Involvement of Endothelin-1 in the Pathophysiology of Normal-Tension Glaucoma



Tetsuya Sugiyama



Tetsuya Sugiyama, Nakano Eye Clinic of Kyoto Medical Co-operative, 2, Jurakumawari-Higashimachi, Nakagyo-ku, Kyoto 604-8404, Japan

Correspondence to: Tetsuya Sugiyama, MD, PhD, Nakano Eye Clinic of Kyoto Medical Co-operative, 2, Jurakumawari-Higashimachi, Nakagyo-ku, Kyoto 604-8404, Japan.


Telephone: +81-75-801-4151        

Fax: +81-75-822-7423

Received: May 21, 2015                

Revised: June 27, 2015

Accepted: June 29, 2015

Published online: September 6, 2015



In this review, the involvement of endothelin (ET)-1 in the pathophysiology of normal-tension glaucoma (NTG) is summarized. Several ETs were first isolated in Japan in 1988, and were identified as some of the most potent vasoconstrictors. The roles of ETs in the eyes and ocular diseases have been investigated worldwide. ET-1 is a potential participant in the local regulation of several fundamental processes, including intraocular pressure (IOP), ocular blood flow, axonal transport, and neural degeneration. Of these, the effects on IOP are not addressed in this review, and we instead focus on the pathophysiology of NTG. Several studies have reported abnormal plasma ET-1 levels or their response to postural changes in NTG. As a chronic ischemic optic nerve head model induced by ET-1 injections produces retinal ganglion cell-specific cell death and many cellular changes similar to glaucoma, many studies have been conducted on neuroprotection for glaucomatous optic neuropathy using this animal model. Genetic studies on ET receptors have provided evidence that polymorphisms of ETA and ETB receptors may be associated with increased NTG risk. In vitro studies have suggested that ET-1 may cause the death of retinal neurons through glutamate and nitric oxide synthase. ET-1 further affects the functions of glial and lamina cribrosa (LC) cells, and may contribute to remodeling of the extracellular matrix at the LC level in glaucoma. Although few studies have yet obtained promising results showing that ET receptor antagonists can be clinically useful for NTG, blockade of ET receptors is a potentially attractive target for treating this critical ocular disease.


© 2015 ACT. All rights reserved.


Key words: Endothelin-1; Normal-tension glaucoma; Optic nerve head; Ocular blood flow; Glutamate; Nitric oxide synthase; Extracellular matrix collagen; Glial cells


Sugiyama T. Involvement of Endothelin-1 in the Pathophysiology of Normal-Tension Glaucoma. International Journal of Ophthalmic Research 2015; 1(2): 36-40 Available from: URL:



Endothelins (ETs) were first isolated and identified as potent vasoconstrictors by a Japanese research group in 1988[1]. The ET family comprises three isoforms: ET-1, ET-2, and ET-3. ET-1 appears to be the most biologically potent and predominant member of the ET family, and is produced by endothelin-converting enzyme (ECE) from a precursor of ET-1, Big ET-1, in vascular endothelial cells. The production of ET-1 is stimulated by several factors, including tumor necrosis factor-α, thrombin, and transforming growth factor-β1. There are at least 4 known ET receptors: ETA, ETB1, ETB2, and ETC. ETA is a subtype for vasoconstriction that is found in the smooth muscle tissues of blood vessels. ETB1 is located in vascular endothelial cells and mediates vasodilation through the release of other bioactive substances such as nitric oxide. ETB2 mediates vasoconstriction[2]. The function of ETC has not yet been clearly defined. ET receptors are also found in the nervous system where they may mediate neurotransmission. ET-1 has been reported to participate in diverse biological activities, including local blood flow regulation, cell growth, embryonic development, tissue remodeling, inflammation, renal functions, pain, cardiovascular homeostasis, pulmonary functions, and in the release of other active substances[3-6]. Whether ET-1 can penetrate through the blood–ocular barrier has yet to be determined, although the susceptibility of the blood–brain barrier to ET-1 was shown to differ between juveniles and adults in pathological conditions[7]. 

