Alpha-adrenergic antagonists: correlation of the effect on intraocular pressure and on alpha 2-adrenergic receptor binding specificity in the rabbit eye

Six alpha-adrenergic antagonists, which have a range of selectivities for alpha 1- and alpha 2-adrenoreceptor subtypes, were compared with respect to their ability to reduce intraocular pressure (IOP) after topical application to the rabbit eye, and their affinity and selectivity for alpha 2-adrenoreceptors, as determined by binding to membranes prepared from rabbit iris-ciliary body. A routine assay for alpha 2-adrenoreceptors using [3H]-rauwolscine was developed for this purpose. ICB contained 200-300 fmol (mg protein)-1 alpha 2-adrenoreceptors which represents approximately two-thirds of the total number of alpha-adrenoreceptor sites present in this tissue. All six antagonists bound at alpha 2-adrenergic receptor sites in an apparently simple competitive manner. The Kd for three of the drugs was about 10 nM (rauwolscine, yohimbine, WB-4101) and the Kd for the other three was greater than 3500 nM (prazosin, corynanthine, thymoxamine). However, all six antagonists were effective ocular hypotensive agents when given topically in a 50 microliter dose of 1% (w/v) concentration. The ability of alpha-adrenergic antagonists to lower IOP in the rabbit did not correlate with a single alpha-receptor subtype and appears to involve at least two separate mechanisms, one mediated by alpha 2-adrenergic receptors and one mediated by alpha 1-adrenergic receptors.     

Effects of prostaglandin F2alpha and latanoprost on phosphoinositide turnover, myosin light chain phosphorylation and contraction in cat iris sphincter.

The effects of the ocular hypotensive agents prostaglandin F(2alpha) (PGF(2alpha)) and its analog latanoprost on intraocular pressure (IOP) in both animals and human have been investigated extensively in the last two decades. While there is general agreement that application of these PGs to the eye alters IOP by altering the aqueous humor outflow of the eye via the uveoscleral and trabecular meshwork pathways, the mechanism of action of these agents on IOP lowering remains unclear. There is evidence which suggests that myosin light kinase (MLC kinase) may be involved in the IOP-lowering effects of these agents. Thus, the purpose of the present work was to investigate in cat iris sphincter the effects of these PGs on the MLC kinase signaling pathway, inositol phosphates production, MLC phosphorylation and contraction, in order to gain more information about the mechanism through which these agents modulate smooth muscle function and lower IOP. [(3)H]myo-inositol phosphates production was measured by ion-exchange chromatography, MLC kinase activity was measured by incorporation of (32)Pi into MLC, and changes in muscle tension were recorded isometrically. PGF(2alpha) and latanoprost induced contraction in a concentration-dependent manner with EC(50) values of 18.6 and 29.9 nM, respectively, and increased inositol phosphates production in a concentration-dependent manner. At 1 microM, PGF(2alpha) and latanoprost increased inositol phosphates formation by 125 and 102% over basal, respectively. PGF(2alpha) and latanoprost increased MLC phosphorylation in a concentration- and time-dependent manner, at 1 microM and 5 min incubation, the PGs increased the MLC response by 181 and 176% over basal, respectively. In general, PGF(2alpha) was slightly more potent in inducing the biochemical and pharmacological responses. Wortmannin, ML-7 and ML-9, selective inhibitors of MLC kinase, inhibited significantly PGF(2alpha)- and latanoprost-induced MLC phosphorylation and contraction. These results demonstrate for the first time involvement of the MLC kinase pathway in the FP receptor function of this ocular tissue. Contraction-relaxation of smooth muscle alters the shape and stiffness of smooth muscle cells and MLC kinase, through myosin phosphorylation and dephosphorylation, has been shown to be involved in cytoskeletal remodeling, cytoskeletal alterations, and IOP lowering. In light of these reports and the findings presented here we suggest that alterations in the MLC kinase signaling pathway and its derived second messengers, which leads to changes in contraction-relaxation of the smooth muscles of the anterior segment, could facilitate aqueous humor outflow and thus contribute to the IOP-lowering effects of the FP-class PGs.     

