The effect of topical CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure and aqueous humor dynamics in rabbits

PURPOSE: To evaluate the ocular hypotensive effect of topical CS-088, an angiotensin AT1 receptor antagonist, and the effect of CS-088 on aqueous humor dynamics. METHODS: The effects of CS-088 on intraocular pressure (IOP) were studied in 2 models of rabbit ocular hypertension. Experimental ocular hypertension was induced in albino rabbits by injecting alpha-chymotrypsin into the anterior chamber (alpha-chymotrypsin rabbit). The effects of the single application of CS-088 were examined. Additionally, CS-088 was repeatedly administered over a period of 3 weeks to hereditary ocular hypertensive rabbits (buphthalmic rabbits, JWHR bu/bu) and the IOPs were monitored throughout the experiment. The effects of CS-088 on aqueous humor dynamics were also examined in normal rabbits. In this study, the methods of IOP recovery rate, two-level constant pressure perfusion and fluorescein-dextran perfusion were used respectively to determine the aqueous inflow, outflow facility and uveoscleral outflow (USF). RESULTS: CS-088 at 1% and 2% significantly lowered the IOP in the alpha-chymotrypsin rabbits with a maximum IOP reduction of 10.1 mmHg. The maximum effect obtained with 2% CS-088 was no greater than that with 1% CS-088. In the buphthalmic rabbits, 2% CS-088 also lowered IOP significantly. Timolol was effective in both models. In the study on aqueous humor dynamics, a slight increase in USF (17%) was seen after a topical application of CS-088 whereas changes in aqueous inflow or outflow facility were not observed. CONCLUSIONS: Topical CS-088 can decrease IOP in rabbits. Despite the USF change, the ocular hypotensive mechanism by CS-088 was not fully determined.     

地塞米松对兔眼房水中一氧化氮及钙离子含量的影响

目的　观测兔眼球结膜下注射地塞米松后其眼压 (P)、房水流畅系数 (C)及房水中一氧化氮 (NO)浓度和Ca2 含量的变化 ,探讨NO、Ca2 在皮质类固醇性青光眼 (GIG)发病中的可能作用。方法　隔日定时给新西兰幼龄白兔双眼球结膜下注射地塞米松 0 5mg ,共 15次 ,3 0d ,隔日定时测定双眼眼压及C值 ,实验结束时抽取房水测定房水中NO及Ca2 浓度。结果　地塞米松使兔眼眼压升高 (P <0 0 5 )、C值及房水中NO浓度下降 (P <0 0 5 ) ;但对兔眼房水中Ca2 的含量无明显影响。结论　眼局部长期应用地塞米松可诱导高眼压 ,引起房水中NO含量显著降低 ,提示NO参与了GIG的发病     

Effects of topical natural ergot alkaloids on intraocular pressure and aqueous humor dynamics in ocular normotensive rabbits.

Although it has been suggested that ergot derivatives may play a role in antiglaucoma therapy, little attention has been paid to the ocular hypotensive action of these drugs. Having previously reported in our laboratory that topical dihydroergocristine decreases intraocular pressure both in ocular normotensive and alpha-chymotrypsin-induced ocular hypertensive rabbits, the aim of the present work was to assess the effect of natural ergot alkaloids, ergocristine, alpha-ergocryptine and ergocornine, on the intraocular pressure and aqueous humor dynamics in ocular normotensive rabbits in order to further explore the ocular actions of these compounds. Intraocular pressure was measured with a pneumatonometer manometrically calibrated for the rabbit eye. Changes in tonographic facility of aqueous humor outflow and rate of aqueous humor inflow were evaluated in anesthetized rabbits. Natural ergot alkaloids were found to reduce intraocular pressure in ocular normotensive eyes in a dose-related fashion. These compounds decreased both tonographic outflow facility and, to a greater extent, aqueous humor inflow, which explains their final hypotensive effect.     

