Ocular effects of a relatively selective alpha 2 agonist (UK-14, 304-18) in cats, rabbits and monkeys

UK-14, 304-18 (UK), a relatively selective alpha 2-agonist, was examined for its effects on intraocular pressure (IOP) and pupil diameter (PD) in rabbits, cats and monkeys and on noradrenergic function in the cat nictitating membrane (CNM) preparation. Topical, unilateral administration of UK (0.0005-0.5 mg) produced dose-dependent decreases in IOP and pupil size in normal, unanesthetized rabbits, cats and monkeys. The ocular hypotensive effect of UK in the ipsilateral eye was delayed relative to the contralateral eye in all three species; UK produced an initial transient ocular hypertension in rabbits which was abolished by surgical transection of three major extraocular muscles. Mean arterial blood pressure in rabbits was not affected by 0.005 mg UK topically. The ocular hypotensive and miotic effects of UK were attenuated in superior cervical ganglionectomized (SX) cats and rabbits. Intra-arterially administered UK (0.33, 1.0, 3.3 and 10 micrograms) produced dose-related systemic hypotension and inhibition of contractions of the CNM elicited by electrically stimulating the pre- and postganglionic sympathetic trunks in the urethane/chloralose anesthetized cat. This inhibition was reversed and prevented by 300 micrograms rauwolscine but not by 300 micrograms domperidone. UK also enhanced the contractile response of the CNM to injected norepinephrine (10 micrograms). UK suppressed ocular hypertension induced by water loading and IOP recovery rate following hypertonic saline infusion in rabbits suggesting that aqueous flow was inhibited. These results indicate that UK lowers IOP, in part, by suppressing sympathetic neuronal function which causes a reduction in aqueous flow.     

Forskolin suppresses sympathetic neuron function and causes ocular hypotension

Recent reports suggest that forskolin can produce ocular hypotension in laboratory animals and man by enhancing formation of cyclic AMP. This proposed mechanism of action implies that forskolin lowers intraocular pressure (IOP) by activating adenylate cyclase at some postjunctional site. Intra-arterial (i.a.) injections of forskolin (10, 33, 100 & 333 micrograms) into the cat nictitating membrane (CNM) preparation produced dose-related inhibition of contractions elicited by electrical stimulation of pre-and postganglionic sympathetic neurons. Interestingly, contractions elicited by i.a. norepinephrine were inhibited less than neuronally mediated contractions. Topically applied forskolin (0.5 mg) to the eyes of unilaterally sympathectomized (SX) rabbits and normal rabbits elicited ocular hypotension in the innervated eyes only. Forskolin (0.5 mg, topically) suppressed the rise in IOP induced by water loading in normal rabbits but was significantly less effective in SX rabbits. These results suggest that forskolin lowered IOP in rabbits and suppressed contraction of the electrically-stimulated CNM, in part, by inhibiting sympathetic neuronal function.     

Medetomidine-induced alterations of intraocular pressure and contraction of the nictitating membrane.

The alpha-2 adrenoceptor agonist, medotomidine (MED), was examined for effects on: (1) intraocular pressure (IOP) in normal and sympathectomized (SX) rabbits; (2) IOP in normal rabbits pretreated with the alpha-2 antagonist idazoxan; (3) contractions of the cat nictitating membrane (CNM) elicited by nerve stimulation and intra-arterial (IA) norepinephrine. Unilateral topical administration of MED (7.5-75 micrograms) caused dose-dependent, bilateral IOP reduction in normal eyes, but MED (25 micrograms) had no appreciable hypotensive activity in SX eyes. The ocular hypotensive effect of MED (25 micrograms) was antagonized by treatment with idazoxan (100 micrograms, bilaterally), a relatively selective alpha-2 antagonist. MED and dexmedetomidine (DMED) also inhibited frequency-related contractions of CNM induced by electrical stimulation of the cervical sympathetic trunk. Rauwolscine (100 micrograms, IA) shifted the MED dose response in the CNM to the right indicative competitive antagonism, whereas SK&F 104078 (300 micrograms, IA), a relatively dose-selective postjunctional alpha-2 antagonist, had no effect on DMED suppression. These results show that MED lowers IOP in part, by interacting with alpha-2 adrenoceptors located on sympathetic nerve endings. An effect of MED on imidazoline sites may also be possible.     