拟胆碱药M受体亚型降眼压作用研究

目的阐明拟胆碱药降眼压作用与M受体亚型的关系.方法用气动眼压计测量兔眼内压;用瞳孔尺测量瞳孔大小;用离体虹膜实验测量兔虹膜收缩.计算拟胆碱药的pD2值和M受体亚型拮抗剂的pA2值.结果拟胆碱药降眼压和缩瞳效应的强弱顺序为丁公藤碱＞乙酰奎宁＞毛果芸香碱,虹膜收缩能力的强弱为丁公藤碱＞毛果芸香碱＞乙酰奎宁.亚型拮抗剂拮抗拟胆碱药效应的强弱表现为4-DAMP(M3)＞Pirenzepine(M1)＞Gallamine(M2).结论拟胆碱药的降眼压和缩瞳效应主要是通过M3受体介导,其次为M1受体,而与M2受体关系甚小.眼科学报2000;16243～245.     

Pharmacology of the intraocular pressure (IOP) lowering effect of systemic dexanabinol (HU-211), a non-psychotropic cannabinoid.

The purpose of this study was to characterize the intraocular pressure (IOP) lowering activity and possible mechanism of action of the synthetic, non-psychotropic cannabinoid dexanabinol (HU-211) [(+)(3S,4S), 7-hydroxy-delta-6-tetrahydrocannabinol 1,1 dimethylheptyl], following intravenous (i.v.) administration in the rabbit. IOP (pneumatonometry), aqueous humor inflow rate (fluorophotometry), blood pressure, and heart rate (computerized physiograph system connected to central ear artery cannula) were measured in unanesthetized albino rabbits. Intravenous administration of HU-211 resulted in a dose-related reduction in IOP; a maximal IOP reduction of 5.0 +/- 0.2 mmHg was observed 4 hr after a 0.5 mg/kg dose. No significant changes in blood pressure or heart rate were observed during the first hr following this dose of HU-21 1. Pupil diameter did not change significantly during the 5 hr following the 0.5 mg/kg i.v. dose. No significant change in the rate of aqueous humor inflow occurred during the 6 hr after a 0.5 mg/kg dose of HU-211, thereby implicating outflow changes as the major source of IOP reduction. IOP reduction by HU-211 following pre-treatment with the alpha2 adrenergic antagonist, yohimbine (1 mg/kg, i.v.), was only 30% of that of HU-211 alone. IOP reduction following pretreatment with the alpha2 agonist, clonidine (0.5 mg/kg i.v.), was twice as large as that of HU-211 alone. Pretreatment with the beta-adrenergic antagonist, propranolol (0.5 mg/kg i.v.), resulted in a 50% reduction in the IOP-lowering effect of HU-211. In summary, HU-211, administered i.v., is an effective IOP-lowering agent, devoid of any significant side effects (blood pressure, heart rate or pupil diameter, all of which have been reported previously for cannabinoids). Involvement of the adrenergic system is indicated in mediating the IOP-lowering effects of HU-211 that appear to reflect a change in fluid outflow from the eye.     

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.     

Effects of serotonergic compounds on aqueous humor dynamics in monkeys

PURPOSE: The effects of several serotonergic agonists on aqueous humor formation (AHF), total outflow facility (OF) and intraocular pressure (IOP) were investigated in living cynomolgus monkeys. METHODS: We determined the effect of a single topical unilateral 300 microg or 3 mg dose of the 5-HT agonists serotonin, 5-carboxamidotryptamine (5-CT), sumatripan, gepirone, and 8-hydroxy-2(di-n-propylaminotetralin) (8-OH-DPAT) and a 450 microg dose of flesinoxan on IOP (Goldmann applanation tonometry), AHF (scanning ocular fluorophotometry) and total OF (8-OH-DPAT only, topically and intracamerally). RESULTS: Serotonin, 5-CT, sumatripan or gepirone had no significant effect on IOP or AHF. 8-OH-DPAT caused an AHF increase of approximately 70% over 6 hr in both ipsilateral drug- and contralateral vehicle-treated eyes, but no significant change in IOP compared with baseline measured on a separate occasion in the same animals. 8-OH-DPAT did not increase protein levels or rate of entry of systemically administered fluorescein in the anterior chamber aqueous humor compared to historic controls, and no difference was seen between ipsilateral and contralateral eyes. Flesinoxan had no effect on IOP and produced an insignificant 25% increase in flow in treated eyes compared to baseline. CONCLUSION: The results for 8-OH-DPAT and possibly flexinoxan indicate the presence of a secretion-stimulating 5-HT1A receptor in monkey ciliary epithelium that has little effect on IOP. OF was unchanged following 8-OH-DPAT administered topically or following intracameral exchange.     

