Factors affecting outflow facility calculations.
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Animals↗
Biomedical subjects
Baohe Tian
Publications and source records attributed to Baohe Tian.
Latrunculin B effects on trabecular meshwork and corneal endothelial morphology in monkeys.
To determine the mechanism of latrunculin B (LAT-B)-induced decrease in outflow resistance and the effect of LAT-B on the cornea, structural changes of the trabecular meshwork (TM) and the corneal endothelium following LAT-B were studied in the live monkey eye. LAT-B (0.5 microM) and vehicle were administered by anterior chamber exchange and infusion with cationized and non-cationized gold solution in opposite eyes. The eyes were fixed by infusing Ito's solution and enucleated. Anterior segments were quadrisected and embedded in Epon-Embed 812. Morphology of the TM and the corneal endothelium was studied by light and electron microscopy. LAT-B-induced morphological changes in the TM included: (1) loss of microfilament integrity in cells, especially in TM cells on the collagen beams; (2) development of numerous cytoplasmic projections of the sub-canalicular cells (SUB); (3) reorganization of intermediate filaments in Schlemm's canal inner wall (IW) cells; (4) massive 'ballooning' of the juxtacanalicular (JXT) region, leading to a substantial expansion of the space between the IW of Schlemm's canal and the trabecular collagen beams; and (5) retention of extracellular matrix (ECM), trapped between the SUB cell layer and IW cells. No detrimental effects on tight junctions, giant vacuoles, and cell-cell and cell-ECM adhesions were observed. Endocytosis of gold particles was not affected. Morphology of the corneal endothelium of the LAT-B-treated eye was unchanged. In conclusion, TM changes in the LAT-B-treated eye suggest that the expansion of the JXT space may account for the decrease in outflow resistance induced by latrunculins. The outflow-effective concentration of LAT-B administered intracamerally does not significantly affect the corneal endothelium.
Actins↗
Effects of the Rho kinase inhibitor Y-27632 and the phosphatase inhibitor calyculin A on outflow facility in monkeys.
Previous studies have shown that the inhibition of Rho kinase is involved in the regulation of outflow facility in the live rabbit eye and the enucleated porcine eye. However, it is unknown whether the Rho kinase inhibition will do the same in non-human primates. To determine if the Rho kinase inhibitor Y-27632 will reduce outflow resistance in the live monkey eye, if Y-27632 and the phosphatase inhibitor calyculin A (Caly-A which antagonises Y-27632-induced MLC dephosphorylation) will affect outflow facility differently, and if the latter will inhibit effect of the former on facility, we studied effects of Y-27632 and Caly-A on outflow facility in living monkeys separately and concurrently. Total outflow facility was measured by 2-level constant pressure perfusion of the anterior chamber (AC) before and after exchange with different doses of Y-27632 (1, 10 and 100 microM) or Caly-A (10, 50 and 100 nM), or vehicles, followed by continuous AC infusion of corresponding drug/vehicle solution, in opposite eyes of cynomolgus or rhesus monkeys. The effect of 100 microM Y-27632 or 100 nM Caly-A vs vehicle and the effect of 100 microM Y-27632+100 nM Caly-A vs 100 microM Y-27632 alone on outflow facility were also determined in monkeys pre-treated topically with 10 microl of 1% atropine in both eyes 1 hr before perfusion. Both Y-27632 and Caly-A dose-dependently increased outflow facility by up to 2-3 fold in monkeys, adjusted for baseline and contralateral control eye washout. Pre-treatment with 1% topical atropine partially inhibited the effect of 100 nM Caly-A, but not 100 microM Y-27632, on outflow facility. 100 nM Caly-A gradually and partially inhibited the Y-27632-induced facility increase. In conclusion, Y-27632 increases outflow facility in monkeys presumably by inhibiting cellular contractility in the TM. Caly-A increases outflow facility by complicated mechanisms perhaps including drug-induced ciliary muscle contraction and cytoskeletal reorganisation in TM cells. The partial inhibitory effect of Caly-A on the Y-27632-induced increase in outflow facility may reflect the former partially inhibiting the latter's relaxation of cells in the TM.
Amides↗
Effect of low-dose latrunculin B on anterior segment physiologic features in the monkey eye.