    A few years after ETs discovery, their roles in the eyes were reported by several other research groups[8-10]. One such report revealed the production of ET-1 by cultured bovine retinal endothelial cells and the presence of ET receptors on associated pericytes[8]. Further, another report suggested ET-1 as a potential participant in the local regulation of intraocular pressure (IOP), ocular blood vessel tone, and iris smooth muscle tone, suggesting that it may be an important mediator in the development of ocular pathologic conditions[9].

    Subsequently, many studies have been conducted regarding the role of ET-1 in ocular blood flow, glaucomatous optic neuropathy (GON) with normal IOP, as well as in IOP control and glaucoma with high IOP. However, this review will focus on the former role, and will not address the latter.



A few research groups, including our own, have reported that plasma ET-1 levels may be associated with the pathogenesis of glaucoma, particularly normal-tension glaucoma (NTG)[11-14]. We and Cellini et al found that plasma ET-1 levels were significantly higher in patients with NTG without systemic vascular or circulatory disorders than in normal controls[11,13]. We also demonstrated higher plasma ET-1 levels in NTG patients at the initial stage of visual field loss than in those at the middle stage[11]. Kaiser et al found no physiological increase in ET-1 plasma levels in NTG patients after changing from the supine to upright position, suggesting that vascular dysfunction may be involved in the pathogenesis of optic nerve damage in NTG[12]. A study using color Doppler imaging revealed vascular insufficiency in NTG patients, particularly in the posterior ciliary arteries that provide the blood supply to the optic nerve head (ONH)[13]. Another study indicated that resistivity index in the ophthalmic arteries was positively related to plasma ET-1 levels[14].

    Buckley et al observed increased sensitivity to ET-1 in arteries dissected from the gluteal fat of NTG patients, which could result in enhanced vasoconstriction and contribute to the vasospasm seen in NTG[15]. In addition, Nicolela et al demonstrated that glaucoma patients showed abnormally high plasma ET-1 levels after the body cooled+. Recently, Terelak-Borys et al provided evidence that abnormal neuro-endothelial function was related to the effects of ET-1 via a vasospastic mechanism in NTG patients[17]. The ET-1-dependent vascular dysregulation known as Flammer syndrome[18] may be one of the important causes of NTG. Moreover, Emre et al reported that glaucoma patients (with either normal IOP or normalized IOP after treatment) showing visual field progression had increased plasma ET-1 levels[19]. However, Chen et al found no correlation between plasma levels of ET-1 and the severity of glaucoma[20]. On the other hand, Lee et al indicated that plasma ET-1 levels were associated with heart rate variability in NTG patients, suggesting that the relationship between autonomic dysfunction and autoregulation might play a role in the pathogenesis of NTG[21].



We and another research group independently reported that ET-1 administration induced chronic ONH ischemia with enlarged excavation of the ONH in animal eyes[22-25]. We injected ET-1 into the posterior vitreous of rabbits twice a week for 4 weeks, which induced continuous reduction in ONH blood flow and enlargement of the ONH excavation (Figure 1) as well as axonal loss and demyelination affecting the prelaminar portion of the optic nerve[22,25]. Cioffi et al also observed the ONH excavation and histologic tissue loss in the anterior optic nerve resulting from ischemia induced by ET-1-incorporated mini-pumps in rabbits and primates[23,24]. Stokely et al reported that intravenous ET-1 administration decreased anterograde axonal transport in the rat optic nerve[26]. Prasanna et al further indicated that ET-1 induced astroglial proliferation in cultured human ONH astrocytes through ET receptor activation, suggesting a possible mechanism for the astrogliosis observed in the glaucomatous ONH[27]. Lau et al provided experimental evidence that acute ET-1 injections could produce retinal ganglion cell (RGC)-specific cell death and many cellular changes that are similar to those observed in glaucoma[28]. Taniguchi et al revealed that a single intravitreous injection of ET-1 impaired retrograde axonal transport in the rat optic nerve, which was correlated with the observed histological optic nerve damage[29]. These various findings suggest that ET-1-induced chronic ONH ischemia could be a candidate model of GON. In fact, many researchers have evaluated neuroprotection mechanisms for GON using this animal model[25,30-34]. Munemasa et al suggested that one of the glaucoma agents, unoprostone, had neuroprotective effects against ET-1-induced neuronal injury through phosphorylation of extracellular signal-regulated kinase. However, a majority of the neuroprotective mechanisms have yet to be determined[33].