The prostanoid EP2 receptor agonist butaprost increases uveoscleral outflow in the cynomolgus monkey

PURPOSE: To investigate the ocular hypotensive effect of the prostanoid EP2 receptor agonist butaprost and to establish its mechanism of action. METHODS: All experiments were performed in cynomolgus monkeys after topical application of butaprost (0.1%). The effects of butaprost on aqueous humor flow were determined by fluorophotometry. Total outflow facility was measured by the two-level, constant-pressure perfusion method, and uveoscleral outflow was determined by perfusion of FITC-labeled dextran through the anterior chamber. Effects on ocular morphology were studied after tissue fixation with transcardial perfusion by paraformaldehyde and immersion fixation of the globe, in animals subjected to long-term treatment with butaprost. Conscious ocular normotensive monkeys and monkeys with unilateral ocular hypertension were used for intraocular pressure (IOP) studies. RESULTS: Butaprost had no significant effect on aqueous humor flow or total outflow facility in ocular normotensive monkeys. Uveoscleral outflow was significantly higher in the butaprost treated eyes than in vehicle treated eyes, 1.03 +/- 0.20 vs. 0.53 +/- 0.18 microL.min(-1). After a 1-year treatment with butaprost, the morphology of the ciliary muscle was changed, showing increased spaces between ciliary muscle bundles and the apparent formation of new outflow channels. In many instances, changes were observed in the trabecular meshwork as well. Butaprost, in a single 0.1% dose, decreased IOP significantly in ocular normotensive monkeys and reduced IOP in laser-induced glaucomatous monkey eyes to the same level as that in the ocular normotensive contralateral eyes. CONCLUSIONS: The prostanoid EP2 receptor agonist butaprost appears to lower IOP by increasing uveoscleral outflow, according to both physiological and morphologic findings. Although the prostanoid EP2 receptor is structurally and functionally distinct from the FP receptor, the effects of EP2 and FP receptor stimulation on aqueous humor outflow are similar.     

The effect of topical natural ergot alkaloids on the intraocular pressure and aqueous humor dynamics in rabbits with α-chymotrypsin-induced ocular hypertension

BACKGROUND: We previously reported that topical natural ergot alkaloids ergocristine, alpha-ergocryptine and ergocornine dose-dependently reduce intraocular pressure in ocular normotensive rabbits, most likely by decreasing aqueous humor inflow. In the present study, the effects of these compounds on intraocular pressure and aqueous humor dynamics in a rabbit model for ocular hypertension were assessed. METHODS: Experiments were conducted in albino rabbits made ocular hypertensive by intracameral injection of alpha-chymotrypsin. Intraocular pressure responses to drug vehicle and seven different doses of topical natural ergot alkaloids were examined in order to obtain dose-response relationships for comparing the intraocular pressure-lowering effect and potency of these drugs. Tonographies were also performed to ascertain the actions of natural ergot alkaloids on aqueous humor dynamics in alpha-chymotrypsin-induced ocular hypertensive rabbits. RESULTS: Topical application of the natural ergot alkaloids ergocristine, alpha-ergocryptine and ergocornine lowered intraocular pressure in alpha-chymotrypsin-induced ocular hypertensive rabbits in a dose-related fashion, with ergocristine displaying the greatest intraocular pressure-lowering effect. Tonographic studies revealed a decrease in the tonographic outflow facility following topical application of natural ergot alkaloids, although only the effects of both ergocristine and alpha-ergocryptine reached statistical significance. All natural ergot alkaloids tested significantly reduced the calculated aqueous humor inflow. CONCLUSION: This study suggests that the natural ergot alkaloids ergocristine, alpha-ergocryptine and ergocornine effectively decrease intraocular pressure in the alpha-chymotrypsin-induced model of ocular hypertension. Since these compounds reduce the tonographic aqueous humor outflow facility, their final ocular antihypertensive effect appears to result from a remarkable reduction of the aqueous humor inflow.     

