maleate at 12 hours on day 15 and at all hours of the subsequent days on which measurements were taken. Timolol maleate produced a significant decrease in IOP at 12 hours on day 15 compared with carteolol. There was not a statistically significant difference between the MS and MD values on perimetry before and after treatment for any treatment. There was a statistically significant decrease in levels of total cholesterol and high-density lipoprotein (HDL) cholesterol and a significant increase in triglyceride levels; these changes were observed for all treatments., Conclusion: The effects of the three medications were not statistically different from each other in terms of IOP reduction and visual field changes. Careful monitoring of blood lipid levels is necessary with long-term treatment with beta blockers, because these agents reduced serum levels of HDL and total cholesterol while increasing triglycerides. Such changes in lipid levels could lead to increased incidence of complications, particularly in patients with atherosclerosis or coronary heart disease.

Purpose: Among ocular hypotensive agents, intrinsic sympathomimetic activity (ISA) is unique to carteolol hydrochloride. This study was conducted to evaluate the central nervous system (CNS) and plasma lipid profiles associated with timolol maleate and carteolol hydrochloride in postmenopausal black women with primary open-angle glaucoma (POAG) or ocular hypertension., Methods: One hundred subjects met the inclusion and exclusion criteria for this randomized, double-masked, multicenter, parallel-group study. After completion of informed consent and complete ophthalmic examination, eligible patients entered a washout period, during which no topical ophthalmic medications were used. Blood samples were obtained for hematology and blood chemistry evaluations. Vital signs, ocular symptoms, Symptom Checklist-90-R (SCL-90-R) evaluation, intraocular pressure (IOP) measurements, and slit-lamp examinations were performed before randomization to treatment with either topical carteolol hydrochloride 1.0% or topical timolol maleate 0.5%. Patients received active medications twice daily and were monitored at 4 weeks and 12 weeks. At the conclusion of treatment, vital signs, ocular symptoms, SCL-90-R evaluation, IOP, slit-lamp examinations, and blood samples were obtained., Results: Compared with baseline, high-density lipoprotein (HDL) cholesterol was significantly decreased (worsened) in the timolol group but did not change significantly in the carteolol group. The between-group difference was statistically significant. Total cholesterol to HDL ratio significantly increased (worsened) in the timolol group compared with baseline but did not change in the carteolol group. The difference between groups was statistically significant. No significant differences were observed between groups in SCL-90-R results for either somatization or depression., Conclusions: These results suggest that topical carteolol hydrochloride may have a more favorable blood lipid profile than topical timolol maleate in postmenopausal black women with POAG or ocular hypertension. Carteolol and timolol appear to have similar CNS side effect profiles.

Intraocular pressure dependent reactions of optic nerve head vasculature and intracapillary haemoglobin oxygenation (HbO(2); oxygen saturation) were studied in the center and at the rim of the rabbit optic nerve head (ONH) as well as in the choroid, by a new combination of microendoscopy and simultaneous haemoglobin spectrophotometry. In 13 anesthetized albino rabbits the vasculature and the intracapillary Hb-oxygenation were studied by a microendoscope which was introduced into the eye bulb. Photometric measurements were performed via a beam splitter with the Erlangen micro-lightguide spectrophotometer (EMPHO) from the center of the endoscopic picture. The haemoglobin oxygenation was calculated by real time analysis of the spectral curves. Intraocular pressure was elevated stepwise from 20-80 mmHg. At the rim of the optic nerve head the vascular diameters as well as the intracapillary HbO(2)-values were stable till an intraocular pressure of 60 mmHg and decrease after IOP elevation to 70 and 80 mmHg. In contrast, in the center of the optic nerve head and in the choroid these parameters decline already from 40-50 mmHg on. At an IOP of 60 mmHg (P<0.01) and 70 mmHg (P<0.05) HbO(2)is significantly lower in the ONH center than at the rim. In the center and the choroid HbO(2)is well maintained between 20 and 40 mmHg. After pressure release at the end of the experiment HbO(2)increased to 94.3+/-4.6% (rim) and 98.8+/-1.5% (center) of the initial value at 20 mmHg (difference not significant).By the high spatial resolution of this new optical method we were able to demonstrate that the center of the optic nerve head is more sensitive to changes in intraocular pressure than the optic nerve head rim. Thus, tissue damage after critical haemodynamic and oxygenation parameters seems more probable in the relatively poor perfused center of the ONH than in the overperfused rim., (Copyright 1999 Academic Press.)

