Showing papers in "Journal of Ocular Pharmacology and Therapeutics in 1985"
TL;DR: It is proposed that the diverse actions of these two sensory neuropeptides conjointly mediate the antidromic ocular injury response.
Abstract: Calcitonin gene-related polypeptide (CGRP) has been localised immunochemically within the rat and guinea pig anterior uvea to nerve fibres of trigeminal origin. As with substance P (1-3) the level of CGRP in the iris-ciliary body is depleted after thermal damage to the Gasserian ganglion and elevated in chronically sympathectically denervated eyes. Unlike substance P, a potent pupillary constrictor (4,5), CGRP has no notable miotic action, but does, however, cause an elevation of the intraocular pressure (IOP) accompanied by disruption of the blood-aqueous barrier. It is proposed that the diverse actions of these two sensory neuropeptides conjointly mediate the antidromic ocular injury response.
93 citations
TL;DR: This article reviews the objectives which must be considered in producing optimal formulations for topical ophthalmic use and the effects of preservatives, vehicles, and adjunct agents.
Abstract: This article reviews the objectives which must be considered in producing optimal formulations for topical ophthalmic use. The effects of preservatives, vehicles, and adjunct agents are described. Anatomical considerations which impact bioavailability of the drug at the desired target site are discussed in detail. Model systems that can aid in determining the best formulations for preclinical and clinical testing are also reviewed. The long term objective of this review is the development of formulations for optimal efficacy and safety, considering all the requirements of the patient.
89 citations
TL;DR: This long term study demonstrates the potential efficacy of CsA in the treatment of severe intra-ocular inflammatory disorders, however, it is firmly believed that only in the context of a randomized clinical trial that a definitive evaluation as to the true effectiveness ofCsA will be reached.
Abstract: Long term followup in 52 uveitis patients treated with Cyclosporine (CsA) is presented here. The patients included in this study all had intermediate or posterior uveitis of noninfectious etiology, and all were considered therapeutic failures to systemic corticosteroids and/or cytotoxic agents. Patients were considered a therapeutic success if the visual acuity in either eye improved two lines or more and/or the vitreal haze improved more than two grading levels. While five patients stopped therapy before the three month interval, 41 of 52 patients or 79% were therapeutic successes at three months after the initiation of CsA as the sole systemic immunosuppressive agent for their disease. Twenty-five of a potential 35 patients (71%) remained on CsA after one year's time, with 63% (22/35) of these individuals receiving the medication considered a therapeutic success. The patients who appeared to respond particularly well to CsA therapy were those with pars planitis, intermediate uveitis of the non-...
75 citations
TL;DR: The rapid systemic absorption of topically applied ocular timolol observed in this study is consistent with the rapid appearance of the cardiovascular and pulmonary side effects reported in connection with timolOL eye drop therapy.
Abstract: Symptoms and findings arising from the systemic beta blockade caused by topical ocularly applied timolol appear shortly after drug application. We studied the systemic absorption of 20 μl ...
57 citations
TL;DR: Data demonstrate that ketanserin lowers IOP more effectively in eyes with intact sympathetic innervation than in SX eyes, appears to lower IOP by suppressing aqueous inflow, and acts primarily by antagonizing the action of norepinephrine on alpha 1-adrenoceptors.
Abstract: Ketanserin has been characterized as a relatively selective antagonist for serotonin (5-HT2) receptors. However, recent evidence suggests that ketanserin can also antagonize activity at alpha 1-adrenoceptors. Topically applied ketanserin lowered intraocular pressure (IOP) in rabbits, cats, and monkeys. Ketanserin also suppressed ocular hypertension induced by waterloading and the IOP recovery rate in response to hypertonic saline. In contrast, the ocular hypotensive activity of ketanserin was markedly attenuated in sympathectomized (SX) rabbits. In the cat nictitating membrane, ketanserin produced dose-related inhibition of contractions elicited by neuronal stimulation and by intra-arterial injection of norepinephrine. These data demonstrate that ketanserin: 1) lowers IOP more effectively in eyes with intact sympathetic innervation than in SX eyes, 2) appears to lower IOP by suppressing aqueous inflow, and 3) acts primarily by antagonizing the action of norepinephrine on alpha 1-adrenoceptors.
57 citations
TL;DR: The results suggest that melatonergic mechanisms in the eye could be responsible for the diurnal rhythm in IOP, and the synthesis and diurnalythm of this melatonin are independent of the pineal gland.