As described in the Introduction, ETA and ETB receptors seem to be critical receptors for ET. ETA receptor plays an important role in vasoconstriction. ETB receptors mediate both vasodilation (ETB1) and vasoconstriction (ETB2), and some of these effects are due to the release of other bioactive substances such as nitric oxide, prostaglandins, and cytokines. Since ETB receptors are clearance receptors for ET-1, their expression levels are important determinants of the plasma ET-1 concentration[35].

    Researchers in Japan investigated whether gene polymorphisms of ET-1 and its receptors ETA (EDNRA) and ETB (EDNRB) were associated with glaucoma phenotypes and clinical features[36]. The GG genotype of EDNRA/C+70G was associated with worse visual field defects in NTG patients, suggesting that this polymorphism of the ETA receptor may be related to NTG risk. Another study conducted in Korea also revealed that a polymorphism of the ETA gene was associated with NTG[37]. Furthermore, a multi-center study conducted in the United States revealed that EDNRB was associated with early paracentral loss in glaucoma patients, suggesting that genes for the ETB receptor may also be related with a certain type of glaucoma[38].

    Henry et al reported that NTG patients have reduced vasodilatation in response to ETA receptor antagonism, which could be due to attenuated ETA receptor-mediated tone and/or increased ETB receptor-mediated contraction[39]. Resch et al indicated that dual inhibition of ET receptors by bosentan increased ocular blood flow both in patients with glaucoma and in healthy subjects[40]. On the other hand, we suggested that ET-1 may act synergistically with glutamate to damage retinal neurons under hypoxic conditions through ETA receptors[41]. In addition, we verified that ET-1 caused the death of retinal neurons through activation of nitric oxide synthase and production of superoxide anions, which were upregulated by ETA receptor-mediated activation of NADPH oxidase[42,43]. Furthermore, Wang et al demonstrated the immunoreactivity of ETB receptor in GON and its association with astrocytes, suggesting that the glia-ET system may be involved in the pathologic mechanisms of neuronal degeneration in glaucoma[44]. We also reported that blocking the ETB receptors by the selective antagonist BQ-788 rescued RGCs from optic nerve injury, most likely by attenuating neuroinflammation[45]. In addition, Rao et al reported that human lamina cribrosa (LC) cells expressed functional ETA and ETB receptors, and their expression and function were altered in response to prolonged exposure to ET-1, suggesting that elevated ET-1 levels could impact LC function, including extracellular matrix (ECM) collagen synthesis, and may contribute to ECM remodeling at the LC level in glaucoma[46,47]. Based on these findings, I summarize the probable involvement of ET-1 in the pathophysiology of NTG as a schema in Figure 2.




There have been several reports that ET antagonists, particularly ETA receptor antagonists, might be useful for neuroprotection in cerebral ischemic injury[48-52]. The ETA receptor antagonist BQ-123 increased rat hippocampal CA1 neuron survival in gerbils subjected to transient global ischemia[48]. The selective ETA receptor antagonist Ro 61-1790 partially preserved tissue perfusion following focal ischemia, and this effect was associated with significant neuroprotection in a rat model of cerebral ischemia[49]. Another selective ETA receptor antagonist, SB 234551, reduced neurological deficits in rat models of closed head injury and focal stroke[50]. The ETA receptor antagonist BSF-208075 reduced the post-ischemic leukocyte activation and showed a neuroprotective effect[51]. Another specific ETA receptor antagonist, S-0139, provided neuroprotection by suppressing ischemia- and rtPA-triggered molecules in a rat model of middle cerebral artery occlusion[52].