A myosin light chain kinase inhibitor,ML-9, lowers the intraocular pressure in rabbit eyes

The role of myosin light chain kinase (MLCK) in regulating the intraocular pressure (IOP) and outflow facility in rabbit eyes were studied. The IOP and pupil diameter were determined before and after intracameral and intravitreal administration of ML-9, a specific MLCK inhibitor. Total outflow facility and uveoscleral outflow facility was determined 3hr after intracameral administration of ML-9. Immunoblotting was performed to identify MLCK and the 20-kDa light chain of myosin (MLC) isoforms in human trabecular meshwork (TM) cells. The phosphorylation status of MLC was examined following ML-9 treatment. The effects of ML-9 on the morphology and actin and vinculin distribution in cultured TM cells were also studied. In rabbit eyes, administration of ML-9 resulted in a dose-dependent decrease in IOP. An increase of the outflow facility was also observed. Immunoblot analysis revealed the presence of MLCK in human TM cells. Exposure to ML-9 dose-dependently inhibited MLC phosphorylation/activation. The inhibitor caused retraction and dissociation of cells, disruption of actin bundles and impairment of focal adhesion formation in TM cells. ML-9 induces a reduction in IOP and an increase in the outflow facility in rabbit eyes. The IOP-lowering effects may be related to alterations in TM cell shapes. Inhibitors of MLCK may potentially be developed into novel medications for glaucoma.     

Comparison of the effects of adrenergic agonists and alpha-, beta 1-, beta 2-antagonists on the intraocular pressure and adenylate cyclase activity in the ciliary processes of the rabbit

The hypotensive effect of different adrenergic agonists and antagonists were screened both in normo- and hypertensive rabbit eyes. The drugs were applicated topically and intraocular pressure (IOP) was monitored constantly with a manometric method. Subsequently the inhibitory effect of the antagonists on isoproterenol-stimulated adenylate cyclase activity in the ciliary processes was analyzed in vitro. In normotensive eyes agonist isoproterenol (beta) and antagonists labetalol (alpha beta), metoprolol (beta 1) and acebutolol (beta 1) decreased significantly IOP. In hypertensive eyes only isoproterenol and labetalol decrease IOP markedly. Timolol (beta) did not decrease IOP, although it inhibited adenylate cyclase activity as actively as labetalol. The other antagonists showed no inhibitory effect on in this respect. The results indicated that alpha-activity (labetalol, alpha beta) seems to potentiate the beta-activity (timolol, beta) in decreasing IOP. Whether this alpha-effect is a presynaptic effect (adrenergic denervation destroys it) is not yet clear. Similarly the beta 1-effect (metoprolol), without affecting adenylate cyclase activity, decreased IOP as well. This might be due to pre-synaptic release of endogenous transmitter(s) which in turn stimulate post-synaptic adenylate cyclase and induce the decreased IOP. Besides this, the possible role of blood vessels and CNS must also be kept in mind.     