Abstract: The proposed role of melatonin as an endogenously synthesized modulator of intraocular pressure in the eye was investigated. Melatonin levels were determined by radioimmunoassay in the iris, ciliary body and retina-choroid of pinealectomized or sham-operated chickens by day and by night. Pinealectomy had no effect on melatonin levels in the ciliary body or retina of chicken eyes; a diurnal rhythm continued to be observed in these tissues, with values higher by night than by day. Chloroform-extracted melatonin levels in the rabbit ciliary body showed a diurnal rhythm but melatonin levels in rabbit retina did not. Intracameral infusion of melatonin into cat eyes caused aqueous humor synthesis to decrease but caused a greater decrease in aqueous humor outflow facility, leading to a significant increase in intraocular pressure. The results suggest that melatonergic mechanisms in the eye could be responsible for the diurnal rhythm in IOP, and the synthesis and diurnal rhythm of this melatonin are independent of the pineal gland.
50 citations
TL;DR: Open-angle glaucoma is treated primarily with drugs, some of which have been used clinically for years and several other types of drugs, such as prostaglandins, diuretics, Na+,K+-ATPase inhibitors, and adenyl cyclase stimulators are just now beginning to be studied.
Abstract: Open-angle glaucoma is treated primarily with drugs, some of which have been used clinically for years. These drugs include: 1) cholinergic agonists that increase aqueous humor outflow, 2)...
35 citations
TL;DR: It is suggested that the early IOP rise after treatment with alpha-agonists is due to stimulation of postsynaptic alpha 1-receptors, possibly located in superficial blood vessels in the anterior segment of the eye, and the mydriatic response to alpha-agonist appears to be mediated by alpha-receptor subtypes which differ from the classical alpha 1 and alpha 2 subtypes.
Abstract: The IOP and pupil response to α-adrenergic agonists and blockers was studied in albino rabbits. Topical ocular application of solutions of methoxamine (α1) and oxymetazoline (α2) caused dose-related early rises in IOP which were inhibited by pretreatment with prazosin, an α1-blocker, or with yohimbine, an α2-blocker. Although both prazosin and yohimbine have ocular hypotensive activity, the effect on the early IOP rise did not appear to be related to this action. Prazosin and yohimbine also inhibited the early IOP rise after treatment with clonidine, a second α2-agonist. Surgically sympathectomized rabbits showed little or no hypersensitivity to methoxamine or oxymetazoline when compared to non-operated normal rabbits. However the treated ipsilateral eyes showed a much greater increase in IOP than the treated contralateral eyes. There was little difference in the IOP response between clonidine-treated ipsilateral and contralateral eyes. Methoxamine and oxymetazoline caused dose-related increases ...
34 citations
TL;DR: The result was interpreted to suggest that glutathione and its redox cycling may play an important role in cellular defense against oxidative stress.
Abstract: A bovine eye perfusion system was developed for detoxification studies. The viability of the system was examined by two criteria: the permeability of the aqueous-blood barrier to protein, ...
24 citations
TL;DR: Melatonergic mechanisms could be involved in the elevation of IOP in LIAG, and no statistical differences in choline acetyltransferase activity, adrenergic transmitter levels or dopamine concentrations could be found in tissues of LIAG eyes vs control eyes, indicating that cholinergic, Adrenergic and dopaminergic mechanisms are probably not involved in LIA G.
Abstract: The possible involvement of a melatonergic mechanism in the control of intraocular pressure (IOP) and the genesis of light-induced avian glaucoma (LIAG) was studied by measuring N-acetyltransferase (NAT) activity and melatonin levels in the iris, ciliary body and retina-choroid during the course of LIAG development, and in normal subjects by day and night. NAT activity was found to be significantly higher than normal in preglaucomatous and glaucomatous chicken eyes at 8, 16, and 24 weeks of age. The increase in NAT activity corresponded well with the decrease in aqueous outflow facility and preceded the development of elevated IOP by 5-6 weeks. Melatonin levels in iris and ciliary body of normal chickens and rabbits were elevated by night relative to day, which corresponded to the diurnal change in IOP. The melatonin levels in glaucomatous chicken iris and ciliary body at 24 weeks were significantly elevated relative to controls. The results suggest that melatonergic mechanisms could be involved ...
24 citations
TL;DR: This review attempts to describe those cellular mechanisms that may be linked to the actions of several classes of antiglaucoma drugs with special emphasis on drug actions and the adenylate cyclase system.