    On the other hand, there have been few reports regarding the neuroprotective effects of ET antagonists for glaucoma. Syed et al provided evidence that the non-selective ET receptor antagonist sulfisoxazole could protect the retina from ischemic-like insults similar to those occurring in glaucoma[53]. Howell et al showed that a novel, orally administered, dual ET receptor antagonist, macitentan, inhibited neurodegeneration in a mouse model of glaucoma[54]. Therefore, considering the current knowledge on the potential involvement of ET-1 in the pathogenesis of NTG, the use of a blockade of ET receptors may be an attractive target for NTG treatment, although further studies are required to confirm these effects and mechanisms. However, it should be noted that ET antagonists might induce side effects, including hepatic dysfunction, peripheral edema, and interstitial pneumonia, when applied systemically[55], although the toxicity of their topical application remains to be verified. In addition, ECE inhibitors might also be potential candidates for glaucoma therapy, although their neuroprotective effects remain to be investigated.



In this article, the involvement of ET-1 and ET receptors in the pathophyisiology of NTG was summarized, and the potential of the application of ET antagonists for NTG treatment was discussed.



I am grateful to my deceased mentor, Professor Emeritus Ikuo Azuma. I would also like to express my appreciation to Professor Tsunehiko Ikeda, Associate Professor Hidehiro Oku, and other colleagues for their warm-hearted collaboration at the Department of Ophthalmology in Osaka Medical College (Takatsuki, Osaka, Japan).



The author has no conflicts of interest to declare.



1        Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1988; 332: 411-415.

2        Sudjarwo SA, Hori M, Takai M, Urade Y, Okada T, Karaki H. A novel subtype of endothelin B receptor mediating contraction in swine pulmonary vein. Life Sci 1993; 53: 431-437.

3        Takuwa Y, Yanagisawa M, Takuwa N, Masaki T. Endothelin, its diverse biological activities and mechanisms of action. Prog Growth Factor Res 1989; 1: 195-206.

4        Krämer BK, Nishida M, Kelly RA, Smith TW. Endothelins. Myocardial actions of a new class of cytokines. Circulation 1992; 85: 350-356.

5        Battistini B, Forget MA, Laight D. Potential roles for endothelins in systemic inflammatory response syndrome with a particular relationship to cytokines. Shock 1996; 5: 167-183.

6        Gensini GF, Conti AA, Prisco D. Endothelins: an overview of recent achievements. Ann Ital Med Int 1998; 13: 88-92.

7        Harati R, Villégier A, Banks WA, Mabondzo A. Susceptibility of juvenile and adult blood–brain barrier to endothelin-1: regulation of P-glycoprotein and breast cancer resistance protein expression and transport activity. J Neuroinflammation 2012; 9: 273.

8        Takahashi K, Brooks RA, Kanse SM, Ghatei MA, Kohner EM, Bloom SR. Production of endothelin 1 by cultured bovine retinal endothelial cells and presence of endothelin receptors on associated pericytes. Diabetes 1989; 38: 1200-1202.

9        MacCumber MW, Jampel HD, Snyder SH. Ocular effects of the endothelins. Abundant peptides in the eye. Arch Ophthalmol 1991; 109: 705-709.

10    Haefliger IO, Flammer J, Lüscher TF. Nitric oxide and endothelin-1 are important regulators of human ophthalmic artery. Invest Ophthalmol Vis Sci 1992; 33: 2340-2343.

11    Sugiyama T, Moriya S, Oku H, Azuma I. Association of endothelin-1 with normal tension glaucoma: clinical and fundamental studies. Surv Ophthalmol 1995; 39 Suppl 1: S49-S56.

12    Kaiser HJ, Flammer J, Wenk M, Lüscher T. Endothelin-1 plasma levels in normal-tension glaucoma: abnormal response to postural changes. Graefes Arch Clin Exp Ophthalmol 1995; 233: 484-488.