Effect of alpha-adrenergic and serotonergic blockers on the acute irritative response in the rabbit eye

The effect of alpha-adrenergic and serotonergic (5-HT) blockers on the acute irritative response in the rabbit eye elicited by topical, neutral formaldehyde (1%), was studied. In the control animals, the peak rise in the intraocular pressure (delta IOP) after irritation was 29.5 +/- 5.7 mm Hg, and the perfusion pressure of the eye at 1 min after irritation was 50.1 +/- 2.8 mm Hg. The peak rise in the IOP was inhibited by phentolamine (alpha- and 5-HT-antagonist, delta IOP = 6.6 +/- 2.1 mm Hg, P less than 0.01), methysergide (5-HT-antagonist, delta IOP = 10.6 +/- 4.4 mm Hg, P less than 0.05), and prazosin (alpha 1-antagonist, delta IOP = 12.8 +/- 3.7 mm Hg, P less than 0.05). Perfusion pressures of the eyes were decreased after pretreatment with phentolamine or prazosin, and were 35.2 +/- 4.8 mm Hg (P less than 0.05) and 25.7 +/- 3.7 mm Hg (P less than 0.01), respectively. Perfusion pressure in the methysergide group remained unchanged (75.4 +/- 14.2 mm Hg). Yohimbine (alpha 2-antagonist) and ketanserin (5-HT2-antagonist) did not inhibit the IOP response. None of the antagonists could inhibit the miosis or disruption of the blood-aqueous barrier induced by topical neutral formaldehyde. In the contralateral eyes, the changes in the IOP, in the integrity of the blood-aqueous barrier, and also in the pupil size, were enhanced by ketanserin. The present study demonstrates the inhibitory actions of methysergide, phentolamine, and prazosin on the neurally mediated, acute irritative response in the rabbit eye. Methysergide seems to inhibit the response, probably acting via the 5-HT1-receptors. A part of the effect of phentolamine might be explained by an inhibitory action via 5-HT1-receptors. The effect of phentolamine and prazosin on the alpha 1-receptors seems to create an inhibitory action on the irritative response by lowering the perfusion pressure of the eye.     

Targeting outflow facility in glaucoma management

Glaucoma is often characterized by decreased pressure-sensitive aqueous outflow through the trabecular meshwork. This defect in pressure-sensitive aqueous outflow is evident from the low tonographic facility of outflow ("C") measured in many patients. The impairment in outflow facility causes the high intraocular pressure (IOP) and large diurnal IOP fluctuations often found in glaucoma. Because large diurnal IOP fluctuations have been shown to be a risk factor for glaucomatous progression, IOP-lowering therapy should aim to achieve a low, stable IOP. Pressure-sensitive aqueous outflow helps prevent and dampen pressure spikes; thus, drugs that enhance outflow facility, in particular, may stabilize as well as lower IOP. Outflow facility is an attractive target for glaucoma treatment because enhancing outflow facility tends to restore the self-regulating tendency of IOP. Older drugs such as the cholinergic pilocarpine and the catecholamine epinephrine act primarily by improving outflow facility. This action is also important for the recently introduced prostamide, bimatoprost, as well as for the prostaglandin prodrug, latanoprost. Realization of the importance of facility of outflow in lowering and stabilizing IOP will stimulate additional research into the mechanism of action of ocular hypotensive agents and will help optimize the medical treatment of glaucoma.     

Dose-related effects of prostaglandin F2 alpha isopropylester on intraocular pressure, refraction, and pupil diameter in monkeys

Topical application of Prostaglandin F2 alpha (PGF2 alpha) to the eye reduces intraocular pressure (IOP) in all mammalian species studied thus far, including humans. The L-isopropylester derivative is currently the one most commonly used in experimental and clinical studies. Dose-response relationships were determined between PGF2 alpha-IE and IOP, pupillary diameter, and refraction in ketamine-anesthetized ocular normotensive cynomolgus monkeys. Single doses of 10 and 30 micrograms had smaller and less consistent but longer lasting IOP-lowering effects than repeated doses (twice daily for 3 days) of 1-5 micrograms. For repeated dosing in this manner, the just-maximal dose is probably between 2-5 micrograms, producing a approximately 70% reduction in IOP to a final IOP of approximately 5 mm Hg. Continuing treatment for up to 18 days did not further enhance the efficacy of twice daily treatment with a submaximal 1-microgram dose. Partial reversal of anesthesia-induced tonic accommodation occurred with single 10- and 30-micrograms doses and with repeated 1-microgram doses, but additional myopia of 0.5-1.5 diopters was induced with repeated higher doses. These physiologic findings and previous morphologic data are consistent with a proposed dual PG action on the ciliary muscle, one involving a short-onset long-lasting direct effect on the muscle fibers (causing relaxation and narrowing of the muscle bundles) and the second involving a slowly developing but shorter duration dissolution of the intermuscular connective tissues.     

