endothelin-1 and Ocular-Hypertension

The roles of vascular dysfunction and chronic stress have been extensively discussed in the pathophysiology of glaucoma. Our aim was to test whether chronic stress causes retinal vascular dysfunction and therewith induces retinal ganglion cells (RGCs) loss.. Twelve mice underwent chronic social defeat (CSD) stress, while 12 mice received control treatment only. Intraocular pressure (IOP) was measured with a rebound tonometer. Blood plasma corticosterone concentration and adrenal gland weight were used to assess stress levels. Brn-3a staining in retinas and PPD staining in optic nerve cross sections were conducted to assess the survival of RGCs and axons respectively. The ET-1 and α-SMA levels were determined in retina. Retinal vascular autoregulation, functional response to various vasoactive agents and vascular mechanics were measured using video microscopy.. No significant difference in IOP levels was observed during and after CSD between CSD mice and controls. CSD stress caused hypercortisolemia 2 days post-CSD. However, increased corticosterone levels went back to normal 8 months after CSD. CSD-exposed mice developed adrenal hyperplasia 3 days post-CSD, which was normalized by 8 months. RGC and axon survival were similar between CSD mice and controls. However, CSD stress caused irreversible, impaired autoregulation and vascular dysfunction of retinal arterioles in CSD mice. In addition, impaired maximal dilator capacity of retinal arterioles was observed 8 months post-CSD rather than 3 days post-CSD. Remarkably, ET-1 levels were increased 3 days post-CSD while α-SMA levels were decreased 8 months post-CSD.. We found that CSD stress does not cause IOP elevation, nor loss of RGCs and their axons. However, it strikingly causes irreversible impaired autoregulation and endothelial function in murine retinal arterioles. In addition, CSD changed vascular mechanics on a long-term basis. Increased ET-1 levels and loss of pericytes in retina vessels may involve in this process.

Topics: Actins; Adrenal Hyperplasia, Congenital; Animals; Cell Survival; Chronic Disease; Corticosterone; Disease Models, Animal; Disorder of Sex Development, 46,XY; Endothelin-1; Intraocular Pressure; Male; Mice; Mice, Inbred C57BL; Ocular Hypertension; Optic Nerve; Retinal Artery; Retinal Diseases; Retinal Ganglion Cells; Social Defeat; Stress, Psychological; Tonometry, Ocular; Transcription Factor Brn-3A; Video Recording

Hypertension is an independent risk factor for diabetic retinopathy, yet anti-hypertensive medications such as blockade of angiotensin II do not completely protect against vision-threatening vascular disease. We hypothesized that the potent vasoactive factor, endothelin (ET), is up-regulated in diabetic retinopathy and antagonism of the ET type A receptor (ETRA) or ET type B receptor (ETRB) ameliorates retinal vascular leakage independently of any blood pressure lowering effects. Spontaneously hypertensive rats (SHR) and their normotensive and genetic controls, Wistar Kyoto rats, were randomized to become diabetic or non-diabetic and studied for 8 weeks. Rats were further randomized to receive by intravitreal injection the ETRA antagonist, BQ123, the ETRB antagonist, BQ788, or vehicle, 5 days after the induction of streptozotocin diabetes and 4 weeks later. The treatments had no effect on systolic blood pressure which remained elevated in SHR. ET-1, ET-2, ETRA and ETRB were expressed in retina and retinal pigment epithelium (RPE)/choroid and increased by hypertension or diabetes. BQ123 reduced ET-1 and ET-2 expression in retina and RPE/choroid, while BQ788 had a similar effect but did not influence the mRNA levels of ET-1 in retina. Retinal vascular leakage and Müller cell stress as well as vascular endothelial growth factor (VEGF) expression in retina and RPE/choroid, were increased by hypertension or diabetes and there was an additive effect of these conditions. Treatment with BQ123 or BQ788 effectively reduced these events as well as the elevated levels of inflammatory factors in the retina. Our findings indicate that local ET systems exist in the retina and RPE/choroid that are up-regulated by hypertension and diabetes. The ability of locally delivered ET receptor antagonists to supress these overactive ET systems and reduce retinal vascular leakage and VEGF in the presence of hypertension indicate the potential of these approaches for the treatment of diabetic retinopathy.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Blood-Retinal Barrier; Choroid; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-2; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Intravitreal Injections; Ocular Hypertension; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Real-Time Polymerase Chain Reaction; Retina; Retinal Pigment Epithelium; Streptozocin

Acute ocular hypertension (AOH) is a condition found in acute glaucoma. The purpose of this study is to investigate the protective effect of Lycium barbarum polysaccharides (LBP) and its protective mechanisms in the AOH insult. LBP has been shown to exhibit neuroprotective effect in the chronic ocular hypertension (COH) experiments. AOH mouse model was induced in unilateral eye for one hour by introducing 90 mmHg ocular pressure. The animal was fed with LBP solution (1 mg/kg) or vehicle daily from 7 days before the AOH insult till sacrifice at either day 4 or day 7 post insult. The neuroprotective effects of LBP on retinal ganglion cells (RGCs) and blood-retinal-barrier (BRB) were evaluated. In control AOH retina, loss of RGCs, thinning of IRL thickness, increased IgG leakage, broken tight junctions, and decreased density of retinal blood vessels were observed. However, in LBP-treated AOH retina, there was less loss of RGCs with thinning of IRL thickness, IgG leakage, more continued structure of tight junctions associated with higher level of occludin protein and the recovery of the blood vessel density when compared with vehicle-treated AOH retina. Moreover, we found that LBP provides neuroprotection by down-regulating RAGE, ET-1, Aβ and AGE in the retina, as well as their related signaling pathways, which was related to inhibiting vascular damages and the neuronal degeneration in AOH insults. The present study suggests that LBP could prevent damage to RGCs from AOH-induced ischemic injury; furthermore, through its effects on blood vessel protection, LBP would also be a potential treatment for vascular-related retinopathy.

Topics: Amyloid beta-Peptides; Animals; Blood-Retinal Barrier; Disease Models, Animal; Down-Regulation; Drugs, Chinese Herbal; Endothelin-1; Gene Expression; Immunoglobulin G; Male; Mice; Mice, Inbred C57BL; Nerve Degeneration; Neuroprotective Agents; Ocular Hypertension; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Retinal Ganglion Cells; Retinal Vessels; Signal Transduction; Tight Junctions

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

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).. 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.. 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.. 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.

Topics: Adult; Aged; Biomarkers; Double-Blind Method; Endothelin-1; Female; Humans; Hypertension; Ischemia; Male; Middle Aged; Ocular Hypertension; Retinal Vein Occlusion; Retinal Vessels