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M. M. Civan - One of the best experts on this subject based on the ideXlab platform.
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Basis of Chloride Transport in Ciliary Epithelium
The Journal of Membrane Biology, 2004Co-Authors: C.w. Do, M. M. CivanAbstract:The Aqueous Humor is formed by the bilayered ciliary epithelium. The pigmented ciliary epithelium (PE) faces the stroma and the nonpigmented ciliary epithelium (NPE) contacts the Aqueous Humor. Cl^− secretion likely limits the rate of Aqueous Humor Formation. Many transport components underlying Cl^− secretion are known. Cl^− is taken up from the stroma into PE cells by electroneutral transporters, diffuses to the NPE cells through gap junctions and is released largely through Cl^− channels. Recent work suggests that significant Cl^− recycling occurs at both surfaces of the ciliary epithelium, providing the basis for modulation of net secretion. The PE-NPE cell couplet likely forms the fundamental unit of secretion; gap junctions within the PE and NPE cell layers are inadequate to maintain constancy of ionic composition throughout the epithelium under certain conditions. Although many hormones, drugs and signaling cascades are known to have effects, a persuasive model of the regulation of Aqueous Humor Formation has not yet been developed. cAMP likely plays a central role, potentially both enhancing and reducing secretion by actions at both surfaces of the ciliary epithelium. Among other hormone receptors, A_3 adenosine receptors likely alter intraocular pressure by regulating NPE-cell Cl^− channel activity. Recently, functional evidence for the regional variation in ciliary epithelial secretion has been demonstrated; the physiologic and pathophysiologic implications of this regional variation remain to be addressed.
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Na^+/H^+ and Cl^–/HCO_3 ^–-antiporters of bovine pigmented ciliary epithelial cells
Pflügers Archiv, 2000Co-Authors: L. Counillon, Nicolas Touret, Michel Bidet, K. Peterson-yantorno, M. Coca-prados, Alan Stuart-tilley, Sabine Wilhelm, S.l. Alper, M. M. CivanAbstract:Medical therapy of glaucoma commonly aims at slowing Aqueous Humor Formation by the ocular ciliary epithelial bilayer, but underlying mechanisms are poorly understood. The first step in secretion is NaCl uptake from the stroma into the pigmented ciliary epithelial (PE) cell layer by electroneutral transporters. After crossing gap junctions into the nonpigmented ciliary epithelial (NPE) cell layer, solute is released into the Aqueous Humor. Published data have indicated that both paired Na^+/H^+ and Cl^–/HCO_3 ^– antiporters and the Na^+-K^+–2Cl^– symporter are involved in net uptake. The molecular identities of the paired antiporters have not been elucidated. We have studied continuously cultured bovine PE cells. Acid-activated ^22Na^+ uptake was inhibited by cariporide, EIPA (ethyl-isopropyl-amiloride) and amiloride, at concentrations characteristic of the NHE-1 isoform. Videomicroscopy of BCECF-loaded PE cells verified the presence of an EIPA-inhibitable Na^+/H^+ antiporter. Removing external Cl^– also triggered an alkalinization, which was Na^+-independent and could be inhibited by 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS). Application of hypotonicity followed by return to isotonicity triggered a regulatory volume increase, which was pharmacologically similar to the uptake mechanisms described for intact rabbit ciliary epithelium. Reverse transcriptase polymerase chain reaction (RT-PCR) amplification of RNA from the human ciliary body detected expression of the AE2 Cl^–/HCO_3 ^– exchanger, but not of AE1, cAE3 or bAE3. Immunostaining of bovine PE cells also revealed the presence of AE2 epitope. We conclude that paired NHE-1 Na^+/H^+ and AE2 Cl^–/HCO_3 ^– antiporters are important components in the initial step in Aqueous Humor Formation.