Ocular hypotensive and aqueous outflow-enhancing effects of AL-3037A (sodium ferri ethylenediaminetetraacetate)

AL-3037A (Sodium ferri ethylenediaminetetraacetate), a novel compound shown to stimulate the degradation of glycosaminoglycans, was evaluated for its effects on aqueous humor outflow and intraocular pressure (IOP) in four experimental models. Its effect on outflow facility was assessed in bovine and human ocular perfusion organ cultures. Its IOP effect was tested in normotensive and dexamethasone-induced ocular hypertensive rabbits. In bovine eyes, perfusion with AL-3037A (0.1% w/v, 2.3 m M) significantly increased the outflow facility well above the normal 'wash-out' effect. At 30 min after perfusion, the outflow facility of drug-treated eyes increased by 26.0+/-2.8% (mean +/- S.E.(M.), n = 8), significantly higher than the 12.1 +/- 2.8% increase in vehicle-treated eyes. This difference sustained throughout the study period (2 hr). The compound also enhanced aqueous outflow in perfused human anterior segments. In non-glaucomatous eyes, it produced a small decrease in IOP (15.4 +/- 4.6%, n = 17), but in tissues derived from glaucoma patients, bolus administration of 3 mg (7 micromol) of AL-3037A lowered the IOP by 52-68% (n = 2) lasting for at least 3 hr. This outflow-enhancing effect of AL-3037A in ex vivo studies was confirmed by in vivo results. In normotensive rabbits, oral (50 mg kg(-1)), intravenous (10 mg kg(-1)), or topical (2 mg; 50 microl of 4% w/v solution) administration of AL-3037A produced maximum reduction of IOP, when compared to vehicle-treated animals, by 34.7+/-3.5% (n = 10), 22.0 +/- 4.6% (n = 10), and 21.6 +/-4.5% (n = 10), respectively. In dexamethasone induced ocular hypertensive rabbits, topical application of the compound (0.5 mg; 25 microl of 2% w/v solution) reduced IOP significantly by 19.2+/- 0.4% (n = 7) at 3 hr after dosing. Importantly, the IOP lowering effect of AL-3037A did not diminish even after repeated treatments in consecutive days. Thus, in the four study models across three animal species, AL-3037A was demonstrated to be an efficacious ocular hypotensive compound whose effect is most likely mediated by augmentation of the aqueous outflow. Its proposed action on the metabolism of glycosaminoglycans may provide a new and unique mechanism for the treatment of glaucoma.     

Effects of topical administration of y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys

PURPOSE: To elucidate the intraocular pressure (IOP)-lowering effects and associated characteristics of Y-39983, a selective Rho-associated coiled coil-forming protein kinase (ROCK) inhibitor derived from Y-27632, in animal eyes. METHODS: Y-39983 was compared with Y-27632 for selectivity of ROCK inhibition by biochemical assay. The IOP was monitored by pneumatonometer in albino rabbits and cynomolgus monkeys that were given topically administered Y-39983. The total outflow facility and uveoscleral outflow were measured by two-level constant-pressure perfusion and perfusion technique using fluorescein isothiocyanate-dextran, respectively, at 2 hours after topical administration of Y-39983 in albino rabbits. The ocular toxicologic effects of topical administration of Y-39983 were observed in albino rabbits and cynomolgus monkeys. RESULTS: A biochemical assay showed that Y-39983 inhibited ROCK more potently than Y-27632. In rabbits, topical administration of Y-39983 significantly increased conventional outflow by 65.5%, followed by significant, dose-dependent reduction in IOP. Maximum IOP reduction was 13.2 +/- 0.6 mm Hg (mean +/- SE) at 0.1% Y-39983 in rabbits. In monkeys, at 3 hours after topical administration of 0.05% Y-39983, maximum reduction of IOP was 2.5 +/- 0.8 mm Hg. No serious side effects were observed in ocular tissues except sporadic punctate subconjunctival hemorrhage during long-term topical administration of Y-39983 four times a day (at 2-hour intervals) in rabbits or monkeys. However, punctate subconjunctival hemorrhage was not observed with administration twice daily (at a 6-hour interval) or three times a day (at 5-hour intervals). CONCLUSIONS: Y-39983 causes increased outflow facility followed by IOP reduction. Y-39983 ophthalmic solution may be a candidate drug for lowering of IOP, since it increases conventional outflow and produces relatively few side effects.     