OBJECTIVES: To determine if low doses of topical latrunculin B (LAT-B) will increase outflow facility and decrease intraocular pressure without damaging the cornea and if they will inhibit miotic and accommodative responses to pilocarpine in monkeys. METHODS: We measured intraocular pressure (Goldmann tonometry) before and after 1 and 9 doses of 0.005% and 0.01% topical LAT-B and vehicle given twice daily on successive weeks; outflow facility (perfusion) following 15 doses; central corneal thickness (ultrasonic pachymetry) before and after 1 and 9 doses of 0.01% LAT-B and vehicle; pupillary diameter (calipers); and accommodation (refractometry) before and after 1 dose of 0.005% and 0.02% LAT-B. RESULTS: Latrunculin-B dose-dependently decreased intraocular pressure, multiple doses more than a single dose. Maximal mean +/- SEM hypotension after 1 dose was 2.5 +/- 0.3 mm Hg (0.005% LAT-B; n = 8; P<.001) or 2.7 +/- 0.6 mm Hg (0.01% LAT-B; n = 8; P<.005); maximal mean +/- SEM hypotension after 9 doses was 3.2 +/- 0.5 mm Hg (0.005% LAT-B; n = 8; P<.001) or 4.4 +/- 0.6 mm Hg (0.01% LAT-B; n = 8; P<.001). Outflow facility was increased by mean +/- SEM 75% +/- 13% (n = 7; P<.005). Central corneal thickness was not changed after 1 or 9 doses of 0.01% LAT-B. Miotic and accommodative responses to intramuscular pilocarpine were dose-dependently inhibited. With 0.02% LAT-B, inhibition of miosis was substantial, whereas the inhibition of accommodation was only about 25%. With 0.005% LAT-B, the effects were trivial. CONCLUSIONS: In ocular normotensive monkeys, 0.005% and 0.01% LAT-B administered topically increases outflow facility and/or decreases intraocular pressure without corneal effects. Multiple doses reduce intraocular pressure more than a single dose. Latrunculin-B dose-dependently relaxes the iris sphincter and ciliary muscle, with some separation of miotic and accommodative effects. Clinical Relevance Multiple treatments with low topical doses of LAT-B may substantially reduce outflow resistance in eyes with glaucoma without adversely affecting the cornea.
Accommodation, Ocular↗
Effects of topical H-7 on outflow facility, intraocular pressure, and corneal thickness in monkeys.
OBJECTIVES: To determine if low concentrations of H-7 (1-[5-isoquinoline sulfonyl]-2-methyl piperazine) topically applied to the eye increases outflow facility and decreases intraocular pressure (IOP) without affecting the cornea in monkeys, and to evaluate if the effect of H-7 on IOP is pressure dependent. METHODS: Single or multiple doses of 5% H-7 or vehicle (20 micro L) were administered topically to opposite eyes of normal monkeys. A single dose of 2% H-7 or vehicle (50 micro L) was administered to the glaucomatous eye of monkeys with laser-induced unilateral glaucoma, with vehicle on day 1 and H-7 on day 2. RESULTS: In normotensive eyes, 1 dose of 5% H-7 maximally decreased IOP by a mean +/- SEM of 2.5 +/- 1.0 mm Hg (-16.7% +/- 5.5%) at 3 hours. Higher baseline IOP and repeated dosing were associated with greater IOP reduction. Outflow facility was increased, but central corneal thickness was not affected. In glaucomatous eyes, 1 dose of 2% H-7 maximally decreased IOP by a mean +/- SEM of 5.8 +/- 0.6 mm Hg (-16.9% +/- 1.6%) at 2 hours. CONCLUSIONS: Five percent H-7 increases outflow facility and decreases IOP, but does not affect corneal thickness. Multiple doses of H-7 induce greater reduction of IOP than a single dose. The effect of H-7 on IOP may be pressure dependent. Clinical Relevance Multiple topical treatments with low doses of H-7 or analogues may substantially reduce outflow resistance in the hypertensive eye without meaningfully affecting the cornea.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Functional and structural reversibility of H-7 effects on the conventional aqueous outflow pathway in monkeys.
To determine the mechanism of H-7-induced outflow resistance decrease, the reversibility of H-7 effects on outflow pathway was studied physiologically and morphologically in live monkey eyes. Total outflow facility was measured by two-level constant pressure perfusion before (baseline measurement) and after (post-drug measurement) anterior chamber (AC) exchange with 300microM H-7 or vehicle in opposite eyes of eight monkeys. H-7 was then removed by AC exchange with drug-free vehicle in both eyes, followed by a 2.5hr waiting period, after which outflow facility was measured again with (Group 2; n=4) or without (Group 1; n=4) another preceding drug-free AC exchange. For morphological study, five monkeys were initially perfused similarly to Group 1 in physiology, but the facility measurement beginning 2.5hr after drug removal was either omitted or replaced by gold solution infusion. Following baseline measurement, two of the five monkeys received H-7 or vehicle in opposite eyes, while three monkeys received H-7 in both eyes 2.5hr apart, contributing one H-7-treated 'recovery' eye and one H-7-treated 'acute' eye. After perfusion, both eyes of all five monkeys were studied by light and electron microscopy. Outflow facility during post-drug measurement in the H-7-treated eye was significantly increased by two-fold. However, the facility increase was reduced when measured beginning 2.5hr after drug removal, with the reduction being greater in Group 1. 'Recovered' outflow facility after drug removal gradually increased again under continuous AC infusion with drug-free vehicle. Morphologically, major changes in and around Schlemm's canal (SC) in the H-7-treated 'acute' eye included protrusion of the entire inner wall (IW) into SC, relaxation of the IW cells and reorganization of the IW cytoskeleton. The changes in IW cells and juxtacanalicular region of the H-7-treated 'recovery' eye were non-uniform, with areas resembling the vehicle-treated eye ('contracted areas') and areas resembling the H-7-treated 'acute' eye ('relaxed areas'). The average junction-to-junction distances in the IW cells of the H-7-treated 'recovery' eye were intermediate between the vehicle-treated eye and the H-7-treated 'acute' eye. In conclusion, H-7's effect on outflow facility seems reversible, but AC exchange or continuous infusion with drug-free vehicle can re-elevate the 'recovered' outflow facility. Major morphological changes in the TM immediately after H-7 include IW protrusion, cellular relaxation and cytoskeleton reorganization. The decrease in 'relaxed areas' in the TM, in conjunction with the reversed outflow facility, 2.5hr after drug removal suggests that cellular relaxation in the TM is the structural basis for H-7-induced increase in outflow facility.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
H-7 effect on outflow facility after trabecular obstruction following long-term echothiophate treatment in monkeys.