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Na+/H+ and Cl–/HCO3–-antiporters of bovine pigmented ciliary epithelial cells
Pflügers Archiv - European Journal of Physiology, 2000Co-Authors: L. Counillon, Kim Peterson-yantorno, Nicolas Touret, Michel Bidet, M. Coca-prados, Alan Stuart-tilley, Sabine Wilhelm, S.l. Alper, M. M. CivanAbstract:Medical therapy of glaucoma commonly aims at slowing Aqueous Humor Formation by the ocular ciliary epithelial bilayer, but underlying mechanisms are poorly understood. The first step in secretion is NaCl uptake from the stroma into the pigmented ciliary epithelial (PE) cell layer by electroneutral transporters. After crossing gap junctions into the nonpigmented ciliary epithelial (NPE) cell layer, solute is released into the Aqueous Humor. Published data have indicated that both paired Na+/H+ and Cl–/HCO3 – antiporters and the Na+-K+–2Cl– symporter are involved in net uptake. The molecular identities of the paired antiporters have not been elucidated. We have studied continuously cultured bovine PE cells. Acid-activated 22Na+ uptake was inhibited by cariporide, EIPA (ethyl-isopropyl-amiloride) and amiloride, at concentrations characteristic of the NHE-1 isoform. Videomicroscopy of BCECF-loaded PE cells verified the presence of an EIPA-inhibitable Na+/H+ antiporter. Removing external Cl– also triggered an alkalinization, which was Na+-independent and could be inhibited by 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS). Application of hypotonicity followed by return to isotonicity triggered a regulatory volume increase, which was pharmacologically similar to the uptake mechanisms described for intact rabbit ciliary epithelium. Reverse transcriptase polymerase chain reaction (RT-PCR) amplification of RNA from the human ciliary body detected expression of the AE2 Cl–/HCO3 – exchanger, but not of AE1, cAE3 or bAE3. Immunostaining of bovine PE cells also revealed the presence of AE2 epitope. We conclude that paired NHE-1 Na+/H+ and AE2 Cl–/HCO3 – antiporters are important components in the initial step in Aqueous Humor Formation.
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Role of ion channels in Aqueous Humor Formation.
American Journal of Physiology-Cell Physiology, 1996Co-Authors: Timothy John Claud Jacob, M. M. CivanAbstract:The Aqueous Humor is secreted by the ciliary epithelium, a bilayered syncytial epithelium comprising a pigmented (PE) cell layer abutting the stroma and a nonpigmented (NPE) cell layer facing the Aqueous phase. As in other epithelia, secretion depends on the transfer of solute, with water passively following. Na+, K+, and Cl- enter the syncytium principally through a Na(+)-K(+)-2Cl- symport, diffusing to the Aqueous surface of the NPE cells. The Na+, K+, and Cl- are secreted into the Aqueous Humor through the Na+/K+ exchange pump, K+ channels, and Cl- channels, respectively. Na+ is also secreted between the cells in response to a small transepithelial potential. The K+ channels are critical not only for K+ release but also for hyperpolarizing the membrane, providing an electrical driving force for Cl- secretion. Some of the K+ channels are Ca2+ sensitive and can be activated by Ca2+ entry through T- and L-type Ca2+ channels. The roles of the ciliary epithelial nonselective and Na+ channels are less clear. This review describes the ion channels thus far identified in the ciliary epithelium in terms of the activation and inactivation of their macroscopic currents, the open probabilities and conductances of the single channels, and their locations and regulation. The review relates each class of channel to known families of channels and indicates how those channels can contribute to the secretion of the Aqueous Humor.
Mortimer M. Civan - One of the best experts on this subject based on the ideXlab platform.
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Pathways for ATP release by bovine ciliary epithelial cells, the initial step in purinergic regulation of Aqueous Humor inflow
American Journal of Physiology-Cell Physiology, 2010Co-Authors: Chi Ting Leung, Kim Peterson-yantorno, Claire H. Mitchell, Mortimer M. CivanAbstract:ATP release by nonpigmented (NPE) and pigmented (PE) ciliary epithelial cells is the enabling step in purinergic regulation of Aqueous Humor Formation, but the release pathways are unknown. We meas...
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Species variation in biology and physiology of the ciliary epithelium: similarities and differences.
Experimental Eye Research, 2009Co-Authors: Mortimer M. CivanAbstract:� secretion HCO3 � secretion abstract Glaucoma is a leading cause of irreversible blindness worldwide. Lowering intraocular pressure (IOP) is the only strategy documented to delay the appearance and retard the progression of vision loss. One major approach for lowering IOP is to slow the rate of Aqueous Humor Formation by the ciliary epithe- lium. As discussed in the present review, the transport basis for this secretion is largely understood. However, several substantive issues are yet to be resolved, including the integrated regulation of secretion, the functional topography of the ciliary epithelium, and the degree and significance of species variation in Aqueous Humor inflow. This review discusses species differences in net secretion, particularly of Cl � and HCO3 secretion. Identifying animal models most accurately mimicking Aqueous Humor Formation in the human will facilitate development of future novel initiatives to lower IOP.