Effect of calcium channel blockers on intraocular pressure

We determined the effects of either topical or systemic calcium channel antagonists on rabbit intraocular pressure (IOP). Topical nifedipine, verapamil or diltiazem had no significant effect on IOP. Intravenous verapamil and nifedipine caused statistically significant reductions in IOP between 2 and 6 h after administration; the nifedipine response followed an increase in IOP at 30 min. Diltiazem, given 3 times daily for 3 days, caused no pressure change. In the rabbit, therefore, calcium channel antagonists have no effect when given topically, but do reduce IOP when given systemically.     

Effects of topical nipradilol, a beta blocking agent with alpha blocking and nitroglycerin-like activities, on intraocular pressure and aqueous dynamics in humans

AIMS: To study the effects of topical nipradilol, a non-selective beta blocker with alpha blocking and nitroglycerin-like activities, on intraocular pressure (IOP) and aqueous humour dynamics in normal humans and in patients with ocular hypertension. METHODS: Nipradilol (0.06%, 0.125%, 0.25%, 0.5%) was applied to normal volunteers (n = 12) to test for IOP lowering effects. In a second group of normal volunteers (n = 11), nipradilol (0.125% and 0.25%) and timolol (0. 5%) were compared for IOP lowering effects. After a single administration of 0.25% nipradilol, IOP, flare intensity in the anterior chamber, aqueous flow, uveoscleral outflow, tonographic outflow facility, and episcleral venous pressure were either directly measured or mathematically calculated. Topical nipradilol (0.25%) was administered to 24 patients with ocular hypertension twice daily for 8 weeks. RESULTS: Administration of 0.25% nipradilol decreased IOP with a maximum reduction of 4.2 mm Hg lasting 12 hours. A single instillation of both 0.25% nipradilol and 0.5% timolol reduced the IOP in normotensive human subjects to the same degree. A single instillation of 0.25% nipradilol decreased the aqueous flow rate in the treated eye by 20%. Nipradilol produced no significant effect in tonographic outflow facility or episcleral venous pressure, but uveoscleral outflow was increased. In patients with ocular hypertension, twice daily instillation of 0.25% nipradilol decreased IOP without tachyphylaxis for the 8 week test period. CONCLUSION: Topical nipradilol (0.25%) reduced IOP by decreasing the aqueous flow rate and probably also by increasing uveoscleral outflow. Nipradilol should be further investigated as a new antiglaucoma drug.     

Angiotensin (1-7) reduces intraocular pressure in the normotensive rabbit eye

PURPOSE: In the present study the effects of exogenous angiotensin II and its breakdown metabolite angiotensin (1-7) on the intraocular pressure (IOP) and on aqueous humor dynamics in normotensive rabbit eye were evaluated. METHODS: Male New Zealand White rabbits with normal IOP were used for intravitreous and topical administration of the test compounds. IOP was measured in conscious rabbits by pneumatonometer after topical anesthesia. Outflow measurements were made with a two-level constant pressure method in anesthetized animals. RESULTS: Angiotensin (1-7) administered intravitreously reduced IOP within 1 to 5 hours (P < 0.05). This effect was abolished by the selective angiotensin (1-7) antagonist A-779, and partially by the selective angiotensin II type 2 receptor antagonist PD123319. When olmesartan, an angiotensin II type 1 receptor blocker, was administered simultaneously with angiotensin (1-7), no antagonism was seen. Intravitreous administration of CGP42112 A, an angiotensin II type 2 receptor agonist, and angiotensin II did not significantly influence IOP, nor did topical administration of these compounds alter IOP. Angiotensin II significantly reduced outflow facility (P < 0.01) dose dependently, whereas angiotensin (1-7) had no effect. CONCLUSIONS: Angiotensin (1-7) is a biologically active vasodilatory and antiproliferative heptapeptide, and its vascular effects counteract those of angiotensin II. It reduces intraocular pressure possibly by a selective Mas receptor, without changing aqueous humor outflow facility in the normotensive rabbit eye.     