Central cholinergic stimulation affects ocular functions through sympathetic pathways

Intracerebroventricular (ICV) injection of carbachol into the third ventricle of conscious rabbits increased pupil size and intraocular pressure (IOP). A significant increase of pupil size by 0.6-1.3 mm for 60-90 min was observed with the dose of 1 microgram and an increase of IOP by 1.1-1.9 mmHg for 15-60 min was observed with doses over 10 ng. These responses were due to central cholinergic stimulation; mydriasis was eliminated by ICV injection of atropine and the elevation of IOP was significantly reduced by ICV injections of atropine and hexamethonium. Transection of the cervical sympathetic trunk eliminated the mydriasis. The efferent pathway for the mydriasis is via the cervical sympathetic nerve. The elevation of IOP was significantly reduced but not eliminated in the decentralized eye. Plasma epinephrine (Epi) and norepinephrine (NE) increased at 30 min after the ICV injection of 1 microgram carbachol. It is hypothesized that the elevation of IOP is due mainly to the stimulation of ocular sympathetic nerves and the increase of circulating catecholamines. Topical treatment of 0.01% timolol significantly reduced the IOP elevation, indicating the involvement of ocular beta-adrenergic mechanism in the elevation of IOP.     

Central imidazoline (I(1)) receptors modulate aqueous hydrodynamics

The purpose of this work is to determine the relative contributions of central imidazoline (I(1)) receptors to the ocular hydrodynamic action of moxonidine. Moxonidine (MOX), an alpha(2) and I(1) receptor agonist, and efaroxan (EFA), a relatively selective I(1) antagonist, were utilized to study alterations in intraocular pressure (IOP) and aqueous flow in New Zealand white rabbits subjected to intracerebroventricular (i.c.v.) cannulation and sympathectomy. Intracerebroventricular administration of MOX (0.033, 0.33 and 3.33 microg) to normal rabbits produced dose-dependent, bilateral IOP decreases of 3, 6, and 8 mmHg, respectively. The ocular hypotensive response to MOX was immediate (10 min. post drug), lasted for one hour, and was inhibited by prior administration of efaroxan (3.33 microg i.c.v.). In unilaterally sympathectomized (SX) rabbits, the ocular hypotensive response induced by i.c.v MOX in the denervated eye was attenuated approximately 50%, but the duration of ocular hypotension in the surgically altered eye was longer than that of the normal eye. MOX (0.33 microg i.c.v.), caused a statistically significant decrease (2.24 to 1.59 ml/min.) in aqueous flow in normal eyes. In SX eyes, there was no change in aqueous flow by MOX, suggesting that IOP effect in i.c.v. MOX observed in the SX eye might be mediated by changes in outflow resistance. Sedation was observed in all the rabbits treated with MOX (i.c.v.) and was dose-dependent. These in vivo data support the suggestion that centrally located I(1) receptors modulate the early contralateral response to topically administered MOX and are involved in lowering of IOP and aqueous flow in rabbit. In addition, expression of the full ocular hypotensive effect of centrally applied MOX depends on intact sympathetic innervation. Ocular hypotension induced by MOX in the SX eye may involve an effect on uveoscleral outflow.     

An in vivo model for dissociating alpha 2-and DA2-adrenoceptor activity in an ocular adnexa: utility of the cat nictitating membrane preparation