PURPOSE: To determine whether H-7 can enhance outflow facility after trabecular meshwork obstruction by extracellular material that accumulates after long-term treatment of monkeys with the cholinesterase inhibitor echothiophate iodide (ECHO). METHODS: Cynomolgus monkeys were treated topically with 150 microg ECHO in one (n = 4 eyes) or both (n = 8 eyes) eyes for up to 48 weeks. Accommodation response to topical pilocarpine was monitored periodically. Outflow facility response to H-7 was measured by two-level constant pressure perfusion on three or four different occasions after intraocular pressure was elevated for 12 to 18 weeks. RESULTS: Long-term treatment with ECHO decreased the accommodative response to pilocarpine and increased intraocular pressure, as has been reported. Baseline outflow facility was decreased by 46% +/- 7% (n = 12, P < 0.001). H-7 partially restored baseline outflow facility measured during subsequent perfusions while ECHO treatment was continued. Concurrent H-7 enhanced outflow facility by 73% +/- 18% (n = 12, P < 0.005) beyond the same-day baseline in ECHO-treated eyes. Cessation of ECHO treatment further restored baseline outflow facility, and the outflow facility response to H-7. CONCLUSIONS: H-7 can enhance OF in the presence of trabecular obstruction produced by long-term ECHO treatment. This suggests that H-7 may be useful in treating glaucoma, even in the presence of accumulated plaque material that has been described previously.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Effects of latrunculin B on outflow facility, intraocular pressure, corneal thickness, and miotic and accommodative responses to pilocarpine in monkeys.
PURPOSE: To determine if low doses of topical latrunculin B (LAT-B) will increase outflow facility and decrease intraocular pressure (IOP) without adversely affecting the cornea, and inhibit miotic and accommodative responses to pilocarpine, in ocular normotensive monkeys. METHODS: Intraocular pressure was measured by Goldmann tonometry before and after one and nine dose(s) of 0.005% and 0.01% topical LAT-B/vehicle given twice daily on successive weeks. Outflow facility was then measured by perfusion following 15 doses. Central corneal thickness was measured by ultrasonic pachymetry before and after one and nine dose(s) of 0.01% LAT-B/vehicle. Pupillary diameter (calipers) and accommodation (refractometry) before and after one dose of 0.005% and 0.02% LAT-B were determined. RESULTS: LAT-B dose-dependently decreased IOP, multiple doses more than a single dose. Maximal hypotension after one dose was 2.5 +/- 0.3 mm Hg (0.005% LAT-B; n = 8; P < .001) or 2.7 +/- 0.6 mm Hg (0.01% LAT-B; n = 8; P < .005); maximal hypotension after nine doses was 3.2 +/- 0.5 mm Hg (0.005% LAT-B; n = 8; P < .001) or 4.4 +/- 0.6 mm Hg (0.01% LAT-B; n = 8; P < .001). Outflow facility was increased by 75 +/- 13% (n = 7; P < .005). Central corneal thickness was not changed after one or nine dose(s) of 0.01% LAT-B. The miotic and accommodative responses to intramuscular pilocarpine were dose-dependently inhibited. At 0.02% LAT-B, the inhibition of miosis was essentially complete when compared with the pre-LAT-B value, whereas the inhibition of accommodation was only about 25%. At 0.005% LAT-B, the effects were trivial. CONCLUSIONS: In ocular normotensive monkeys, 0.005/0.01% LAT-B administered topically increases outflow facility and/or decreases IOP, but does not affect the cornea. Multiple doses reduce IOP more than a single dose. LAT-B dose-dependently relaxes the iris sphincter and ciliary muscle, with some separation of the miotic and accommodative effects.
Accommodation, Ocular↗
Tyrphostins which interfere with the actin cytoskeleton do not increase outflow facility.
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Actins↗