Modulation of Aqueous Humor Outflow by Ionic Mechanisms Involved in Trabecular Meshwork Cell Volume Regulation

Soto, David; Comes, Núria; Ferrer, Elisa; Morales, Miguel; Escalada, Artur; Palés, Jorge; Solsona, Carles; Gual, Arcadi; Gasull, Xavier

doi:10.1167/iovs.04-0060

Cited by 63 publications

(95 citation statements)

References 36 publications

(63 reference statements)

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“…2 and 3) (Crosson et al, 2004;Soto et al, 2004), bradykinin (Llobet et al, 1999), and carbachol (Shade et al, 1996). Interestingly, drugs that induce large and sustained Ca 2ϩ mobilizations either decrease outflow facility (bradykinin, carbachol, and endothelin-1) (Wiederholt et al, 1995;Llobet et al, 1999) or do not modify it (Up 4 U and ATP; this study and D. Soto and X. Gasull, unpublished observations).…”

Section: Discussionmentioning

confidence: 59%

“…Other mechanisms proposed as playing important roles in TM function include changes in extracellular matrix (Tian et al, 2000), up-regulation/down-regulation of genes (Borras, 2003), and changes in cell shape (Gills et al, 1998) or cell volume (Al-Aswad et al, 1999;Soto et al, 2004). It is possible that dinucleotides could modify some of these parameters such as cell volume, as proposed for other compounds (Fleischhauer et al, 2003;Srinivas et al, 2004).…”

Section: Dinucleotide Effects In Aqueous Humormentioning

confidence: 99%

“…In the eye, P2Y receptors have been found in different tissues, including retina, ciliary body, cornea, conjunctiva, choroids, and optic nerve head (Cowlen et al, 2003;Pintor et al, 2003b). Moreover, it is known that TM cells release ATP upon stimulation with hypotonic stimuli (Cui et al, 2001;Fleischhauer et al, 2003;Soto et al, 2004) or shear stress (Cui et al, 2001), and recently the presence of purinergic P2Y receptors has also been found in a human TM cell line (Crosson et al, 2004). However, a detailed study of the effects of purinergic receptor activation on outflow facility has yet to be conducted.…”

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confidence: 99%

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Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Soto¹,

Pintor²,

Peral³

et al. 2005

J Pharmacol Exp Ther

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The most important risk factor for the development of glaucoma is elevated intraocular pressure (IOP). Hypotensive drugs decrease IOP, preventing optic nerve damage and further vision loss. The balance between aqueous humor (AH) production and drainage determines IOP, and problems in AH outflow pathways are associated with open-angle glaucoma development. Previous studies have shown the presence of diadenosine tetraphosphate (Ap 4 A) and pentaphosphate (Ap 5 A) in the AH. Topic application of Ap 4 A to the cornea decreased IOP, whereas Ap 5 A increased it. Because dinucleoside polyphosphates stimulate P2Y purinergic receptors, we studied their presence in trabecular meshwork (TM) cells. Additionally, the effects of diadenosine polyphosphates (Ap n As; n ϭ 3-5) and Up 4 U (P 1 ,P 4 -(diuridine 5Ј)-tetraphosphate; INS365) in outflow facility were tested. P2Y 1 , P2Y 2 , and P2Y 4 receptors were detected in TM cells by Western blot and immunocytochemistry. In TM cells, Ap 3 A, Ap 4 A, and Ap 5 A induced discrete intracellular calcium concentration ([Ca 2ϩ ] i ) mobilizations compared with higher and more sustained [Ca 2ϩ ] i mobilizations after Up 4 U application. In bovine ocular anterior segments perfused at constant pressure, 1 M Ap 3 A or Ap 4 A increased outflow facility, whereas Up 4 U or Ap 5 A did not modify it. 2-MeSADP, a selective P2Y 1 agonist, induced outflow facility increases similar to those obtained after Ap 3 A and Ap 4 A, and these were prevented by addition of the selective P2Y 1 receptor antagonist MRS-2179 (2Ј-deoxy-N 6 -methyladenosine-3Ј,5Ј-diphosphate). Our results demonstrate that the hypotensive effect of Ap 4 A and other dinucleotides is mediated, at least in part, by increasing trabecular outflow facility through activation of P2Y 1 receptors. The latter would seem to be an interesting target in the development of antiglaucomatous drugs to selectively increase AH outflow.In the eye, elevated intraocular pressure (IOP) due to impaired aqueous humor (AH) drainage is a major risk factor in the development of glaucoma. Glaucoma is the most important cause of irreversible nontraumatic blindness in the world and affects more than 66 million people. The main determinant of IOP is the volume of AH contained in the anterior and posterior chambers. AH is produced in the ciliary epithelium and eliminated through the outflow pathways in the anterior chamber angle. In several species, but especially in the primate eye, most AH flows through the trabecular meshwork (TM), a sponge-like filtering tissue, where it reaches Schlemm's canal and the collector channels before finally entering the venous system. The structure of the TM and its ability to modify its resistance to AH outflow play a key role in maintaining the IOP in the anterior chamber within its physiological range. TM cells express several receptors to substances released either in the AH from different ocular tissues (Mitchell et al., 1998;Coca-Prados et al., 1999) or from ocular innervation (Selbach et al., 2000) in physiologic...