Topical verapamil lowers outflow facility in the rabbit eye.

Results of studies examining the mechanism of the ocular hypotensive effect of topical calcium channel blockers are controversial. Whereas evidence obtained in perfused human eyes indicates that these drugs lower intraocular pressure by increasing the aqueous humor outflow, tonographic studies in rabbits have revealed that they reduce both the aqueous humor outflow and inflow. In order to clarify such a discrepancy, the aim of this study was to assess whether the effect of topical verapamil on the facility of aqueous humor outflow in the rabbit eye was dose-related. Total outflow facility was determined by two-level constant pressure perfusion in anesthetized rabbits. The effect of 5 different concentrations on aqueous humor outflow at 60 minutes postdrug was studied in groups of 10 rabbits each. Baseline outflow facility was also determined in a group of 15 rabbits. In order to check the reliability of the method for detecting drug-induced changes in aqueous outflow, the effect of pilocarpine was also tested. Topical verapamil was shown to lower outflow facility in the rabbit eye in a dose-related fashion. On the contrary, topical pilocarpine was found to significantly increase outflow facility. Our data indicate that topical verapamil reduces outflow facility in the rabbit eye.     

Effects of brinzolamide on aqueous humor dynamics in monkeys and rabbits.

This study examines the mechanisms by which brinzolamide reduces intraocular pressure (IOP) in healthy rabbits and in monkeys with unilateral ocular hypertension. Intraocular pressures were measured by pneumatonometry and aqueous flow was determined by fluorophotometry before and after three twice-daily drops of 1% brinzolamide to both eyes per monkey and after similar treatment to one eye per rabbit. In monkeys, outflow facility was determined by fluorophotometry and uveoscleral outflow was calculated. In rabbits, outflow facility was determined by two-level constant pressure infusion and uveoscleral outflow was measured by an intracameral tracer technique. Compared with contralateral vehicle-treated rabbit eyes, IOP was reduced in brinzolamide-treated eyes by 2.5 +/- 1.9 mmHg (mean +/- standard deviation; p =.006) at four hours after the second dose. Aqueous flow was reduced by 0.50 +/- 0.65 microl/min (p =.02). This effect was found in rabbits previously treated with brinzolamide but not in naive rabbits. Treated hypertensive eyes of monkeys had a reduction in IOP of 7.3 +/- 8.8 mmHg (p = 0.01) and aqueous flow of 0.69 +/- 1.10 microL/min (p = 0.05) when compared with baseline. Brinzolamide did not affect outflow facility or uveoscleral outflow in either rabbits or monkeys. It is concluded that, in normotensive eyes of rabbits and hypertensive eyes of monkeys, brinzolamide reduces IOP by reducing aqueous flow and not by affecting aqueous humor drainage.     

Topical 8-bromo-cyclic GMP lowers intraocular pressure in rabbits

The topical application of 8-bromo-3'-5'-cyclic guanosine monophosphate (8BrcGMP) produces significant decreases in intraocular pressure (IOP) in rabbit eyes. Maximum effects are obtained with a 4% concentration, and IOP is reduced significantly (P less than 0.001) between 30 and 240 min after administration of the agent. The decrease in IOP occurs without significant change in tonographic outflow facility. A significant further decrease in IOP can be induced by topical 8BrcGMP in rabbits whose IOP has been lowered by the systemic administration of the carbonic anhydrase inhibitor acetazolamide.     

