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.     

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 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.     

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.     

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 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.     

Noninvasive assessment of aqueous humor turnover in the mouse eye

PURPOSE: To develop a noninvasive test for monitoring changes in aqueous humor turnover in the mouse eye. METHODS: After topical instillation of fluorescein, the rate of decay of fluorescence from aqueous humor and cornea was monitored in Black Swiss, C57 Bl6, and DBA 2J mice with a microscope equipped with epifluorescence and a charge-coupled device (CCD) camera. RESULTS: The rate of decay of fluorescence was identical in right and left eyes over an approximately 70-minute measurement period. The rate of decay was similar in normal mice aged 2 and 18 months. Pilocarpine and latanoprost, known to enhance aqueous humor outflow in humans, accelerated the decay of fluorescence. Levobunolol, known to inhibit aqueous humor inflow in humans, slowed decay. Dimethylamiloride, an inhibitor of the Na(+),H(+) exchanger that is known to act on cultured cells of both the ciliary epithelium and trabecular meshwork and to lower mouse intraocular pressure (IOP), enhanced decay. DBA 2J mice, in which secondary glaucoma develops, displayed a slower decay of fluorescence at 18 months of age than age-matched unaffected animals. CONCLUSIONS: Monitoring decay of fluorescence provides a noninvasive index of aqueous humor dynamics in the mouse eye that facilitates study of ocular hypotensive drugs and mouse models of glaucoma. Coupled with knowledge of IOP, it permits semiquantitative conclusions about the relative roles of aqueous humor inflow and outflow in conditions with altered IOP. Based on this approach, dimethylamiloride appears to lower mouse IOP primarily by enhancing outflow of aqueous humor.     

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.     

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 angiotensin II on uveoscleral outflow in rabbits

PURPOSE: In our previous study, we showed that the AT1 receptor antagonist increased uveoscleral outflow (USF) when topically applied to the rabbit eye. However this increase was too small to demonstrate a clear physiological role for ocular angiotensin II (AII). Hence, the purpose of this study was to determine whether ocular AII influenced USF regulation, and if so, how this occurred. METHODS: USF was measured by the FITC-dextran perfusion method in albino rabbits. AII and its receptor antagonists were directly applied into the anterior chamber by adding into the perfusate and by perfusing with FITC-dextran. We also analyzed angiotensin receptors on the rabbit ciliary body membrane by a receptor binding assay with 125I-[Sar1), Ile8]-AII as a ligand. RESULTS: CS-088 (1 microg/ml) increased USF by 24% while AII decreased USF in a concentration-dependent manner between 10 and 500 nM. Its maximum decrease of 19% occurred at 500 nM. At this AII concentration the USF reduction was antagonized by 1 microg/ml CS-088, an AT1-receptor antagonist, but not by the same concentration of PD-123,177, an AT2-receptor antagonist. Specific 125I-[Sar1, Ile8]-AII binding to the rabbit ciliary body membranes was inhibited by CS-088 with an inhibition constant of 7.05 nM, whereas inhibition by PD-123,177 was not observed. CONCLUSIONS: Ocular AII was indicated to attenuate USF via AT1 receptors in rabbits, however its physiological effect was not critical in IOP regulation.     

The ocular hypotensive effects of demeclocycline, tetracycline and other tetracycline derivatives

Demeclocycline, tetracycline and other tetracycline derivatives lowered intraocular pressure (IOP) in rabbits following intravitreal injection, but the onset of this effect was not evident until 1 or more days after drug administration. Of the drugs tested, demeclocycline was the most active ocular hypotensive agent. Demeclocycline caused a dose-dependent decrease in IOP. The maximum IOP decrease of approximately 12 mm Hg occurred 5 days after intravitreal administration of 0.5 mg, with the effect persisting for over a week. Demeclocycline did not alter tonographically measured aqueous humor outflow facility or episcleral venous pressure. Based on calculated aqueous humor flow rates following 0.2 mg demeclocycline, a 62% decrease in aqueous humor formation occurred 7 days after intravitreal injection. The flow-to-diffusion ratio for ascorbate was reduced 54% 6 days after the intravitreal administration of demeclocycline, a change also consistent with suppression of aqueous humor formation. Anterior chamber aqueous humor protein concentration was increased 6 days after demeclocycline administration. No histologic changes were present in the treated eyes by light microscopy. Intravitreal demeclocycline similarly lowered IOP in cats, with the duration of effect lasting up to 20 days.     