Purpose: Although acute dynamic exercise reduces intraocular pressure (IOP), the factors that provoke this response remain ill-defined. To determine whether changes in colloid osmotic pressure (COP) cause the IOP changes during exercise, standardized exercise was performed after dehydration and hydration with isosmotic fluid., Methods: Progressive cycle ergometer exercise to volitional exhaustion was performed after 4 hours' dehydration, and after hydration with 946 ml isosmotic liquid (345 mOsM). In each experiment, venous blood taken before and immediately after exercise was analyzed for hematocrit, plasma protein concentration, total plasma osmolality, and plasma COP., Results: Exercise in both experiments significantly reduced IOP and elevated COP (each P < 0.01). Dehydration, compared with hydration, also significantly reduced IOP and elevated COP, when measured before and after exercise (P < 0.05). The correlation of mean IOP with mean COP, over the entire range created by varying exercise and hydration statuses, was statistically significant (r = -0.99; P < 0.001). In contrast, other indexes of hydration status, including hematocrit, total plasma osmolality, and plasma protein concentration, failed to change as IOP changed and failed to correlate with IOP, on either a group or individual basis, in conditions of varying levels of exercise and hydration., Conclusions: Acute dynamic exercise and isosmotic fluid ingestion each seem to change IOP through changes in COP.

Purpose: To determine the effect on serum lipid levels of carteolol hydrochloride 1.0% or timolol maleate 0.5% given twice a day to women age 60 years and older with primary open-angle glaucoma or ocular hypertension., Method: We included 112 patients in this double-masked, randomized, multicenter trial. Fasting clinical laboratory studies were evaluated at baseline and at 12 weeks. Patients were instructed not to change their dietary, alcohol consumption, or exercise habits during the study., Results: For the carteolol group, the high-density lipoprotein (HDL) and total cholesterol/high-density lipoprotein (TC/HDL) ratio at baseline of 50.1 +/- 1.5 mg/dl and 4.7 +/- 0.2 changed by the 12-week visit to 51.3 +/- 1.9 mg/dl (P = .25) and 4.6 +/- .02 (P = .47), respectively. For the timolol maleate group, the baseline HDL and TC/HDL ratio of 53.6 +/- 2.2 mg/dl and 4.4 +/- 0.2 changed to 50.2 +/- 1.9 mg/dl (P < .001) and 4.7 +/- 0.2 (P = .001), respectively, at the 12-week visit. Carteolol patients showed no significant change from baseline, whereas the HDL (P < .001) and TC/HDL ratio decreased (P = .001) significantly in the timolol maleate group. There also was a significant difference in the change from baseline at 12 weeks between carteolol and timolol maleate groups for the HDL and TC/HDL ratio (P = .01 and .012, respectively). No differences in TC, low-density lipoprotein (LDL), or triglycerides (TG) or in changes from baseline were observed between groups at 12 weeks (P > .05). At 12 weeks, no differences were observed between carteolol and timolol maleate groups in intraocular pressure or safety (P > .05), except that patients given carteolol demonstrated fewer solicited ocular symptoms (P = .007)., Conclusions: Carteolol appears to be neutral in its effect on serum lipid levels, whereas timolol maleate adversely affects the HDL and TC/HDL ratio in women age 60 years and older with ocular hypertension or primary open-angle glaucoma.

Aims: To investigate whether plasma levels of endothelin-1 (ET-1), a potent vasoconstricting peptide that is crucial in regulating retinal blood flow, were elevated in patients with retinal vein occlusion (RVO)., Methods: ET-1 plasma concentrations were determined by radioimmunoassays in a double blind fashion in a group of 18 selected patients with RVO, in 20 healthy age matched non-smoking, normoglycaemic, normotensive control subjects, and in 15 patients with uncomplicated essential hypertension in the same age range., Results: Patients with RVO had significantly increased ET-1 plasma levels (14.22 (SD 4.6) pg/ml) compared with both normal subjects (7.90 (1.6) pg/ml; p < 0.05) and hypertensive patients (8.50 (2.9) pg/ml; p < 0.05). The highest concentrations of circulating ET-1 were found in patients with RVO of the ischaemic type (16.97 (3.5) pg/ml; p < 0.01; n = 7). Systemic hypertension alone did not account for the observed increase in plasma ET-1 concentrations., Conclusions: These findings raise the possibility that the increased circulating ET-1 levels in patients with RVO may be a marker of the occlusive event, thereby suggesting that ET-1 homeostasis may be relevant to RVO pathogenesis and retinal ischaemic manifestations.