Recent reports from this laboratory indicate that dopamine (DA2) agonists can lower intraocular pressure (IOP) in rabbits, monkeys and rats. This communication suggests that the cat nictitating membrane (CNM) preparation is a useful model for localizing the site(s) and mechanism(s) of action of dopamine (DA2) agonists and that this model can be used to discriminate between alpha 2 and DA2 activity. This in vivo preparation consists of indirect (neuronal)- and direct (agonist)-induced activation of the CNM by: 1) pre- and postganglionic stimulation of sympathetic nerves and 2) injection of norepinephrine (NEPI) into the external carotid artery (i.a.). A variety of DA2-agonists (ergolines, azepines, aminotetralins, aporphines) can cause dose-dependent depression of neuronally mediated contractions with minimal effects on contractions elicited by NEPI i.a. Characteristically, DA2-agonists depressed contractions elicited by low frequency (2 & 4 Hz) stimulation more than high frequency (6 & 8 Hz) stimulation. For example, the inhibitory effects of an ergoline derivative LY141865 on neuronally mediated contractions of the CNM could be reversed (or prevented) by relatively selective DA2 antagonists, such as sulpiride and domperidone, but not by relatively selective alpha 2-antagonists, such as yohimbine and rauwolscine. Interestingly, alpha 2-adrenoceptor agonists, such as clonidine and xylazine, caused less depression of nerve-stimulated responses than did DA2-agonists at the same dose. This modest suppression by alpha 2-agonists could be inhibited by yohimbine but not by sulpiride or domperidone. These results with the CNM document the presence of DA2 receptors on sympathetic neurons innervating an ocular adnexa and demonstrate a model for dissociating DA2 from alpha 2 activity.     

莫索尼定滴眼液点眼对家兔眼压及血压的影响

目的探讨不同剂量莫索尼定（MOX）滴眼液点眼对眼压、瞳孔、血压和心率的影响。方法 32只家兔全身麻醉后行双眼前房穿刺并连接于生理记录仪描记眼压,行单侧颈动脉插管并连接于生理记录仪描记血压、心率波动。分别将质量分数0.05%、0.1%和0.2%的MOX单侧点眼,同步观察点眼后8h内双侧眼压、瞳孔、血压和心率的变化。结果 0.05%、0.1%、0.2%MOX组点眼后实验眼最大眼压下降幅度分别为3.01mmHg（18.31%）、3.70mmHg（22.13%）和4.46mmHg（25.60%）,降眼压持续时间分别为6h、8h和8h以上。对侧眼眼压下降持续时间较短,最大眼压下降幅度分别为2.64mmHg（15.46%）、3.10mmHg（18.82%）和2.62mmHg（16.48%）。3组MOX滴眼液点眼均可使实验眼瞳孔散大,最大散瞳幅度分别为2.6、3.2、3.9mm。MOX滴眼液点眼对心率影响轻微,0.05%MOX组和0.1%MOX组点眼不影响实验动物的血压,0.2%MOX组可使实验动物舒张压下降,最大下降值为8.85mmHg（9.93%）。结论 MOX滴眼液点眼对家兔有降眼压作用,中低剂量的MOX对实验动物的血压、心率等无明显影响。     

Long-term maintenance of reduced intraocular pressure by daily or twice daily topical application of prostaglandins to cat or rhesus monkey eyes

Substantial evidence indicates that a single topical application of prostaglandins (PGs) can reduce intraocular pressure (IOP) in the eyes of several species. However, earlier literature, dealing with ocular hypertensive and inflammatory responses, shows the development of tachyphylaxis to subsequent doses of PGs. If similar tolerance developed to the ocular hypotensive effects of PGs, it would preclude the use of these agents in the treatment of chronic glaucoma. The present study shows, however, that although tachyphylaxis to the ocular hypotensive effects of PGs develops in rabbits, this is not a typical response among mammals. Significant IOP reduction was maintained in cats for up to 9 months by topical application of PGE2 at 12-, 24-, or 48-hr intervals. The IOP reduction was jeopardized seriously only when the PG was applied every other day for several days or when, on a few occasions, 3 days were allowed to elapse between PGE2 applications. Ocular hypotension was also maintained during the course of topical treatment of rhesus monkey eyes with PGF2 alpha. Short periods of pupillary constriction followed the application of each dose of PGF2 alpha to cat eyes, but the miotic response of rhesus monkeys to PGF2 alpha and cats to PGF2 was negligible. Other apparent side effects were noted, but none of these were severe or progressive. These results clearly demonstrate that tachyphylaxis, or tolerance, is not expected to present an obstacle to the development of eicosanoids and/or their derivatives as therapeutic agents for the long-term treatment of ocular hypertension and chronic glaucoma.     