Effects of Adenosine Agonists on Intraocular Pressure and Aqueous Humor Dynamics in Cynomolgus Monkeys

The effects of single or multiple topical doses of the relatively selective A₁adenosine receptor agonists (R)-phenylisopropyladenosine (R-PIA) and N⁶-cyclohexyladenosine (CHA) on intraocular pressure (IOP), aqueous humor flow (AHF) and outflow facility were investigated in ocular normotensive cynomolgus monkeys. IOP and AHF were determined, under ketamine anesthesia, by Goldmann applanation tonometry and fluorophotometry, respectively. Total outflow facility was determined by anterior chamber perfusion under pentobarbital anesthesia. A single unilateral topical application of R-PIA (20–250 μg) or CHA (20–500 μg) produced ocular hypertension (maximum rise=4.9 or 3.5 mmHg) within 30 min, followed by ocular hypotension (maximum fall=2.1 or 3.6 mmHg) from 2–6 hr. The relatively selective adenosine A₂antagonist 3,7-dimethyl-1-propargylxanthine (DMPX, 320 μg) inhibited the early hypertension, without influencing the hypotension. Neither 100 μg R-PIA nor 500 μg CHA clearly altered AHF. Total outflow facility was increased by 71% 3 hr after 100 μg R-PIA. In conclusion, the early ocular hypertension produced by topical adenosine agonists in cynomolgus monkeys is associated with the activation of adenosine A₂receptors, while the subsequent hypotension appears to be mediated by adenosine A₁receptors and results primarily from increased outflow facility.     

A new procedure for the measurement of the outflow facility in conscious rabbits

A new procedure for measuring the outflow facility in conscious rabbits is described. The Langham pneumatic tonometer is applied horizontally against the eye; the intraocular pressure (IOP) is recorded before, during and immediately following 2 min of a pre-determined increased ocular pressure that is maintained at a fixed value by digital pressure applied through the eyelids. An increased volume of aqueous humor outflow resulting from the IOP increase is evaluated from the initial and final IOP values and the pressure volume relation for eyes of living rabbits. Close agreement in values of the outflow facilities in pairs of eyes of individual rabbits and excellent reproducibility of the procedure were found in repeated measurements made over a 24-hr period. The mean values of the IOP and the total outflow facility in 60 eyes of 30 rabbits were 20.5 +/- 0.2 mmHg and 0.17 +/- 0.01 microliter min-1 mmHg-1 respectively. Thirty minutes after an intravenous injection of acetazolamide, the IOP had decreased in both eyes of individual rabbits. This was associated with a decrease in the outflow facility and with a decrease of more than 50% in the rate of aqueous humor formation. One hour after the unilateral application of epinephrine the IOP had decreased in the treated eyes while the outflow facility remained unchanged.     

Aqueous humor dynamics in monkeys after topical 8-iso PGE(2)

PURPOSE: To determine in normotensive cynomolgus monkeys, the effects of topical 8-iso prostaglandin (PG)E(2) on intraocular pressure (IOP), aqueous humor formation (AHF), uveoscleral outflow (Fu), and total and trabecular outflow facility. METHODS: IOP was measured by Goldmann applanation tonometry under ketamine anesthesia after single or twice-daily topical treatments with 8-iso PGE(2). With animals under pentobarbital anesthesia, AHF and flow to blood (equated to trabecular outflow) were determined by anterior chamber perfusion with radioactively labeled albumin solution. Fu and trabecular outflow facility were calculated from these measurements. Total outflow facility was measured by two-level, constant-pressure perfusion. RESULTS: IOP was not significantly changed after single or multiple 10- micro g doses of 8-iso PGE(2). The 25- micro g dose significantly decreased IOP by 2 to 3 mm Hg compared to the contralateral vehicle-treated control 4 to 6 hours after a single dose and by 3 to 5 mm Hg within 1.5 hours after twice-daily treatments for 4 to 5 days. Total outflow facility corrected for control eye washout was increased by an apparent 37% (P < 0.02, n = 7) from 2 to 3.5 hours after the ninth dose, largely due to outlier values obtained in one monkey. Isotope studies performed after twice-daily treatments totaling 9 to 29 doses showed no change in AHF, trabecular outflow facility, or total outflow facility. Relative to AHF, trabecular outflow was significantly decreased, and the calculated Fu was significantly increased when all data were analyzed. CONCLUSIONS: The present findings are consistent with lowering of IOP by 8-iso PGE(2), primarily by increasing Fu. A direct effect on the trabecular meshwork was not indicated by these in vivo studies.     