Abstract: There are several classes of drugs currently in use for the therapeutic management of the glaucomas. Although the ocular hypotensive effects of these agents have been well characterized an...
TL;DR: Although the role of cholinergic retinal neurons in the processing of visual information is not known, their input to ganglion cells generally increases the rate of spontaneous activity or the number of action potentials in light-evoked responses, which seems to modify the overall neuronal input to the ganglions from the receptive fields.
Abstract: Acetylcholine (ACh), choline acetyltransferases and cholinesterases occur in cornea, iris-ciliary body complex and retina of several vertebrates. In cornea, ACh may serve as a sensory transmitter as well as a local hormone, the function of which is not delineated. The function of ACh as the parasympathetic neurotransmitter at the iris and ciliary body is well established. The muscarinic receptors on the iris smooth muscle are similar to the muscarinic receptors (M2 type in two way classification) at other smooth muscles towards their interaction with agonists and antagonists. Binding studies using radiolabeled antagonists and their displacement by agonists indicate that muscarinic receptors in membranes of iris-ciliary body complex are heterogeneous indicating more than one subtype of muscarinic receptors. A subtype other than M2 receptors may occur at the presynaptic sites of parasympathetic nerves, which have yet to be investigated using specific agonists and antagonists. Cholinergic markers, choline acetyltransferase and acetylcholinesterase, differ quantitatively and qualitatively in retinas of different species. However, amacrine cells are cholinergic in all vertebrate species. Although they make up 1% of retinal neurons, they influence the activity of a majority of ganglion cells. Cholinergic effects in ganglia are mediated through nicotinic and muscarinic receptors. Both of these types of cholinergic receptors are heterogeneous. They have yet to be investigated for their subtypes using specific agonists and antagonists. Although the role of cholinergic retinal neurons in the processing of visual information is not known, their input to ganglion cells generally increases the rate of spontaneous activity or the number of action potentials in light-evoked responses. Thus, the cholinergic input seems to modify the overall neuronal input to the ganglion cells from the receptive fields. Endothelial cells of blood vessels contain muscarinic receptors, which are activated by ACh to cause relaxation. Although retinal blood vessels provide recognizable characteristic signs in diabetes mellitus and hypertensive disease, no information is available on the muscarinic receptors of these vessels.
TL;DR: The results suggest that deleterious side effects sometimes seen with the drug or its lack of efficacy with rabbits is not due to ocular metabolism by these tissues.
Abstract: The ocular metabolism of timolol has been studied in the iris/ciliary body, vitreous humor, neuro-retina and cornea from an albino rabbit, pigmented rabbit and cynomolgus monkey by incubat...
TL;DR: Ketoconazole, a water-insoluble antifungal agent, has also been introduced successfully into vitreous humor by anodal iontophoresis after protonation in weak acid.
Abstract: Bactericidal levels of gentamicin were obtained in vitreous humor by iontophoresis of antibiotic directly through the sclera. A silicone rubber tube of small diameter filled with gentamicin sulfate formed the electrode. A two milliampere current applied for three minutes to each of four perilimbal sites introduced gentamicin sufficient to maintain therapeutic levels for more than 24 hours. The proportion of drug reaching vitreous versus aqueous humor was dependent on electrode position relative to retina and pars plana. An endogenous antibacterial agent was apparently released during iontophoretic stimulation and interfered with the bacterial growth inhibition assay. Ketoconazole, a water-insoluble antifungal agent, has also been introduced successfully into vitreous humor by anodal iontophoresis after protonation in weak acid.
TL;DR: Among all lipoxygenase inhibitors studied, REV 5901 was found to be the most potent one to reduce lens protein-induced ocular inflammation in rabbits.
Abstract: Among all lipoxygenase inhibitors studied, REV 5901 was found to be the most potent one to reduce lens protein-induced ocular inflammation in rabbits. It reduced ocular inflammation effectively by either injection into the ear vein (10 mg/kg) (65% inhibition) or topical administration (50 microliters of 5% ointment) (40% inhibition). Local administration was less effective than intravenous injection presumably because of slower drug delivery into the eyes.
TL;DR: The present study has found that the oncotic pressure of HypoTears is nearly sixty times higher than that of the leading artificial tear, thus it is comparable to the on cephalic pressure of Dehydrex, which is thought to be the drug of choice for the treatment of recurrent epithelial erosion when other treatment modalities have failed.