Ocular pigmentation and intraocular pressure response to forskolin

We studied the effects of a forskolin suspension on intraocular pressure (IOP) in normal albino and pigmented rabbits and in alpha-chymotrypsin induced ocular hypertensive rabbits. Experimental-induced ocular hypertensive rabbits were produced by injecting of alpha-chymotrypsin (167 units) into the posterior chamber of the eye of albino rabbits. Ocular hypertensive rabbits were classified into 3 groups according to the IOP (Group A; 15-19 mmHg, B; 20-24 mmHg, C; 25-29 mmHg). Topical application of 1% forskolin caused a significant decrease in IOP in Groups B and C, as well as in normal albino and pigmented rabbits. The hypotensive effects were lower in pigmented rabbits than in albino rabbits, although the duration was longer. Subconjunctival injection of 1% forskolin reduced IOP 1 to 5 hrs after treatment in albino rabbits. However, in pigmented rabbits, a slight increase in IOP was observed at 30 min, followed by a significant decrease 5 to 10 hrs after injection. Furthermore, the binding ability of forskolin to melanin granules was determined in vitro. Forskolin exhibited specific affinity towards melanin granules obtained from bovine eyes, with the binding reaching a plateau after 5 min of incubation.     

The intraocular pressure lowering effects of UF-021, a novel prostaglandin related compound, in animals]

The ophthalmic solution of UF-021, a novel prostaglandin (PG) related compound, was investigated for its intraocular pressure (IOP) reducing activity and local ocular side effects in different species of animals. UF-021 ophthalmic solution (0.03 to 0.24%), when topically applied to the eyes of rabbits, caused dose-dependent IOP reduction (2.8 to 5.2 mmHg), without transient IOP rise. Both in cats and monkeys, UF-021 ophthalmic solution (0.12%) elicited rapid, significant IOP reduction (ca. 9 mmHg and 2 mmHg, respectively), without any controversial, local ocular side effects being revealed. On the other hand, PGE2, PGF2 alpha-isopropyl ester all brought about marked increases in IOP prior to development of their IOP reducing activities. In addition, these primary PGs showed intense local ocular irritation, which presented a striking contrast with UF-021. Enhancement of IOP reducing activity, coupled with freedom from any significant ocular side effects, as described above, suggests that UF-021 ophthalmic solution could be promising as a new anti-glaucoma agent.     

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.     

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 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.     

Detergents modify uveal flow and intraocular pressure

Detergents were administered intra-arterially to isolated arterially perfused eyes of rabbits and cats. Tween 80, Triton X-100, digitonin and sodium dodecyl sulphate (SDS) constricted uveal vessels and raised intraocular pressure (IOP) except for SDS which lowered IOP. Digitonin, a type B detergent was more active than three other detergents of type A. None of the four detergents did affect pupil size. After preconstriction with epinephrine low concentrations of nonionic detergents dilated uveal vessels but the fall in IOP by epinephrine was not affected; higher doses raised IOP. After preconstriction by eserine + Ach there were no effects of detergents on uveal flow and IOP. Mepacrine decreased the ocular effects of detergents suggesting that at least part of the effects from detergents is due to liberation of phospholipids.     

Modulation of ocular hydrodynamics and iris function by bremazocine, a kappa opioid receptor agonist

This study was designed to determine the activity of bremazocine (BRE), a relatively selective kappa opioid receptor agonist, on intraocular pressure (IOP), aqueous humor formation and pupil diameter (PD) in conscious, normal, dark-adapted New Zealand white (NZW) rabbits. IOP was measured in normal and unilaterally sympathectomized rabbits using a calibrated pneumatonometer and the aqueous flow rate was determined by the use of a Fluorotron Master. A masked-design study was conducted in which the rabbits' eyes were treated with BRE topically and unilaterally; the fellow eyes received vehicle. IOP and PD measurements were taken at 0.5 hr and 0 time before BRE and 0.5, 1, 2, 3, 4 and 5 hr post-treatment. Fluorophotometry recordings were taken at 1 hr before and 0.5, 1.5, 2.5 and 3.5 hr after topical application of the drug or vehicle. The effect of the relatively selective kappa opioid receptor antagonist, nor-binaltorphimine (nor-BNI), on bremazocine-induced changes in IOP, PD and aqueous flow was also determined. BRE (10 and 100 micrograms 25 microliters-1 vehicle) produced dose-related, bilateral reductions in IOP, PD and aqueous humor flow. A large increase in IOP (14 mmHg) was observed when BRE (100 micrograms) was applied to sympathectomized eyes. This ocular hypertensive effect was antagonized when the sympathectomized eyes were pretreated with naloxone (200 micrograms), a non-selective opioid receptor antagonist. BRE (10 and 100 micrograms) decreased the aqueous humor flow rate bilaterally by approximately 48 and 60%, respectively, at 0.5 hr after administration to the ipsilateral eye. Nor-BNI (100 micrograms) antagonized the effect of BRE (10 micrograms) on IOP and aqueous flow rates more effectively than on PD. These data indicate that bremazocine causes reductions in IOP by suppressing aqueous flow, but the ocular hypotensive effects are dependent on the presence of intact sympathetic nerves. Antagonism of BRE's effects on aqueous humor dynamics by nor-BNI suggests that the mechanism of IOP and aqueous flow reduction may involve, in part, an action on kappa receptors. Further experiments are necessary to fully define the opioid receptor populations in the ciliary body.     