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.     

Contributions of adenosine receptor activation to the ocular actions of epinephrine.

PURPOSE: Epinephrine is an effective drug for glaucoma treatment. However, the mechanisms responsible for the ocular hypotensive action of this compound are not completely understood. Adenosine is an autacoid released by all cells. This study evaluated the role of adenosine receptor activation in epinephrine-induced changes in ocular function. METHODS: Rabbits were pretreated topically with the moderately selective adenosine A1 antagonist 8-(p-sulfophenyl)theophylline (8-SPT) or the adenosine A2 antagonist 3,7-dimethyl-l-propargylxanthine (DMPX). Epinephrine (500 microg) was then administered, and intraocular pressures (IOPs), pupil diameters (PDs), or total outflow facility was evaluated. In a separate group of animals, epinephrine or vehicle was administered, and aqueous humor samples obtained to evaluate changes in aqueous humor purine levels by means of high-performance liquid chromatography. RESULTS: In control animals, epinephrine produced a biphasic change in IOP: an initial rise in IOP of approximately 1 mm Hg from 1/2 to 1 hour followed by significant reduction in IOP of 8 to 9 mm Hg from 3 to 5 hours postadministration. These animals also exhibited a significant increase in PD of 2 to 3 mm from 1/2 to 2 hours postadministration. Pretreatment with 8-SPT (1000 microg) enhanced the initial rise in IOP, while significantly inhibiting the ocular hypotensive response. Pretreatment with 8-SPT also significantly enhanced the epinephrine-induced increase in PD. Inhibition of the epinephrine-induced reduction in IOP by 8-SPT was dose-related with an IC50 of 446 microg. Administration of 8-SPT alone did not significantly alter IOP or PD. The A2 antagonist DMPX did not alter the epinephrine-induced change in IOP or PD. In rabbits pretreated with 8-SPT, the epinephrine-induced increase in outflow facility was significantly reduced by 60% when compared with those in rabbits treated with epinephrine alone. In vehicle-treated rabbits, aqueous humor adenosine and inosine levels were 2.7 +/- 0.38 and 29 +/- 4.2 ng/100 microl, respectively. Three hours after epinephrine administration, adenosine and inosine levels had significantly increased to 11 +/- 1.6 and 66 +/- 4.4 ng/100 microl, respectively. CONCLUSIONS: These results support the idea that in rabbits epinephrine administration stimulates adenosine release in the anterior segment. This rise in endogenous levels of adenosine then leads to the activation of ocular adenosine receptors and is in part responsible for the ocular hypotensive action of epinephrine.     

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.     

Effect of flunarizine, a calcium channel blocker, on intraocular pressure and aqueous humor dynamics in monkeys