A comparative study of topical natural ergot alkaloids on the intraocular pressure and aqueous humor dynamics in oclular normotensive and α-chymotrypsin-induced ocular hypertensive rabbits

Background Although it has been suggested that ergot derivatives may play a role in antiglaucoma therapy, little attention has been paid to the ocular hypotensive action of these drugs. Having previously reported that topical natural ergot alkaloids ergocristine α-ergocryptine and ergocornine dose-dependently reduce intraocular pressure in ocular normotensive and α-chymotrypsin-induced ocular hypertensive rabbits, the aim of the present work was to compare the effect of ergocristine, α-ergocryptine and ergocornine on the intraocular pressure and aqueous humor dynamics in ocular normotensive and α-chymotrypsin-induced ocular hypertensive rabbits, in order to further explore the ocular actions of these compounds. Methods Experiments were conducted in albino ocular normotensive and hypertensive rabbits by intracameral injection of α-chymotrypsin. Intraocular pressure responses to drug vehicle and seven different doses of topical natural ergot alkaloids were examined, in order to obtain dose–response relationships for comparing the intraocular pressure-lowering effect and potency of these drugs. Tonographies were also performed to ascertain the actions of natural ergot alkaloids on aqueous humor dynamics. Results All natural ergot alkaloids tested reduced intraocular pressure in a dose-related fashion. The ocular hypotensive effect was greater in α-chymotrypsin-induced ocular hypertensive rabbits for the three compounds tested. All natural ergot alkaloids tested decreased both tonographic outflow facility and, to a greater extent, aqueous humor inflow in ocular normotensive and in α-chymotrypsin-induced ocular hypertensive rabbits. Conclusion Taken together, our data suggest that these compounds decrease both tonographic outflow facility and, to a greater extent, aqueous humor inflow, which explains their final effect in ocular normotensive and in α-chymotrypsin-induced ocular hypertensive rabbits. Reductions in aqueous humor inflow observed after topical application of natural ergot alkaloids in α-chymotrypsin-induced ocular hypertensive rabbits can only be explained by a marked inhibition of active secretion of aqueous humor, since processes involved in aqueous humor formation may probably be altered after α-chymotrypsin injection.     

Effects of vasoactive intestinal polypeptide (VIP) on intraocular pressure, facility of outflow and formation of aqueous humor in the monkey