pH dependency of effect of topically applied dipivefrine hydrochloride on intraocular pressure and pupil size in rabbits: comparative studies with epinephrine

The pH and dose dependencies of topically applied dipivefrine hydrochloride (DPE) on intraocular pressure (IOP) reduction and mydriasis were compared with those of epinephrine bitartrate (EPI) in normal rabbits. Statistically significantly greater IOP lowering and mydriatic effects of DPE solutions were achieved by increasing their pH from 3 to 6 or their concentrations from 0.02% to 0.1%. The ocular hypotensive and mydriatic effects of EPI also depended on their concentrations, but not on their pH. On the other hand, blink rates of rabbits following topical application of DPE tended to be reduced by the increase of pH, while they were not influenced by the concentrations. From these results, it was indicated that the pharmacological effects of DPE were augmented about 3 times by increasing the pH of its solutions from 3 to 5, which also was associated with reduction of ocular irritation, while the effects of EPI were not altered by the changes of pH. As the result of the increase of pH from 3 to 5, DPE became about 50 times more potent than EPI as a ocular hypotensive agent.     

Ocular rigidity evaluation after photorefractive keratectomy: an experimental study

PURPOSE: To evaluate possible changes of the ocular rigidity coefficient in vivo after photorefractive keratectomy (PRK) in a series of rabbit eyes, using an invasive ocular rigidity measurement device. METHODS: Sixteen eyes of 8 rabbits were used in this study. One eye from each rabbit underwent PRK for -10.00 diopters (D) in a 5-mm optical zone (92 microm) while the fellow eye served as the control. Five weeks later, the rabbits were examined under general anesthesia. The pressure-volume relationship and the ocular rigidity coefficient were determined in all 16 eyes, by injecting 200 microL of saline solution (in increments of 4.5 microL) through the limbus into the anterior chamber, while the intraocular pressure (IOP) was continually monitored with a transducer, up to a maximum limit of 40 mmHg. Data within an IOP range of 10 to 40 mmHg were used to calculate the ocular rigidity coefficient. RESULTS: The preoperative central corneal thickness was comparable (P = .73, paired t test) in the pre-PRK eyes (mean: 347.5 +/- 17.11 microm) and control eyes (mean: 349.1 +/- 17.46 microm). No statistically significant difference was noted in measured ocular rigidity coefficient between eyes treated with PRK and control eyes (mean rigidity coefficient: 0.42 +/- 0.12 mmHg/microL [range: 0.23 to 0.56] and 0.47 +/- 0.12 mmHg/microL [range: 0.28 to 0.62], respectively, with 95% confidence interval of the difference, lower: -0.10 to upper: 0.015, P = .121). CONCLUSIONS: Photorefractive keratectomy did not significantly alter ocular rigidity measurements in this experimental model.     

Role of norepinephrine in the rabbit ganglionectomy response

Superior cervical ganglionectomy (SCG) produced delayed mydriasis and ocular hypotension in rabbits. Norepinephrine (NE) was lost from the iris-ciliary body exponentially with onset of about 11 h. NE in aqueous humor peaked at twice control levels (from 7 to 14 ng/ml) at 16.5 h and subsequently declined to below control levels by 24 h. Intracameral administration of radiolabeled NE (150 ng) to control eyes resulted in a calculated outflow of 1.6 microliter/min, comparable to that seen with fluorescein (1.7 microliter/min). NE administered to ganglionectomized eyes (26 h after surgery) resulted in a calculated outflow of 3.1 microliter/min. These results suggest that mydriasis following SCG may be due to NE released from degenerating sympathetic nerve endings. However, NE concentration in the aqueous humor appears inadequate to produce the delayed increase in outflow observed in rabbits after SCG.     