Purpose: To detect the mechanism of intraocular pressure elevation during hemodialysis., Methods: We measured intraocular pressure, as well as serum osmolality and plasma CO2 pressure, every 30 min during hemodialysis, in 5 eyes with severely compromised aqueous outflow facility (Group A) from 4 renal failure patients. The same measurements were repeated on the same eyes using intravenous hyperosmotic Glyceol to prevent a rapid change in serum osmolality. We also measured the same parameters on 8 eyes with normal aqueous outflow facility (Group B) from 5 patients. The mean +/- SE of percent changes in each parameter was used for the statistical analysis., Results: In Group A, the mean percent change of intraocular pressure increased significantly after 90 min, with the exception of the change at 180 min. The mean percent change of serum osmolality decreased significantly after starting dialysis. A negative correlation in the mean percent change of intraocular pressure with serum osmolality was detected (r = -0.759, r < 0.0001). The administration of intravenous hyperosmotic agent prevented significant changes in not only serum osmolality but also intraocular pressure. In Group B, the mean percent change in intraocular pressure showed no significant difference at any time, although the change in serum osmolality decreased significantly., Conclusion: A remarkable rise in intraocular pressure occurs during hemodialysis in eyes with an impaired aqueous outflow, when serum osmolality decreases rapidly.

Dorzolamide is a powerful inhibitor of carbonic anhydrase (CA) II that penetrates the sclera and cornea to reach the ciliary process and lowers formation of HCO3 and aqueous humor. The usual dose applied to the eye in treatment of glaucoma is 1 drop (30 microL of 2% solution) every 8 hr to each eye, or a total daily dose of 4 mg. On this regime, the red cells accumulated drug over a period of 8 days, reaching a value of 20-25 microM, which corresponds to the concentration of CA II in human red cells. This drug concentration persisted throughout the 18 months of application. The plasma concentration was 0.034 microM, or 1/700 that of the red cells. This plasma concentration corresponds to that calculated from the dilution of administered drug into body water. The data are well fitted into the equilibrium expression for KI of dorzolamide against CA II at 37 degrees C, as 8 x 10(-9) M. The red cells also contain a small amount (5 microM) of the N-des-ethyl metabolite, probably reflecting its modest binding to CA I. In the initial 8-day drug period, virtually none appeared in the urine since CA II sites were being filled. At steady state, renal excretion was 1.3 mg/day and the renal clearance 90 ml/min. These excretion numbers include the small (20%) amount of the des-ethyl metabolite of dorzolamide. The relation of these data to lowering of intraocular pressure is clear. By the systemic route, an inhibitor such as acetazolamide is effective when free drug concentration in plasma is 2.5 microM. In the case of topical drugs, as shown here, the plasma concentration is some 100 x lower, but the concentration in ciliary process is 2-10 microM, comparable to that following systemic drugs (1). In conclusion, the concentration in plasma (reflecting free drug) of dorzolamide is about 1/200 of that needed for systemic effects as seen following acetazolamide or methazolamide. Thus, there is a clear pharmacological basis for the lack of any physiological effects of ocular dorzolamide, except on the eye itself.

Purpose: To determine whether high-density lipoprotein and total cholesterol levels were risk factors for increased intraocular pressure in patients with chronic open-angle glaucoma or ocular hypertension., Methods: We measured total cholesterol, high-density lipoprotein, and total cholesterol/high-density lipoprotein ratio in 25 patients with open-angle glaucoma or ocular hypertension who had taken no glaucoma medications for four weeks. We individually matched these patients to 25 control subjects who had no history of open-angle glaucoma or ocular hypertension, on the basis of age, race, gender, and history of vascular disease or diabetes mellitus., Results: We found no statistical difference in the high-density lipoprotein (P = .702) or total cholesterol (P = .177) levels or total cholesterol/high-density lipoprotein ratio between groups (P = .178, paired t test)., Conclusion: This study indicates that increased high-density lipoprotein and total cholesterol levels are not risk factors for increased intraocular pressure.