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Mechanisms of Aqueous Humor Formation
Ocular Transporters In Ophthalmic Diseases And Drug Delivery, 2008Co-Authors: Chi-wing Kong, Chu-yan Chan, Mortimer M. CivanAbstract:Glaucoma is a leading cause of irreversible blindness in the world (1). Primary openangle glaucoma (POAG) is the most common form of glaucoma and its onset, as well as progression, is often insidious, leading to significant visual loss before being clinically diagnosed. POAG is frequently associated with elevated intraocular pressure (IOP) of the eye. It is incurable at present, although its progression can be retarded by lowering the IOP by medication and/or surgery. If pharmacological agents fail to attain a targeted hypotensive response within the framework of the clinical characteristics and course, surgery will be indicated. The IOP is physiologically maintained within a relatively narrow range bracketing a mean of approximately 15 mmHg. The level of IOP reflects a dynamic balance between secretion (inflow) and drainage (outflow) of Aqueous Humor. The Aqueous Humor is a transparent fluid that is formed by the ciliary processes (epithelium) of the eye. After its production, Aqueous Humor flows from the posterior chamber to the anterior chamber of the eye via the pupil (Fig. 1). In the anterior chamber, the temperature difference between the warmer iris and the cooler cornea results in a convectional fluid circulation.
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Electron microprobe analysis of rabbit ciliary epithelium indicates enhanced secretion posteriorly and enhanced absorption anteriorly
American Journal of Physiology-Cell Physiology, 2007Co-Authors: C. W. Mclaughlin, Sylvia Zellhuber-mcmillan, Anthony D. C. Macknight, Mortimer M. CivanAbstract:The rate of Aqueous Humor Formation sequentially across the pigmented (PE) and nonpigmented (NPE) ciliary epithelial cell layers may not be uniform over the epithelial surface. Because of the tissu...
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Chapter 1 Transport Components of Net Secretion of the Aqueous Humor and Their Integrated Regulation
The Eye's Aqueous Humor - From Secretion to Glaucoma, 1997Co-Authors: Mortimer M. CivanAbstract:Publisher Summary This chapter presents an overview of the current consensus concerning Aqueous Humor Formation and discusses the functional components underlying transport by the ciliary epithelium. It describes pathways that may regulate net secretion and focuses on the Formation of the Aqueous Humor of the anterior chamber and its outflow from the eye into the venous circulation. The mechanisms and regulation of Aqueous Humor secretion are of importance because (1) most of the effective ocular hypotensive drugs act by reducing secretion, (2) the efficacy of hypotensive therapy would be enormously enhanced by developing a drug capable of lowering secretion to the normal early morning rate, and (3) inFormation concerning the molecular and cell biology and physiology of these mechanisms can provide a general perspective on transepithelial secretion and absorption. Net Aqueous Humor Formation can be accelerated both by stimulating unidirectional secretion and by slowing unidirectional reabsorption. A wide range of regulatory pathways modifies the rate of Aqueous Humor Formation, including the adrenergic system, arachidonic acid metabolites, melatonin, and corticosteroids.
Maurizio Giacinto Uva - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological management of ocular hypertension: current approaches and future prospective
Current Opinion in Pharmacology, 2012Co-Authors: Claudio Bucolo, Antonio Longo, Michele Reibaldi, Filippo Drago, Salvatore Salomone, Maurizio Giacinto UvaAbstract:Elevated eye pressure is the main risk factor for glaucoma, and intraocular pressure rises when the balance between Aqueous Humor Formation and outflow resistance is compromised. In a normal eye there is a precise tune of Aqueous outflow under the fine control of ciliary body and trabecular meshwork. Current pharmacological therapies for lowering the intraocular pressure in glaucoma include increasing Aqueous Humor outflow and suppression of Aqueous Humor production. However, most of antiglaucoma drugs currently on the market do not target the trabecular meshwork that represents the site of the pathology. This review focuses on pharmacological management of ocular hypertension with a particular attention to the future pharmacotherapy scenario.