13    Cellini M, Possati GL, Profazio V, Sbrocca M, Caramazza N, Caramazza R. Color Doppler imaging and plasma levels of endothelin-1 in low-tension glaucoma. Acta Ophthalmol Scand Suppl 1997; 224: 11-13.

14    Galassi F, Giambene B, Varriale R. Systemic vascular dysregulation and retrobulbar hemodynamics in normal-tension glaucoma. Invest Ophthalmol Vis Sci 2011; 52: 4467-4471.

15    Buckley C, Hadoke PW, Henry E, O'Brien C. Systemic vascular endothelial cell dysfunction in normal pressure glaucoma. Br J Ophthalmol 2002; 86: 227-232.

16    Nicolela MT, Ferrier SN, Morrison CA, Archibald ML, LeVatte TL, Wallace K, Chauhan BC, LeBlanc RP. Effects of cold-induced vasospasm in glaucoma: the role of endothelin-1. Invest Ophthalmol Vis Sci 2003; 44: 2565-2572.

17    Terelak-Borys B, Czechowicz-Janicka K.Investigation into the vasospastic mechanisms in the pathogenesis of glaucomatous neuropathy. Klin Oczna 2011; 113: 201-208.

18    Konieczka K, Ritch R, Traverso CE, Kim DM, Kook MS, Gallino A, Golubnitschaja O, Erb C, Reitsamer HA, Kida T, Kurysheva N, Yao K. Flammer syndrome. EPMA J 2014; 5: 11.

19    Emre M, Orgül S, Haufschild T, Shaw SG, Flammer J. Increased plasma endothelin-1 levels in patients with progressive open angle glaucoma. Br J Ophthalmol 2005; 89: 60-63.

20    Chen HY, Chang YC, Chen WC, Lane HY: Association between plasma endothelin-1 and severity of different types of glaucoma. J Glaucoma, 2013, 22:117–122.

21    Lee NY, Park HY, Na KS, Park SH, Park CK. Association between heart rate variability and systemic endothelin-1 concentration in normal-tension glaucoma. Curr Eye Res 2013; 38: 516-519.

22    Oku H, Sugiyama T, Kojima S, Watanabe T, Azuma I. Experimental optic cup enlargement caused by endothelin-1-induced chronic optic nerve head ischemia. Surv Ophthalmol 1999; 44 Suppl 1: S74-S84.

23    Cioffi GA, Sullivan P. The effect of chronic ischemia on the primate optic nerve. Eur J Ophthalmol 1999; 9 Suppl 1: S34-S36.

24    Cioffi GA, Wang L, Fortune B, Cull G, Dong J, Bui B, Van Buskirk EM. Chronic ischemia induces regional axonal damage in experimental primate optic neuropathy. Arch Ophthalmol 2004; 122: 1517-1525.

25    Sugiyama T, Mashima Y, Yoshioka Y, Oku H, Ikeda T. Effect of unoprostone on topographic and blood flow changes in the ischemic optic nerve head of rabbits. Arch Ophthalmol 2009; 127: 454-459.

26    Stokely ME, Brady ST, Yorio T. Effects of endothelin-1 on components of anterograde axonal transport in optic nerve. Invest Ophthalmol Vis Sci 2002; 43: 3223-3230.

27    Prasanna G, Krishnamoorthy R, Clark AF, Wordinger RJ, Yorio T. Human optic nerve head astrocytes as a target for endothelin-1. Invest Ophthalmol Vis Sci 2002; 43: 2704-2713.

28    Lau J, Dang M, Hockmann K, Ball AK. Effects of acute delivery of endothelin-1 on retinal ganglion cell loss in the rat. Exp Eye Res 2006; 82: 132-145.

29    Taniguchi T, Shimazawa M, Sasaoka M, Shimazaki A, Hara H. Endothelin-1 impairs retrograde axonal transport and leads to axonal injury in rat optic nerve. Curr Neurovasc Res 2006; 3: 81-88.