PURPOSE: To evaluate the effects of flunarizine, a nonselective calcium channel blocker, on intraocular pressure (IOP) in monkeys with laser-induced unilateral glaucoma and on aqueous humor dynamics in normal monkeys. METHODS: The IOP was measured before and hourly for 6 hours after single-dose administration of 0.5%, 1%, or 2% flunarizine to the glaucomatous eye of 8 monkeys with unilateral laser-induced glaucoma. In a separate multiple-dose study, 0.5% flunarizine was applied twice daily for 5 consecutive days to the glaucomatous eye of the same 8 monkeys. IOP was measured at untreated baseline, after treatment with vehicle only, and on treatment days 1, 3, and 5. Tonographic outflow facility and fluorophotometric flow rates of aqueous humor were measured in 7 normal monkeys before and after the fifth dose of twice-daily treatment with 0.5% flunarizine. RESULTS: Unilateral application of 50 microL of 0.5%, 1%, or 2% flunarizine reduced IOP bilaterally. In the treated glaucomatous eyes, flunarizine reduced the IOP for 2, 3, or 5 hours, with a maximum reduction of 2.5+/-0.5 (mean+/-SEM) mm Hg (9%), 3.0+/-0.4 mm Hg (10%), and 5.0+/-0.8 mm Hg (18%) following the 0.5%, 1%, and 2% concentrations, respectively (P<0.01). The maximum reductions in IOP in the contralateral untreated eyes were 1.3+/-0.5 mm Hg, 1.5+/-0.3 mm Hg, and 2.9+/-0.7 mm Hg following the 0.5%, 1%, and 2% concentrations, respectively (P<0.05). Both the magnitude and duration of the ocular hypotensive effect of 0.5% flunarizine were enhanced with twice-daily administration for 5 days. Outflow facility in normal monkey eyes was increased (P<0.05) by 39% in the treated eyes compared with vehicle-treated contralateral eyes and by 41% compared with baseline values, and aqueous humor flow rates were unchanged (P>0.30). CONCLUSIONS: Flunarizine reduces IOP in a dose-dependent manner when administered to glaucomatous monkey eyes, but also has an ocular hypotensive effect on the contralateral untreated eyes. An increase in tonographic outflow facility seems to account for the IOP reduction in normal monkey eyes.     

Intraocular pressure responses to the adenosine agonist cyclohexyladenosine: evidence for a dual mechanism of action.

PURPOSE. Previous studies have shown that adenosine agonists are effective in reducing intraocular pressure (IOP). However, the mechanism(s) responsible for this ocular hypotensive effect has not been established. This study evaluates the relative contribution of changes in aqueous flow and outflow facility associated with the ocular hypotensive response to the adenosine agonist cyclohexyladenosine (CHA). METHODS. New Zealand White rabbits were treated topically in one eye with the adenosine A(1) agonist CHA. Changes in IOP, aqueous flow, and total outflow facility at various times after CHA administration were then determined. RESULTS. These studies demonstrated that CHA produces a dose-related reduction in IOP. Analysis of the dose-response curve revealed an ED(50) and a Hill coefficient of 87 microg and 1.9, respectively. Aqueous flow measurements demonstrated that 1.5 hours after CHA administration, aqueous flow was reduced by 35%. However, by 3.5 hours postdrug, no significant change in aqueous flow was observed. Measurement of the outflow facility found no significant change in facility 1.5 hours after CHA administration. However, by 3.5 hours after CHA administration, outflow facility was significantly increased by 85%. CONCLUSIONS. These data demonstrate that the adenosine agonist CHA lowers IOP in a dose-related fashion. This hypotensive action results from an early reduction in aqueous flow followed by a subsequent increase in outflow facility. This dual mechanism of action is consistent with analysis of CHA dose-response curve, which indicates that the reduction in IOP induced this agonist's results from multiple mechanisms of action.     

Iloprost, a stable prostacyclin analog, reduces intraocular pressure

Topical application of Iloprost caused a dose-dependent decrease in intraocular pressure (IOP) in rabbits and ocular hypertensive beagles. In rabbits, the IOP response was biphasic and miosis was observed. In beagles, there was no initial hypertensive phase, and the fall in IOP was more pronounced (up to 37%). In beagles, Iloprost did not influence pupillary diameter. A mild transient hyperemia was noted in both rabbit and beagle eyes. Iloprost led to an increase in the aqueous humor protein concentration in rabbits but not in beagles. The use of artificial tears as vehicle enhanced the effect on intraocular pressure but also aqueous protein in rabbits. The central corneal temperature was increased after application of Iloprost in both rabbits and beagles. In rabbits, tonography revealed an increase in outflow facility during both the hypertensive and the hypotensive phases. Iloprost caused a decrease in mean arterial pressure in beagles; the effect on pulse rate was inconsequential. It is suggested that similar low doses of an analog of Iloprost or carboprostacyclin that does not affect the hemodynamic equilibrium could be of value in the treatment of glaucoma.     

The effect of topical PGF2 alpha on uveoscleral outflow and outflow facility in the rabbit eye.