High intensity focused ultrasound for glaucoma: 1-year results from a prospective pragmatic study

BackgroundCiclo plasty using high-intensity focused ultrasound (HIFU) technology acts through the selective coagulation of the ciliary body. Our aim was to evaluate the safety and efficacy profiles of 8-s probe HIFU cyclocoagulation using the EyeOP1 device.MethodsProspective pragmatic trial. Inclusion criteria: adult glaucoma patients with uncontrolled IOP despite optimised medical therapy, and/or intolerant to medical therapy required to achieve target IOP. Primary outcome: surgical success defined as IOP reduction from baseline >20% with final IOP ≤21 mmHg, without adding any IOP-lowering drugs, and without loss of light perception; or decreased use of IOP-lowering drugs with stable/decreased IOP, without loss of light perception. Secondary outcomes: mean IOP, intra and postoperative complications, best-corrected visual acuity (BCVA) and number of IOP-lowering drugs at each visit. Outcome data were collected preoperatively and at postoperative day 1, and months 1, 3, 6 and 12.ResultsForty-nine eyes of forty-nine patients (28 male) with a mean age of 70 ± 14 years were enroled. Pre-operative IOP was 26.9 ± 7.4 mmHg under 2.8 ± 0.9 topical medications, decreasing to 17.8 ± 6.4 mmHg under 2.3 ± 1 drugs at 12 months (p < 0.01). One-year surgical success was achieved in 71.4% of patients (IOP-reduction criteria: 59.2%; decreased use of IOP-lowering drugs: 38.8%). Eight patients were ultimately submitted to other glaucoma surgical interventions. Five patients experienced serious adverse events (loss of light perception n = 5; hypotony n = 1).ConclusionsThis innovative non-invasive technology seems to be effective in decreasing IOP and/or the number of administered drops in patients with refractory glaucoma. It seems a valuable tool to delay or preclude the need for filtering procedures in the majority of the patients.Subject terms: Glaucoma, Optic nerve diseases     

Effect of 5-MCA-NAT, a putative melatonin MT3 receptor agonist, on intraocular pressure in glaucomatous monkey eyes

PURPOSE: 5-MCA-NAT, a putative melatonin MT3 receptor agonist, reduced intraocular pressure (IOP) in ocular normotensive rabbit eyes. This study evaluates the effect of topical application of 5-MCA-NAT on IOP in monkey eyes with laser-induced unilateral glaucoma. METHODS: A multiple-dose study was performed in 8 glaucomatous monkey eyes. One 25-microL drop of 5-MCA-NAT (2%) was applied topically to the glaucomatous eye at 9:30 am and 3:30 pm for 5 consecutive days. IOP was measured hourly for 6 hours beginning at 9:30 am for one baseline day, one vehicle-treated day, and treatment days 1, 3, and 5 with 5-MCA-NAT. RESULTS: Compared with vehicle treatment, twice daily administration of 5-MCA-NAT for 5 days reduced (P < 0.05) IOP from 1 hour to 5 hours after the first dose, and the IOP-lowering effects were shown to last at least 18 hours following administration, based on IOP measurements made after the fourth and eighth doses. The ocular hypotensive effect of 5-MCA-NAT was enhanced with repeated dosing. The maximum reduction (P < 0.001) of IOP occurred at 3 hours after each morning dose, and was 4.0 +/- 0.5 (mean +/- SEM) mm Hg (10%) on day 1, 5.6 +/- 0.8 mm Hg (15%) on day 3, and 7.0 +/- 1.1 mm Hg (19%) on day 5. Adverse ocular or systemic side effects were not observed during the 5 days of treatment. CONCLUSIONS: 5-MCA-NAT, a putative melatonin MT3 receptor agonist, reduces IOP in glaucomatous monkey eyes. Melatonin agonists with activity on the putative MT3 receptor may have clinical potential for treating elevated IOP.     

AL-34662: a potent, selective, and efficacious ocular hypotensive serotonin-2 receptor agonist.