Chi-wing Kong - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of Aqueous Humor Formation
Ocular Transporters In Ophthalmic Diseases And Drug Delivery, 2008Co-Authors: Chi-wing Kong, Chu-yan Chan, Mortimer M. CivanAbstract:Glaucoma is a leading cause of irreversible blindness in the world (1). Primary openangle glaucoma (POAG) is the most common form of glaucoma and its onset, as well as progression, is often insidious, leading to significant visual loss before being clinically diagnosed. POAG is frequently associated with elevated intraocular pressure (IOP) of the eye. It is incurable at present, although its progression can be retarded by lowering the IOP by medication and/or surgery. If pharmacological agents fail to attain a targeted hypotensive response within the framework of the clinical characteristics and course, surgery will be indicated. The IOP is physiologically maintained within a relatively narrow range bracketing a mean of approximately 15 mmHg. The level of IOP reflects a dynamic balance between secretion (inflow) and drainage (outflow) of Aqueous Humor. The Aqueous Humor is a transparent fluid that is formed by the ciliary processes (epithelium) of the eye. After its production, Aqueous Humor flows from the posterior chamber to the anterior chamber of the eye via the pupil (Fig. 1). In the anterior chamber, the temperature difference between the warmer iris and the cooler cornea results in a convectional fluid circulation.
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Chloride Secretion by Porcine Ciliary Epithelium: New Insight into Species Similarities and Differences in Aqueous Humor Formation
Investigative Opthalmology & Visual Science, 2006Co-Authors: Chi-wing KongAbstract:PURPOSE. To investigate the electrophysiology and mechanisms of chloride (Cl - ) transport across the ciliary body-epithelium (CBE) of the porcine eye. The pig is widely believed to be a good model for studying human physiology. Current results strengthen our understanding of the physiology of Aqueous Humor Formation (AHF). METHODS. Freshly isolated porcine CBE were maintained in modified Ussing-Zerahn-type chambers. The effects of the bathing anion substitution (Cl - and HCO 3 - ) and transport inhibitors including bumetanide, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt (DIDS), heptanol, and two chloride channel inhibitors, 5-nitro-2-(3-phenylpropylamino> benzoic acid (NPPB), and niflumic acid, on the electrical properties and transepithelial Cl - transport were investigated. RESULTS. Viable porcine CBE preparations were maintained in vitro. A spontaneous transepithelial potential difference (PD) of approximately 1 mV was found across the CBE (Aqueous side negative). The magnitudes of the PD and short-circuit current (I sc ) were found to be dependent on both the bathing Cl - and HCO 3 - concentrations. In short-circuited conditions, a significant net Cl - transport (1.01 μEq ·h -1 ·cm -2 ; n = 109; P < 0.001) in the stromal-to-Aqueous direction (f net Cl) was detected. The magnitude of the Cl - current carried by the J net Cl was approximately 2.2 times the measured I sc , suggesting there was cation (e.g., Na + ) transport along with Cl - and/or anion transport (e.g., HCO 3 - ) in the opposite direction. Bilateral bumetanide (0.1 mM) reduced the J net Cl by ∼56% while stromal DIDS (0.1 mM) produced no inhibition. Instead, Aqueous DIDS (0.1 mM) triggered a sustained stimulation of both I sc and J net Cl. Even if bilateral DIDS was used at a higher concentration (1 mM), together with bilateral dimethylamiloride (DMA, 0.1 mM), no inhibition of the I sc was observed. Bilateral heptanol (3.5 mM) drastically reduced the I sc and J net Cl. NPPB (0.1 mM), a common chloride channel inhibitor, did not inhibit the J net Cl, whereas NFA (1.0 mM) virtually abolished it. CONCLUSIONS. In the porcine eye, active secretion of Cl - into Aqueous was identified that may act as a driving force for AHF. The bumetanide-sensitive Na + /K + /2Cl - cotransporter (NKCC) clearly contributes to the Cl - uptake into the pigmented epithelium (PE), whereas the DIDS-sensitive Cl - /HCO 3 - anion exchanger (AE) may exert a minor role. The intercellular gap junctions couple the porcine ciliary bilayers and thus the transepithelial Cl transport, as in other species. The Cl channel/ efflux pathway located in the nonpigmented epithelium (NPE) is niflumic acid-sensitive but NPPB-insensitive. We also hypothesize that the AE located on the NPE may regulate the activity of a putative Cl - channel on the basolateral membrane facing Aqueous via modulation of the intracellular pH (pH,). This work reinforces the general consensus that active secretion of Cl is the major driving force of AHF in mammalian eye and further substantiates the existence of species differences in the mechanism that accomplishes transepithelial Cl-transport.