Stimulation of the facial nerve causes a non-cholinergic vasodilation in the uvea and a rise in the intraocular pressure in rabbits, cats and monkeys. Vasoactive intestinal polypeptide (VIP) has been suggested as the neurotransmitter mediating these effects. In the present investigation, the effects of VIP on aqueous humor dynamics were studied in cynomolgus monkeys. After intracameral injection of 1 microgram VIP, the outflow facility was higher in the experimental eye than in the control; 0.42 +/- 0.46 compared with 0.33 +/- 0.03 microliter cm H20-1 min-1, difference 0.09 +/- 0.04 microliter cm H2O-1 min-1. Intravenous infusion of VIP, 160 ng min-1, increased aqueous humor flow from 1.12 +/- 0.07 to 1.65 +/- 0.09 microliter min-1. Almost the same effect, a 50% increase in aqueous humor flow, was found after intracameral administration of 90 micrograms VIP. This dose of VIP caused a significant increase in intraocular pressure (IOP) in the experimental eye. The maximal difference in IOP between the experimental eye and the control eye was 7.5 +/- 0.4 cm H2O. A lower dose of VIP, 30 micrograms intracamerally, increased aqueous humor flow by about 20%, but had no consistent effect on IOP. The effect of VIP on aqueous humor flow was not affected by pretreatment with indomethacin. The results suggest that most of the rise in IOP caused by intracameral VIP administration is due to a rise in the pressure in the veins into which the aqueous humor is drained. Enhanced formation of aqueous humor plays a smaller role. The effects of VIP on aqueous humor formation and outflow facility suggest that the facial nerve may be involved in nervous control of aqueous humor dynamics, as VIP is most probably released in the eye by stimulation of the facial nerve.     

The 5-HT(1A)Receptor agonist 8-OH-DPAT lowers intraocular pressure in normotensive NZW rabbits

The aims of this study were first to investigate the effect of topical instillation of the 5-HT(1A)receptor agonist 8-OH-DPAT on intraocular pressure (IOP) in normotensive rabbits and second to establish whether the drug reaches the aqueous humour of treated and contralateral eyes at concentrations sufficient to activate ciliary epithelial 5-HT(1A)receptors. Following topical unilateral instillation of (+/-), (+) or (-)8-OH-DPAT, the IOP of rabbits was measured using an applanation tonometer. For the penetration study, [(3)H]8-OH-DPAT was instilled into one eye of each rabbit. Animals were killed after 30 min and the radioactive content of treated and contralateral ocular tissues was assessed. Administration of (+/-)8-OH-DPAT caused dose-dependent decreases in IOP in treated eyes of rabbits during the light and dark. The full 5-HT(1A)agonist (+)8-OH-DPAT was shown to be a more effective hypotensive agent than the partial agonist (-)8-OH-DPAT. The effect of (+/-)8-OH-DPAT on IOP was blocked by pretreatment with pindolol, a mixed 5-HT(1A)antagonist/beta-blocker, but not by the specific beta-blocker betaxolol. After instillation of [(3)H]8-OH-DPAT, peak levels of radioactivity were found in the cornea, followed by similar amounts in the iris-ciliary body and aqueous. There was negligible radioactivity present in tissues of the contralateral eye. This study demonstrates that topical administration of the 5-HT(1A)agonist 8-OH-DPAT dose-dependently decreases IOP in normotensive rabbits during the light and dark. The action of 8-OH-DPAT is presumably local to the anterior uvea as IOP was reduced only in treated eyes and [(3)H]8-OH-DPAT failed to reach the contralateral eye after unilateral instillation. Moreover, since 5-HT(1A)receptors are located in the rabbit ciliary epithelium and the effect of 8-OH-DPAT is blocked by a recognized 5-HT(1A)antagonist, the mechanisms of action of 8-OH-DPAT may well involve a decreased secretion of aqueous humour.     

Effect of oral losartan potassium administration on intraocular pressure in normotensive and glaucomatous human subjects

The effects of the type 1 angiotensin II receptor antagonist Losartan potassium on intraocular pressure (IOP) were studied. Four groups of subjects were analysed: group A, ten controls; group B, ten patients with essential arterial hypertension and with IOP within the normal range; group C, ten patients with primary open angle glaucoma (POAG), but without essential arterial hypertension; group D, ten patients with arterial hypertension and POAG. The study design was held in a randomized crossover double-blind fashion. Systolic and diastolic arterial pressure, heart rate, pupil diameter, IOP and total outflow facility were recorded at baseline and at 1 hr intervals up to 6 hr, following the oral administration of 50 mg of Losartan potassium and/or placebo. The alternative treatment was given a week later. Drug administration significantly reduced IOP in all subjects. No variation in heart rate and pupil diameter was observed during the follow-up period. Blood pressure dropped only in arterial hypertensive patients (groups B and D). Total outflow facility increased significantly in all groups. Placebo did not induce any variation in all groups. These findings demonstrate that the mechanism by which Losartan potassium reduces intraocular pressure is not mediated by a decrease in blood pressure, but rather it is more specific, confirming the role of the renin-angiotensin system also in the regulation of intraocular pressure in man.     