PURPOSE AND METHODS: The aim of this study was to determine the ocular pharmacological characteristics of AL-34662 (1-((S)-2-aminopropyl)-1H-indazole-6-ol), a new synthetic serotonin-2 (5-HT2) receptor-agonist ocular hypotensive agent. A variety of well-documented in vitro and in vivo procedures were utilized to study the pharmacological attributes of AL-34662. RESULTS: AL-34662 exhibited a high affinity for the rat and human 5-HT2 receptor (IC50=0.8-1.5 nM) and for cloned human 5-HT2A-C receptors (IC50=3-14.5 nM). AL-34662 stimulated phosphoinositide turnover in human ciliary muscle (h-CM; EC50=289+/-80 nM) and in human trabecular meshwork (h-TM; EC50=254+/-50 nM) cells. AL-34662 also mobilized intracellular Ca2+ ([Ca2+]i) in h-CM (EC50=140+/-23 nM) and h-TM (EC50=38+/-8 nM) cells, being a full agonist like 5-HT itself. AL-34662's effects in the h-CM (and h-TM) cells were potently antagonized by 5-HT2A-antagonist M-100907 (IC50=1.8+/-0.7 nM), but weakly by 5-HT2B-antagonist (RS-127445 IC50>10 microM), 5-HT2B/C- antagonist (SB-242084 IC50=2.08 microM) and 5-HT2C antagonist (RS-102221 IC50>1 microM). AL-34662 caused relatively minimal ocular discomfort and hyperemia in rabbit and guinea pig eyes. It efficaciously lowered intraocular pressure (IOP) in the conscious ocular hypertensive monkey eyes (33% at 300 microg). The (R)-enantiomer (AL-34707) and the racemate (AL-34497) were less potent and/or efficacious than AL-34662 in all of these assays. CONCLUSIONS: AL-34662 is a high-affinity 5-HT2 receptor agonist that potently mobilizes [Ca2+]i in h-CM and h-TM cells, and which efficaciously lowers IOP in conscious ocular hypertensive cynomolgus monkey eyes through a local effect with minimal side-effects.     

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.     

M-7 lowers rabbit intraocular pressure

Changes in intraocular pressure (IOP) and pupil diameter were studied in albino rabbits following topical administration of TL-99, M-7 (N,N-dimethyl analogues of 2-aminotetralin), DiPr-5,6-ADTN, DiPr-6,7-ADTN (dipropyl analogues of aminotetralin) and DPDA (N,N-di-n-propyl-dopamine), known as mixed alpha-adrenoceptor/dopamine receptor agonists with variable alpha 1/alpha 2-adrenoceptor/selectivity. The potencies of those compounds to decrease IOP were compared with each other. We found that M-7 has the most potent IOP-lowering properties, caused minimal ocular discomfort and is of interest as a potential antiglaucoma agent. The ocular hypotension was completely inhibited by rauwolscine and slightly antagonized by various other blocking agents. The results strongly suggest that the IOP-lowering effect of M-7 is mediated by the stimulation of alpha 2-adrenoceptors.     

Effect of fluoxetine on intraocular pressure in the rabbit

The effects of fluoxetine, which is a selective inhibitor of serotonin reuptake (SSRI) have been studied on the intraocular pressure (IOP) in the rabbit. IOP was measured using a Perkins tonometer. Intravenous administration of fluoxetine (6.0 mg kg-1) significantly increased IOP by 7.2 +/- 1.3 mmHg (P < 0.001). Fluoxetine administration also reduced the amount of urine excreted during the 24 hr, and increased the urine concentration of 5-hydroxyindole acetic acid (5-HIAA). Topical preadministration of ketanserin prevented a rise in IOP, without there being any effects on the other parameters examined. These findings indicate that intravenous administration of fluoxetine is able to raise IOP, through increased plasma levels of serotonin, which is confirmed by elevated 5-HIAA urine excretion and reduction in diuresis. Ketanserin, a specific 5-HT2A antagonist, counteracts the IOP increase brought about by fluoxetine, thus emphasizing the role of serotonin in the regulation of IOP and stressing the importance of including ophthalmological examination in the protocol of depressed patients undergoing SSRI therapy.