Purpose: To determine whether two topical beta-blockers, timolol and carteolol, differently affect plasma lipids and lipoproteins in normolipidemic Japanese patients with glaucoma., Patients and Methods: Thirty-three normolipidemic patients with primary open-angle glaucoma or ocular hypertension were randomly allocated to and completed 16 weeks of bilateral treatment with 0.5% timolol, 1.0% carteolol, or 2.0% carteolol twice daily in a three-center, prospective study. Patients using any drugs affecting plasma lipids or with a history of beta-blocker use of hyperlipoproteinemia were excluded. Fasting blood lipids and lipoproteins, including total cholesterol, high-density lipoprotein cholesterol, triglyceride, and apoproteins, were measured three times before therapy was initiated. These measurements were repeated every 4 weeks during the treatment period., Results: The level of high-density lipoprotein cholesterol significantly decreased in the timolol treatment group but did not change in the carteolol treatment groups. The ratio of total cholesterol minus high-density lipoprotein cholesterol to high-density lipoprotein cholesterol increased in the timolol treatment group., Conclusions: Topical beta-blockers do affect plasma lipids in Japanese patients with glaucoma. The effects of timolol are greater than those of carteolol.

Intraocular pressure (IOP) in light-dark entrained rabbits changes in a circadian pattern. Previous studies indicate that signals for the circadian IOP elevation in the early dark phase come from the central nervous system (CNS) via the ocular sympathetic nerves. Its neural circuitry in the CNS was totally unclear. In the present study, the role of the suprachiasmatic nucleus in the circuitry was investigated. Adult New Zealand albino rabbits were entrained in a daily 12 hr/12 hr light-dark cycle, and their circadian IOP elevations around the onset of dark were determined. Bilateral lesions of the suprachiasmatic nuclei were made by heat probe and verified by histology. Change in the circadian IOP elevation was monitored for up to 3 months. After the lesion, there was a significant reduction of the circadian IOP elevation for 2 weeks. Elevations in the plasma concentration of melatonin and the aqueous humor concentration of norepinephrine (NE) in the early dark phase were significantly reduced. When exposed to constant light, the residual circadian IOP elevation in the postoperative rabbits was further reduced to the level seen in intact rabbits exposed to constant light. In postoperative weeks 6-10, the circadian IOP elevation returned to the initial value. A full, inhibitory effect of constant light on the circadian IOP elevation was observed. In postoperative months 2-3, concentrations of plasma melatonin and aqueous humor NE regained the circadian pattern. These results indicate that the suprachiasmatic nucleus is in the neural circuitry which propagates the circadian elevation of IOP in rabbits.

Background: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelial cells. ET-1 may have a role in the pathogenesis of various vascular diseases. There are reports in the literature that ET-1 plasma levels are raised in normal-tension glaucoma (NTG) patients., Methods: ET-1 concentration, plasma renin activity, and 24-h blood pressure were measured in 21 high-tension glaucoma (HTG) patients, 19 NTG patients, and 20 non-glaucomatous controls in supine and upright positions., Results: ET-1 plasma levels tended to be higher in NTG patients (3.2 +/- 2.2 pg/ml) than in HTG patients (2.2 +/- 0.6 pg/ml) and controls (2.6 +/- 0.7 pg/ml). The differences, however, were not statistically significant. The individual scatter was significantly greater in the NTG group, indicating that our NTG patients are a heterogeneous population. The physiological increase in ET-1 plasma level after changing from the supine to the upright position was absent in NTG patients. Plasma renin activities tended to be lower in NTG patients (1.2 +/- 1.2 ng/ml/h) than in HTG patients (1.3 +/- 0.8 ng/ml/h) and controls (2.0 +/- 1.7 ng/ml/h). This may explain why NTG patients had relatively low blood pressure despite high ET-1 levels., Conclusions: Our data support the hypothesis that vascular dysfunction may be involved in the pathogenesis of optic nerve damage in normal-tension glaucoma.

Platelet aggregation in vitro, deterioration of visual field defects (VFD) and the prevalence of disc haemorrhages (DH) were assessed in 49 patients with primary open angle glaucoma (POAG) and compared with the findings for 67 individuals with suspected glaucoma (GS) in a seven-year follow-up study (range 5.8 to 8.2 years). The percentage patients with spontaneous platelet aggregation (SPA) was higher for POAG patients with visual field deterioration (60%) than both POAG patients without progressive loss of visual fields (12.5%; P less than 0.005) and those with suspected glaucoma (22.4%; P less than 0.005). The occurrence of DH was higher among POAG patients with progressive loss of visual field (28%) compared to the GS group (8.4%; P less than 0.025) and the group of patients consisting of POAG patients without deterioration of VFD and GS (9.9%; P less than 0.05). DH also occurred more often in patients with low tension glaucoma (41.6%) than in the remaining POAG patients (13.5%; P less than 0.05). No relation between the patients with SPA and the patients with DH was observed.