Correlation of aqueous humor ascorbate with intraocular pressure and outflow facility in hereditary buphthalmic rabbits

The hypotensive effect of ascorbate on intraocular pressure has been reported following topical application, oral administration, or anterior chamber infusion in animals. The present report describes the correlation of aqueous humor ascorbate concentration with intraocular pressure as well as outflow facility in vivo. Low aqueous ascorbate level was seen in buphthalmic eyes with high intraocular pressure and low outflow facility. The opposite correlation was observed in normal eyes. Ascorbate concentration in the anterior chamber of the rabbit eye is apparently related to the alteration of outflow facility and the movement of fluid in the anterior chamber.     

Effects of topical PGF2 alpha on aqueous humor dynamics in cynomolgus monkeys

Single topical applications of prostaglandin F2 alpha (PGF2 alpha) tromethamine salt to living cynomolgus monkey eyes reduced intraocular pressure (IOP). Twice daily topical application was far more effective, so that after the 7th 50 micrograms or 100 micrograms dose on day 4, IOP fell 40-50%, to 8-10 mm Hg. Following twice daily application of 50 or 100 micrograms for greater than 3 days: (1) no increase in total outflow facility could be demonstrated by 2-level constant pressure perfusion or Schiotz tonography; (2) no decrease in aqueous humor formation rate could be demonstrated by fluorophotometry--rather, aqueous flow may have increased; (3) anterior chamber aqueous humor protein concentration was unaltered, but entry of intravenously injected fluorescein into the cornea and anterior chamber tended to increase; (4) there was a weak but sometimes statistically significant miosis of up to approximately 0.5 mm. We conclude that in the cynomolgus monkey: (1) PGF2 alpha is a potent ocular hypotensive agent with only very weak miotic and blood-aqueous barrier-disrupting effects; (2) the ocular hypotensive action of PGF2 alpha is definitely not due to increased conventional outflow facility or decreased aqueous production, but probably to increased uveoscleral drainage of aqueous humor.     

Aqueous humor dynamics in alpha-chymotrypsin-induced ocular hypertensive rabbits.

Aqueous humor dynamics were studied in alpha-chymotrypsin-induced ocular hypertensive rabbits either by tonographic or two-level constant pressure perfusion techniques. A significant correlation was obtained between the values of outflow facility in alpha-chymotrypsin-induced ocular hypertensive rabbits as determined by tonography and constant pressure perfusion. The mean value of tonographic outflow facility in ocular hypertensive rabbits was not statistically different from that found in ocular normotensive rabbits. On the contrary, the estimated rate of aqueous inflow in ocular hypertensive rabbits was about 1.5-fold higher than that of ocular normotensive ones. While topical timolol lowered intraocular pressure and aqueous humor inflow in ocular hypertensive rabbits, pilocarpine did not produce any significant effect. Aqueous humor protein was significantly increased in ocular hypertensive eyes. The results of this study show that accurate measurements of outflow facility can be obtained in alpha-chymotrypsin-induced ocular hypertensive rabbits by tonographic technique. Our data suggest that the long-term ocular hypertension induced by alpha-chymotrypsin in albino rabbits may be secondary to an increase in the rate of aqueous humor inflow, likely produced by a breakdown of the blood-aqueous barrier. This finding strongly conflicts with the hypothesis of trabecular blockage as the cause of alpha-chymotrypsin-induced ocular hypertension in this species.