30    Kim TW, Kim DM, Park KH, Kim H. Neuroprotective effect of memantine in a rabbit model of optic nerve ischemia. Korean J Ophthalmol 2002; 16: 1-7.

31    Goto W, Oku H, Okuno T, Sugiyama T, Ikeda T. Amelioration of endothelin-1-induced optic nerve head ischemia by topical bunazosin. Curr Eye Res 2005; 30: 81-91.

32    Aktaş Z, Gürelik G, Akyürek N, Onol M, Hasanreisoğlu B. Neuroprotective effect of topically applied brimonidine tartrate 0.2% in endothelin-1-induced optic nerve ischaemia model. Clin Experiment Ophthalmol 2007; 35: 527-534.

33    Munemasa Y, Kitaoka Y, Hayashi Y, Takeda H, Fujino H, Ohtani-Kaneko R, Hirata K, Ueno S. Effects of unoprostone on phosphorylated extracellular signal-regulated kinase expression in endothelin-1-induced retinal and optic nerve damage. Vis Neurosci 2008; 25: 197-208.

34    Sugiyama T, Shibata M, Kajiura S, Okuno T, Tonari M, Oku H, Ikeda T. Effects of fasudil, a Rho-associated protein kinase inhibitor, on optic nerve head blood flow in rabbits. Invest Ophthalmol Vis Sci 2011; 52: 64-69.

35    Fukuroda T, Fujikawa T, Ozaki S, Ishikawa K, Yano M, Nishikibe M. Clearance of circulating endothelin-1 by ETB receptors in rats. Biochemical and Biophysical Research Communications. 1994; 199: 1461–1465.

36    Ishikawa K, Funayama T, Ohtake Y, Kimura I, Ideta H, Nakamoto K, Yasuda N, Fukuchi T, Fujimaki T, Murakami A, Asaoka R, Hotta Y, Kanamoto T, Tanihara H, Miyaki K, Mashima Y. Association between glaucoma and gene polymorphism of endothelin type A receptor. Mol Vis 2005; 11: 431-437.

37    Kim SH, Kim JY, Kim DM, Ko HS, Kim SY, Yoo T, Hwang SS, Park SS. Investigations on the association between normal tension glaucoma and single nucleotide polymorphisms of the endothelin-1 and endothelin receptor genes. Mol Vis 2006; 12: 1016-1021.

38    Kang JH, Loomis SJ, Yaspan BL, Bailey JC, Weinreb RN, Lee RK, Lichter PR, Budenz DL, Liu Y, Realini T, Gaasterland D, Gaasterland T, Friedman DS, McCarty CA, Moroi SE, Olson L, Schuman JS, Singh K, Vollrath D, Wollstein G, Zack DJ, Brilliant M, Sit AJ, Christen WG, Fingert J, Forman JP, Buys ES, Kraft P, Zhang K, Allingham RR, Pericak-Vance MA, Richards JE, Hauser MA, Haines JL, Wiggs JL, Pasquale LR. Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma. Eye (Lond) 2014; 28: 662-671.

39    Henry E, Newby DE, Webb DJ, Hadoke PW, O'Brien CJ. Altered endothelin-1 vasoreactivity in patients with untreated normal-pressure glaucoma. Invest Ophthalmol Vis Sci 2006; 47: 2528-2532.

40    Resch H, Karl K, Weigert G, Wolzt M, Hommer A, Schmetterer L, Garhöfer G. Effect of dual endothelin receptor blockade on ocular blood flow in patients with glaucoma and healthy subjects. Invest Ophthalmol Vis Sci 2009; 50: 358-363.

41    Kobayashi T, Oku H, Fukuhara M, Kojima S, Komori A, Ichikawa M, Katsumura K, Kobayashi M, Sugiyama T, Ikeda T. Endothelin-1 enhances glutamate-induced retinal cell death, possibly through ETA receptors. Invest Ophthalmol Vis Sci 2005; 46: 4684-4690.