Hemin, an inducer of heme oxygenase-1, lowers intraocular pressure in rabbits.

AIM: Carbon monoxide (CO) generated from heme may induce vasodilation and exert cyto-protective properties in the eye. This study was undertaken to investigate the effects of hemin, a potent inducer of heme oxygenase-1 (HO-1), on models of ocular hypertension in rabbits. METHODS: Ocular hypertension was induced by injecting alpha-chymotrypsin in both eyes under local anesthesia. Only rabbits with an intraocular pressure (IOP) of 25 mmHg or more were used. The dose-response study of the hemin effect on IOP was made by an intravenous injection of the drug (50, 75, and 100 mg/kg) and subsequent IOP monitoring every 6 h. A separate set of animals was pretreated with the HO-1 inhibitor, zinc protoporphyrin-IX (ZnPP-IX, 0.1 mg/kg) 6 h before the vehicle or a 100-mg/kg hemin injection. Ocular hypertension was also obtained by the subconjunctival injection of betamethasone 21-phosphate disodium (4 mg/mL) in both eyes every week for 4 weeks. Only animals with an IOP of 30 mmHg or more were included in the experimental session. A group of these animals was pretreated with ZnPP-IX (0.1 mg/kg) 6 h before the vehicle or a 100-mg/kg hemin injection, and IOP was assessed every 6 hours. RESULTS: Hemin caused a significant dose-related reduction of IOP in rabbits with alpha-chymotrypsin-induced ocular hypertension. No significant effect was observed in the normotensive eyes of the control animals or on pupil diameter. Pretreatment with the HO-1 inhibitor, ZnPP-IX, abolished the decrease of IOP that was induced by the maximum dose of hemin (100 mg/kg). A similar reduction in IOP was observed in those rabbits with betamethasone-induced ocular hypertension who were treated with 100 mg/kg of hemin. Furthermore, pretreatment with ZnPP-IX prevented the hemin effect on IOP. CONCLUSIONS: The induction of HO-1 by hemin leads to a reduction of IOP in the alpha-chymotrypsin and betamethasone models of ocular hypertension. These results suggest an involvement of CO in the regulation of ocular pressure in rabbits.     

Ocular blood flow evaluation in injured and healthy fellow eyes

PURPOSE: To assess if injured eyes develop ocular blood flow disturbances that may contribute to development of traumatic glaucoma. METHODS: Twenty-five eyes of 25 patients hospitalized from January 1997 to July 1999 for blunt (15) or penetrating (10) eye injury and elevated intraocular pressure (IOP) (>23 mm Hg) were controlled at least 24 months after the trauma and underwent visual field examination, pulsatile ocular blood flow (pOBF), and color Doppler imaging (CDI) analysis of ophthalmic artery, central retinal artery, nasal and temporal short posterior ciliary arteries. Uninjured healthy eye was used as control. RESULTS: IOP was significantly higher in injured eyes (15.1+/-3.3 vs 13.0+/-2.7 mmHg; p<0.01), but only 2 eyes (8%) were under medical treatment. pOBF values were significantly lower in injured eyes: 11.25+/-6.56 microL/sec in the trauma eyes and 15.40+/-7.29 in fellow eyes (p=0.002). Resistivity index of all investigated retrobulbar vessels was very significantly higher in injured eyes than in fellow eyes (p<0.0001). There is no significant correlation between IOP and ocular blood flow disturbance. CONCLUSIONS: Long-term follow-up (mean 39+/-12 months) of injured eyes shows, besides a slight but significant increase of IOP, a very significant impairment of ocular blood supply to injured eyes compared to healthy fellow eyes with reduction of pulsatile ocular blood flow and marked increase of resistance to flow in all retrobulbar vessels. These anomalies may be considered an independent risk factor to develop traumatic glaucoma.