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Aqueous Humor Formation and Its Regulation by Nitric Oxide: A Mini Review
Neuroembryology and Aging, 2006Co-Authors: Chi-wing Kong, Chu-yan Chan, Chuen LamAbstract:Glaucoma is a common and severe aging eye disease which can cause permanent visual loss if untreated. One common strategy of glaucoma treatment is to lower the intraocular pressure (IOP) of the eye. S
Paul L Kaufman - One of the best experts on this subject based on the ideXlab platform.
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Studies on the mechanism of action of timolol and on the effects of suppression and redirection of Aqueous flow on outflow facility
Experimental Eye Research, 2004Co-Authors: Julie A. Kiland, B'ann T. Gabelt, Paul L KaufmanAbstract:Long-term use of drugs that suppress Aqueous Humor Formation, such as timolol and dorzolamide, or that redirect Aqueous Humor outflow from the trabecular meshwork, such as prostaglandin F2alpha analogues, could cause underperfusion of the trabecular meshwork and a secondary decrease in outflow facility. We investigated the mechanism of suppression of Aqueous Humor Formation by timolol in monkey eyes by measuring Aqueous Humor ascorbate levels. We also determined whether suppression of Aqueous Humor Formation with and without redirection of Aqueous Humor away from the trabecular meshwork could lead to a subsequent reduction in outflow facility, and whether this reduction was correlated with increased fibronectin levels in anterior chamber Aqueous Humor. In cynomolgus monkeys, unilateral dose/Aqueous Humor Formation response curves were generated for timolol, dorzolamide, and a combination of timolol + dorzolamide. Aqueous Humor Formation and/or outflow facility were measured in both eyes after approximately four days, four weeks and seven weeks of twice daily treatment with 3.5 microg timolol + 1.0 mg dorzolamide to one eye and 30% DMSO to the other. In some monkeys, 5 microg prostaglandin F2alpha-isopropyl ester (PG) was added to timolol + dorzolamide for 4-week treatments. Intraocular pressure and corneal endothelial transfer coefficients (k(a)) were also measured at four weeks. Aqueous Humor fibronectin levels were determined in four monkeys after approximately 9.5 weeks of timolol + dorzolamide treatment. Aqueous Humor Formation, intraocular pressure, and Aqueous Humor ascorbate levels were also determined in rhesus monkeys at baseline and after a single unilateral topical administration of 25 microg timolol. Compared to baseline for the same eye, Aqueous Humor Formation was significantly decreased in treated eyes at all doses of timolol and at 1.8 and 4 mg dorzolamide. Compared to the opposite control eye, Aqueous Humor Formation was lower in treated eyes after 3.5 and 5 microg timolol and after all doses of dorzolamide. Aqueous Humor Formation after treatment with 3.5 microg timolol + 1.0 mg dorzolamide was decreased in treated vs. control eyes, after four days and was suppressed in both treated and control eyes after four weeks of treatment, but not when PG was added. There was no difference in k(a) values with or without the addition of PG. Intraocular pressure was significantly lower in both treated and control eyes vs. baseline after approximately 6.5 weeks treatment with timolol + dorzolamide when taken 2 hr after the last dose and after approximately 3.5 weeks treatment with timolol + dorzolamide + PG when measured 6 hr after the last dose. Outflow facility after treatment with timolol + dorzolamide was unchanged after four days, tended to be lower in the treated vs. control eyes after four and seven weeks, and was significantly lower in treated vs. control eyes after four weeks treatment with timolol + dorzolamide + PG (0.352 +/- 0.052 vs. 0.515 +/- 0.096 microl min(-1) mmHg(-1), p < or = 0.02). Both treated vs. control eye Aqueous Humor fibronectin levels were below the level of detection for our assay (0.01 microg ml(-1)). The 25 microg timolol dose decreased ipsilateral, but not contralateral intraocular pressure (12.6 +/- 1.7 vs. 15.2 +/- 0.9; p < 0.05) and Aqueous Humor Formation (1.40 +/- 0.08 vs. 2.03 +/- 0.09 microg ml(-1), p < or = 0.01). There was no difference in anterior chamber ascorbate levels in treated vs. control eyes or compared to their respective baselines. Our findings indicate that timolol affects neither ciliary epithelial transport of ascorbate nor Aqueous fibronectin levels. Our data also indicate that decreasing Aqueous Humor Formation over a period of time can lead to reduction in outflow facility, particularly when combined with therapy that redirects Aqueous from the trabecular meshwork. Future intraocular pressure-lowering therapies for glaucoma may better be directed at enhancing flow through the trabecular pathway as opposed to decreasing Aqueous Humor Formation or rerouting Aqueous Humor away from the trabecular meshwork.