42    Oku H, Fukuhara M, Komori A, Okuno T, Sugiyama T, Ikeda T. Endothelin-1 (ET-1) causes death of retinal neurons through activation of nitric oxide synthase (NOS) and production of superoxide anion. Exp Eye Res 2008; 86: 118-130.

43    Matsuo J, Oku H, Kanbara Y, Kobayashi T, Sugiyama T, Ikeda T. Involvement of NADPH oxidase and protein kinase C in endothelin-1-induced superoxide production in retinal microvessels. Exp Eye Res 2009; 89: 693-699

44    Wang L, Fortune B, Cull G, Dong J, Cioffi GA. Endothelin B receptor in human glaucoma and experimentally induced optic nerve damage. Arch Ophthalmol 2006; 124: 717-724.

45    Tonari M, Kurimoto T, Horie T, Sugiyama T, Ikeda T, Oku H. Blocking endothelin-B receptors rescues retinal ganglion cells from optic nerve injury through suppression of neuroinflammation. Invest Ophthalmol Vis Sci 2012; 53: 3490-3500.

46    Rao VR, Krishnamoorthy RR, Yorio T. Endothelin-1, endothelin A and B receptor expression and their pharmacological properties in GFAP negative human lamina cribrosa cells. Exp Eye Res 2007; 84: 1115-1124.

47    Rao VR, Krishnamoorthy RR, Yorio T. Endothelin-1 mediated regulation of extracellular matrix collagens in cells of human lamina cribrosa. Exp Eye Res 2008; 86: 886-894.

48    Feuerstein G, Gu JL, Ohlstein EH, Barone FC, Yue TL. Peptidic endothelin-1 receptor antagonist, BQ-123, and neuroprotection. Peptides 1994; 15: 467-469.

49    Dawson DA, Sugano H, McCarron RM, Hallenbeck JM, Spatz M. Endothelin receptor antagonist preserves microvascular perfusion and reduces ischemic brain damage following permanent focal ischemia. Neurochem Res 1999; 24: 1499-1505.

50    Barone FC, Ohlstein EH, Hunter AJ, Campbell CA, Hadingham SH, Parsons AA, Yang Y, Shohami E. Selective antagonism of endothelin-A-receptors improves outcome in both head trauma and focal stroke in rat. J Cardiovasc Pharmacol 2000; 36: S357-S361.

51    Hauck EF, Hoffmann JF, Heimann A, Kempski O. Endothelin A receptor antagonist BSF-208075 causes immune modulation and neuroprotection after stroke in gerbils. Brain Res 2007; 1157: 138-145.

52    Zhang RL, Zhang C, Zhang L, Roberts C, Lu M, Kapke A, Cui Y, Ninomiya M, Nagafuji T, Albala B, Zhang ZG, Chopp M. Synergistic effect of an endothelin type A receptor antagonist, S-0139, with rtPA on the neuroprotection after embolic stroke. Stroke 2008; 39: 2830-2836.

53    Syed H, Safa R, Chidlow G, Osborne NN. Sulfisoxazole, an endothelin receptor antagonist, protects retinal neurones from insults of ischemia/reperfusion or lipopolysaccharide. Neurochem Int 2006; 48: 708-717.

54    Howell GR, MacNicoll KH, Braine CE, Soto I, Macalinao DG, Sousa GL, John SW. Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma. Neurobiol Dis 2014; 71: 44-52.

55    Rosenthal R and Fromm M. Endothelin antagonism as an active principle for glaucoma therapy. Br J Pharmacol 2011; 162: 806–816.


Peer reviewers: Petia Nikolova Kupenova, Associate Professor, Deptartmenet of Physiology, Medical University-Sofia, 1 G Sofiiski St, 1431, Sofia, Bulgaria; Alime Güneş, Department of Ophthalmology, Süleyman Demirel University, Faculty of Medicine, The East Campus, Cünür, Isparta, 32260, Turkey.



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