Total biologic plasma glucocorticoid activity of normal, ocular hypertensive, and open-angle glaucoma patients was compared using a glucocorticoid receptor-based competitive binding assay. Multiple linear-regression analysis was used to adjust for the effects of significant ocular and nonocular variables, including therapy for glaucoma. The glaucoma patients had significantly greater plasma glucocorticoid activities than did normal subjects. A comparison of receptor-based assay values to values obtained with a cortisol radioimmunoassay showed that significant amounts of biologic glucocorticoid activity in the plasma of the glaucoma patients could not be explained by cortisol alone. In the normal and ocular hypertensive groups, however, virtually all of the plasma glucocorticoid activity could be accounted for by cortisol. These results suggest that in open-angle glaucoma patients, noncortisol glucocorticoids are responsible for elevating biologic plasma glucocorticoid activity. Thus, open-angle glaucoma may be associated with a disturbance of the hypothalamic-pituitary-adrenal axis that produces increased plasma levels of both cortisol and other noncortisol glucocorticoids.

In this study platelet aggregation was determined in 79 patients with primary open angle glaucoma (POAG) and 81 patients suspected of having glaucoma (ocular hypertension). There is a positive association between high age and the presence of vascular diseases (p less than 0.01). An age dependent association between spontaneous platelet aggregation (SPA) and the presence of POAG was also observed (p less than 0.05). This indicates that the incidence of SPA in the elder group of patients with POAG is higher than in the elder glaucoma suspect group and in the group of younger patients. The association between vascular diseases and SPA and between vascular diseases and the presence of POAG were not significant at the 5% level. The incidence of SPA is not influenced by sex distribution, by the presence of diabetes, smoking or the use of timolol maleate topically.

We carried out analysis of plasma lipid and lipoprotein levels in 183 patients (92 women and 91 men) referred because of suspected glaucoma. We found an excess of hypertriglyceridemia among the women. Type IV lipoproteinemia was the most common lipoprotein abnormality. Lipid analysis was unhelpful in determining whether glaucoma was present or what type of glaucoma was present. The prevalence of cardiovascular disease was similar among patients with and without a lipoprotein abnormality.

Values of plasma free cortisol (not bound to plasma proteins), total plasma cortisol, and percent free cortisol were determined in normal, ocular hypertensive, and open angle glaucomatous subjects. Median total plasma, plasma free, and percent free cortisol levels were higher in ocular hypertensive and glaucomatous individuals. The most significant differences occurred with percent free cortisol values between normal and glaucomatous subjects. There was a significant positive correlation between percent free cortisol and total cortisol levels in normal subjects only. For subjects with glaucoma and hypertension, the percent free cortisol values were independent of the total cortisol values. Multilinear regression analysis also indicated that besides diagnosis and level of total plasma cortisol, male sex, blood sampling late in the day, and increased diastolic blood pressure were the only variables significantly related to increased values of plasma free cortisol and percent free cortisol. Ocular medication for glaucoma and use of beta-blockers were not found to be significant independent variables in the regression models for either plasma free cortisol or percent free cortisol. These observations further suggest that a disorder of the pituitary adrenal axis and/or a binding of plasma cortisol is associated with ocular hypertension and open angle glaucoma.

Blood viscosity and its determinants were measured in 27 patients with primary open-angle glaucoma, 15 patients with ocular hypertension and 18 healthy control subjects matched for sex, blood pressure and smoking habits. The mean blood viscosity value was significantly higher in the glaucoma group than in the two other groups at all three shear rates studied; there was no difference in viscosity between the hypertension group and the control group. The mean hematocrit value was significantly lower in the hypertension group than in the two other groups. The results suggest that blood viscosity may contribute to nerve damage in patients with primary open-angle glaucoma. The low hematocrit observed in the patients with ocular hypertension may, by contributing to low viscosity, in some measure protect this group from optic nerve damage.