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Section: Discussionmentioning

confidence: 59%

Section: Dinucleotide Effects In Aqueous Humormentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Soto¹,

Pintor²,

Peral³

et al. 2005

J Pharmacol Exp Ther

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“…Moreover, this effect has been linked to the presence of P2Y 1 receptors in the place when the aqueous humour is drained, the trabecular meshwork [33]. On the other hand, the effect on P2Y 6 has also been described and moreover, it has been suggested that it is connected to a change in the ciliary body blood vessels [29].…”

Section: Discussionmentioning

confidence: 99%

Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

Fonseca

Martínez-Águila

Lara

et al. 2016

Purinergic Signalling

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Glaucoma is a neurodegenerative disease that produces blindness. The main factor associated with this disease is an abnormally elevated intraocular pressure (IOP). To date, some attempts have been made to demonstrate the role of nucleotides modulating IOP, but never in a model of glaucoma. The DBA/2J mouse is an animal that develops the pathology spontaneously, starting from the typical rise in IOP at 9 months of age. Using this animal model, together with a control mouse, C57BL/6J, it has been possible to monitor the elevation in IOP in the glaucomatous mice and to check the ability of the dinucleotide diadenosine tetraphosphate AKA Ap 4 A to reduce IOP. The topical application of Ap 4 A when IOP is maximal (9-12 months) reduced IOP 30.6 ± 6.6% in the DBA/2J and 17.9 ± 4.0% in the C57BL/ 6J mice. Concentration response curves in both animal strains produced similar pD2 values; these being 4.9 ± 0.5 and 5.1 ± 0.4 for the normotensive C57BL/6J and the glaucomatous DBA/2J respectively. Antagonist studies showed differences between the control and the glaucomatous animals. In particular, the main receptor reducing IOP in the control animal was the P2Y 1 receptor and in the glaucomatous model the P2Y 6 , although the participation of other P2 receptors cannot be ruled out. The long-term effect of Ap 4 A applied three times a week for 3 months showed a clear stop in the elevation of IOP in the glaucomatous model, thus indicating the possibility of using Ap 4 A as an effective compound for the treatment of glaucoma.

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“…Intracellular calcium concentration ([Ca 2+ ] i ) was measured as described in detail previously (Bataller et al, 2001;Soto et al, 2004). Briefly, BV2 cells were plated on 25-mm diameter glass coverslips (VWR Scientific Inc., Philadelphia, PA) and then loaded with 4 µM fura-2/acetoxymethyl ester (Calbiochem, San Diego, CA)…”

Section: Measurement Of Cytosolic-free Ca 2+ and Stimulation Of Vgccmentioning

confidence: 99%

The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity

Espinosa-Parrilla

Martínez-Moreno

Gasull

et al. 2015

Molecular and Cellular Neuroscience

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Modulation of Aqueous Humor Outflow by Ionic Mechanisms Involved in Trabecular Meshwork Cell Volume Regulation

Cited by 63 publications

References 36 publications

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Effects of Dinucleoside Polyphosphates on Trabecular Meshwork Cells and Aqueous Humor Outflow Facility

Diadenosine tetraphosphate as a potential therapeutic nucleotide to treat glaucoma

The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity

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