Prostaglandin F2 alpha (PGF2 alpha) is a powerful ocular hypotensive agent in rabbit, cat, dog, monkey and human. In cynomolgus monkeys, the intraocular pressure (IOP) lowering is due to increased uveoscleral outflow (Fu). Because the anatomy of the rabbit outflow apparatus differs significantly from that of the primate, we sought to determine whether the mechanism of the PGF2 alpha-induced IOP fall was the same. PGF2 alpha tromethamine salt (PGF2 alpha-TS) (50 micrograms) applied to one eye of 14 conscious rabbits produced a significant IOP fall of 7.4 +/- 0.9 mmHg (P less than 0.001). In untreated control eyes, Fu determined from the quantity of intracamerally perfused [125I]albumin found in the ocular and periocular tissues accounted for 5-8% of total aqueous outflow. In 15 unilaterally PGF2 alpha-treated rabbits, after 4-6 hr dosing Fu was 49 +/- 14% higher in the treated than in the contralateral control eyes. Total outflow facility of outflow from the anterior chamber to the general circulation were measured concurrently in 11 rabbits using a two-level constant pressure perfusion and isotope accumulation technique. Both facilities tended to be higher in the treated eyes than in the controls, with a strong correlation between drug-induced changes in total facility and changes in facility of flow to blood (r = 0.85, P less than 0.001). In eight rabbits treated unilaterally with 50 micrograms PGF2 alpha-TS, the fluorophotometrically determined aqueous formation rate was probably not decreased relative to control eyes. Protein levels in the aqueous humor were approximately eight-fold higher in PG-treated vs. control eyes, suggesting a drug-induced compromise of the blood-aqueous barrier.(ABSTRACT TRUNCATED AT 250 WORDS)     

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     

Effect of 15-keto latanoprost on intraocular pressure and aqueous humor dynamics in monkey eyes

PURPOSE: To compare the ocular hypotensive effects of 15-keto latanoprost (KL) with the commercial preparation of latanoprost (Xalatan; Pfizer, New York, NY) in monkey eyes with laser-induced unilateral glaucoma and to evaluate the effects of topical 0.005% KL on aqueous humor dynamics in normal monkey eyes. METHODS: Intraocular pressure (IOP) was measured hourly for 6 hours beginning at 9:30 AM on day 1 (untreated baseline); day 2 (vehicle only); and treatment days 1, 3, and 5 (topical, 30 microL of study drug) in the glaucomatous eyes of four to eight monkeys with unilateral laser-induced glaucoma. KL concentrations of 0.0001%, 0.001%, and 0.01% and latanoprost at 0.005% were studied separately, with a minimum washout period of 2 weeks between studies. Tonographic outflow facility (C) and fluorophotometric aqueous humor flow rates (F) were measured in nine normal monkeys before and after a single topical dose of 0.005% KL in one eye, with a vehicle-only control in the fellow eye. RESULTS: When applied once daily to glaucomatous monkey eyes, all three concentrations of KL and a 0.005% concentration of latanoprost produced significant (P < 0.05) reductions in IOP, with the maximum reduction on treatment day 5, regardless of the drug or concentration studied. The maximum reduction (P < 0.001) from vehicle-only baseline IOP was (mean +/- SEM) 3.0 +/- 0.3 mm Hg (9%) for 0.0001% KL, 7.6 +/- 0.6 mm Hg (23%) for 0.001% KL, 6.3 +/- 0.4 mm Hg (18%) for 0.01% KL, and 6.6 +/- 0.6 mm Hg (20%) for 0.005% latanoprost. After application of a single dose of 0.005% KL in nine normal monkey eyes, neither C nor F was altered (P > 0.80) when compared with untreated baseline values or vehicle-treated control eyes. CONCLUSIONS: The reduction in IOP produced by 0.001% KL was equivalent to, and at some measured time points, greater than the effect produced by 0.005% latanoprost. The IOP reduction by KL in normal monkeys appeared to have no effect on aqueous humor production or tonographic outflow facility and may thus indicate a drug-induced increase in uveoscleral outflow.