Regulation of outflow rate and resistance in the perfused anterior segment of the bovine eye

Wiederholt, Michael; Bielka, Simone; Schweig, Friederice; Lütjen–Drecoll, Elke; Lepple-Wienhues, Albrecht

doi:10.1016/s0014-4835(05)80042-9

Cited by 92 publications

(83 citation statements)

References 24 publications

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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(Wiederholt et al, 1995;Llobet et al, 1999) or do not modify it (Up 4 U and ATP; this study and D. Soto and X. Gasull, unpublished observations). Large and long-lasting Ca 2ϩ increases may lead to cellular contraction or activation of different intracellular pathways, producing a decrease in TM permeability and thus reducing outflow facility.…”

Section: Discussionmentioning

confidence: 57%

“…Large and long-lasting Ca 2ϩ increases may lead to cellular contraction or activation of different intracellular pathways, producing a decrease in TM permeability and thus reducing outflow facility. In fact, TM contractions have been described after application of carbachol or endothelin-1, known also to decrease outflow facility (Wiederholt et al, 1995(Wiederholt et al, , 2000.…”

Section: Discussionmentioning

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: 57%

Section: Discussionmentioning

confidence: 99%

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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“…Currently, application of ocular hypotensive drugs is the mainstream approach to glaucoma therapy, and extensive efforts have been made to develop anti-glaucoma drugs that lower IOP. These drugs are intended either to modulate aqueous humor outflow at sites in the trabecular meshwork or ciliary muscle, [1][2][3][4][5] or to inhibit the production of aqueous humor by the ciliary body. Aqueous humor outflow consists of conventional trabecular meshwork outflow and unconventional uveoscleral outflow.…”

mentioning

confidence: 99%

Effects of the New Ethacrynic Acid Derivative SA9000 on Intraocular Pressure in Cats and Monkeys

Shimazaki

Ichikawa

Rao

et al. 2004

Biological & Pharmaceutical Bulletin

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In glaucoma, the second most common cause of blindness, an elevated intraocular pressure (IOP) is one of the risk factors for damage to the optic nerve. Currently, application of ocular hypotensive drugs is the mainstream approach to glaucoma therapy, and extensive efforts have been made to develop anti-glaucoma drugs that lower IOP. These drugs are intended either to modulate aqueous humor outflow at sites in the trabecular meshwork or ciliary muscle, [1][2][3][4][5] or to inhibit the production of aqueous humor by the ciliary body. Aqueous humor outflow consists of conventional trabecular meshwork outflow and unconventional uveoscleral outflow. It has been proposed that TM plays the major role in the regulation of normal aqueous humor outflow to maintain normal range of IOP. [6][7][8][9] At present, many ocular hypotensive agents that modulate uveoscleral outflow (such as the prostaglandin derivatives) are in use as anti-glaucoma drugs. In contrast, there are no drugs that act directly on the trabecular meshwork to increase conventional outflow, even though this constitutes approximately 90% of the normal eye's total aqueous outflow. 10)Thus, an effective modulator of conventional outflow might be capable of exerting a powerful ocular hypotensive effect and be of great value as a next-generation ocular hypotensive drug.Ethacrynic acid (ECA) is well known as a sulfhydryl (SH) reactive diuretic and a NaϪ co-transport system inhibitor, 11,12) and it has been observed to increase aqueous humor outflow and lower IOP. ECA has been reported to increase aqueous humor outflow facility in enucleated animal and human eyes and in living monkey eyes, [13][14][15][16][17] and these effects have been correlated with changes in human trabecular meshwork cell shape and cytoskeleton in vitro.18) IOP lowering also has been observed in living human eyes with glaucoma. 19) ECA thus seems to have the potential to become an ocular hypotensive agent by its targeting of the trabecular meshwork, a site at which it seems to cause reversible changes in both cell shape and attachment.18) Nevertheless, because of its possible ocular side effects, there is a need for derivatives of ECA with even greater ocular safety 16,17) and corneal penetration. 20) To broad the therapeutic index, which is shown as the ratio of doses between the IOP reducing effects and potential side effects, may lead to find the clinically useful ocular hypotensive drugs. We, therefore, synthesized thirty-two compounds and evaluated ECA derivatives that might retain the strong cytoskeletal modulating activity of ECA while having a lower cytotoxicity potential, i.e. a broader therapeutic index. The structural modifications of ECA examined involved both the phenoxyacetic acid and the acryloyl moieties. Among these, we found a new ECA derivative, SA9000, which appeared to have a broader therapeutic index. In the present study, we examined the effects of SA9000 on IOP in cats and monkeys, and also evaluated changes in corneal endothelial and epithelial morphology as surrog...

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“…In organ cultured bovine eyes in which the iris, ciliary body and ciliary muscle are removed, ET-1 at concentrations of 2 and 20 nM inhibited outflow relative to baseline by ±30% (Wiederholt et al 1995). Thus, the reported ET-1 effects on facility could be primarily either ciliary muscle-or trabecular meshwork-based, and the direction of the response could be variable.…”

Section: Discussionmentioning

confidence: 97%

“…Human ciliary muscle contracted more sluggishly to ET-1, producing a maximum of 37% of the carbacholinduced contraction. (Lepple-Wienhues et al 1992) ET-1 induced TM contraction, in the perfused bovine anterior segment in organ culture, inhibited baseline outflow by ±30% (Wiederholt et al 1995).…”

mentioning

confidence: 90%

Endothelin‐1 effects on aqueous humor dynamics in monkeys

Millar

Gabelt

Hubbard

et al. 1998

Acta Ophthalmologica Scandinavica

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ABSTRACT.Purpose: To report data showing no effect of endothelin-1 on aqueous humor formation and total outflow facility in the cynomolgus monkey, in contrast to the enhancement of outflow facility in monkeys and the suppression of aqueous humor flow in rabbits previously reported by others. Methods: Living monkeys received, unilaterally: (i) intracameral endothelin-1 (10 ml bolus, or 2ml or 4ml exchange; final intracameral concentration 1 or 10 nM) with total outflow facility measured for up to 1 hr post-treatment by twolevel constant pressure perfusion, and (ii) intravitreal endothelin-1 (20 ml, final intravitreal concentration 0.1 or 1 mM) with aqueous humor flow measured by scanning fluorophotometry for 5 hr starting 12 hr post-treatment. Contralateral eyes received vehicle. Results: Endothelin-1 had no effect on total outflow facility or aqueous humor flow with any of the methods described. Conclusion: Endothelin-1 seems have a variable effect on aqueous humor dynamics within and between species.

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Regulation of outflow rate and resistance in the perfused anterior segment of the bovine eye

Cited by 92 publications

References 24 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

Effects of the New Ethacrynic Acid Derivative SA9000 on Intraocular Pressure in Cats and Monkeys

Endothelin‐1 effects on aqueous humor dynamics in monkeys

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