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Anterior segment physiology after bumetanide inhibition of Na-K-Cl cotransport.
Investigative ophthalmology & visual science, 1997Co-Authors: B'ann T. Gabelt, Michael Wiederholt, F. Clark, Paul L KaufmanAbstract:Purpose. To determine the effect of bumetanide inhibition of Na-K-Cl cotransport on Aqueous Humor Formation and outflow facility in living cynomolgus monkeys, outflow facility in organcultured human eyes, and contraction in bovine ciliary muscle and trabecular meshwork strips, in vitro. Methods. Aqueous Humor Formation in monkeys was measured fluorophotometrically for 6 hours, 1 to 6 weeks before, immediately after, and 2 to 6 weeks after bumetanide was administered intravitreally (final concentration ~100 or 500 /iM) or intravenously (0.01 or 0.03 mg/ kg at 0 and 3 hours). Outflow facility in monkeys was determined by two-level, constantpressure perfusion of the anterior chamber for 45 to 60 minutes before and after bumetanide was administered by bolus intracameral injection (100 fjM, initial anterior chamber concentration) or by exchanging the anterior chamber with 2 ml 10, 100, or 500 fj,M bumetanide. Urine volume was measured 3 hours after administration of intravenous bumetanide in various diluents. The effect on intraocular pressure in organ-cultured human eyes was determined for 48 hours by constant-flow-variable-pressure perfusion with 10 fjM bumetanide. Contraction of fresh bovine ciliary muscle and trabecular meshwork was measured isometrically with a forcelength transducer system after exposure to 100 fjM bumetanide ± 1 fjM carbachol. Results. The bumetanide concentrations used had litde effect on outflow facility or on Aqueous Humor Formation in normal monkeys, on intraocular pressure in organ-cultured human eyes, or on contraction of bovine ciliary muscle and trabecular meshwork strips. Intravenous bumetanide increased urine volume, regardless of the diluent used. Conclusions. These results suggest that Na-K-Cl cotransport is not involved functionally in regulation of Aqueous Humor inflow and outflow and in contractility of ciliary muscle and trabecular meshwork. Invest Ophthalmol Vis Sci. 1997:38; 1700-1707. INa-K-Cl cotransporters are membrane proteins that transport Na, K, and Cl into and out of cells in an electrically neutral manner. They appear to be important in the maintenance and regulation of cell volume and of ion gradients. Characteristic features of this cotransport include an absolute requirement for all three ion species, and specific inhibition by "loop"
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Dose-dependent suppression of Aqueous Humor Formation by timolol in the cynomolgus monkey.
Journal of Glaucoma, 1993Co-Authors: James C. Robinson, Paul L KaufmanAbstract:SUMMARY The effect of topical timolol on the fluorophotometrically determined Aqueous Humor Formation rate in the cynomolgus monkey was studied. A timolol dose of 2.5, 5, 15, 30, 45, 90, or 180 $mUg was administered as a single topical dose to one eye of five monkeys. Postdrug flow rates were compared with no-drug baselines obtained on separate occasions. Our findings were that (a) topical timolol decreases Aqueous Humor Formation rates in a dose-dependent fashion, with 30 $mUg and 50% flow suppression at or near the top of the single dose-response curve; (b) there is a significant contralateral effect, and only at extremely low doses can treated versus control eye effects be separated; and (c) doses as small as 2.5 $mUg can suppress Aqueous Formation by a statistically significant 20%. In the monkey, as in the human, timolol is a far more potent suppressor of Aqueous Formation than is generally realized, and standard clinical doses may in fact be overdoses in both species.