Abstract: While the total osmolality of the aqueous tears and tear substitutes has received much attention in the past few years, the colloidal osmolality or the oncotic pressure (which includes the Donnan effect), has received practically no attention except for one single foreign publication. The colloidal osmolality of tears is twentyfold less than that of the corneal stroma, which in turn is less than 1% of the total osmolality of an isotonic solution, i.e. the magnitude of the colloidal osmolality is only a few hundreths of a per cent of total osmolality. This may be the reason why its role was thought to be unimportant by many researchers. Despite its relatively small magnitude when compared to total osmotic pressure, the oncotic pressure has been shown to play a major role in the maintenance of the water balance of bodily tissues and has been used as a diagnostic parameter in alveolar edema. The same principle has been used to formulate a collyrium, Dehydrex, or dextran-containing storage media for excised corneas such as the Kaufman-McCarey medium that have a colloidal osmolality at least equal to that of deturgescent corneal stroma. Such formulations are able to dehydrate corneal stroma even in the total absence of epithelium. Dehydrex has been shown to have a beneficial effect on damaged epithelium and is thought to be the drug of choice for the treatment of recurrent epithelial erosion when other treatment modalities have failed. In the present study, the total osmolality and the oncotic pressure of several artificial tear preparations presently marketed was determined and compared with the oncotic pressure of tears and the corneal stroma. We have found that the oncotic pressure of HypoTears is nearly sixty times higher than that of the leading artificial tear, thus it is comparable to the oncotic pressure of Dehydrex. We believe that the favorable patient acceptance of HypoTears is more likely due to this unusually high oncotic pressure than to its hypoosmolality. Such an artificial tear formulation should be effective in ameliorating microcystic epithelial edema and in increasing impaired epithelial adhesion to the underlying tissue in the cornea.
TL;DR: The data indicate the presence of specific adenosine receptors which stimulate adenylate cyclase in cultured bovine corneal endothelium.
Abstract: Adenosine receptor agonists increased cyclic AMP in cultures of bovine corneal endothelium up to 12-fold pver control Effects were dose-dependent between 1 μM and 05 mM adenosine N6-met
TL;DR: The results suggest that the in vivo decarboxylation of L-DOPA may be modulated by neuronal activity in the rat retina, and that dopamine neurons of retina are activated when rats are placed in a lighted environment.
Abstract: Dopaminergic neurons of retina are activated when rats are placed in a lighted environment. L-DOPA, the precursor of dopamine, was administered to rats that were housed either in the light or the dark. In the light more dopamine and its metabolite 3,4-dihydroxyphenylacetic acid were formed from L-DOPA when compared with animals given the same dose of L-DOPA, but kept in the dark. Our results suggest that the in vivo decarboxylation of DOPA may be modulated by neuronal activity in the rat retina.
TL;DR: The data suggest that B-HT 920 produces ocular hypotension in the cat by interacting predominantly with DA2 receptor on peripheral sympathetic nerves.
Abstract: Topical administration of B-HT 920 (50 μg) to the eyes of normal unanesthetized cats produced decreases in intraocular pressure and pupil diameter The ocular hypotensive effect of B-HT 92
TL;DR: Results indicated that the degree of reduction of intraocular pressure by Δ9-THC was not affected by removal of input from either branch of the autonomic nervous system.
Abstract: Sympathetic input to the anterior segment of the eyes of cats was unilaterally removed by either superior cervical ganglionectomy or treatment with 6-hydroxydopamine. Parasympathetic input was unilaterally removed by extirpation of the ciliary ganglion. Δ9-tetrahydrocannabinol ( Δ9-THC; 20 μg/hr) was delivered unilaterally to the denervated eyes and to eyes of surgically intact control cats via osmotic minipumps and connecting extraocular cannulas over a total period of nine days. The results indicated that the degree of reduction of intraocular pressure by Δ9-THC was not affected by removal of input from either branch of the autonomic nervous system. Outflow facility during chronic administration of THC showed a two-to-three fold increase. Ciliary ganglionectomy alone produced a moderate decrease in intraocular pressure that endured for one week. These findings indicate that neither adrenergic nor cholinergic input to the cat eye is apparently required for the mediation of the tension lowering e...
TL;DR: The results of the present study may improve the understanding of ocular pharmacology of adrenergic stereoisomers and the ability to separate the dose-response profiles of pupillary and IOP effects of these agents may have potential therapeutic significance and thus warrants further investigation.
Abstract: Because of the need to develop ocular hypotensive agents with low incidence of side effects, the dextrorotatory enantiomers of adrenergic agents have prompted some attention. In the present study, the relative potency and efficacy of various adrenergic stereoisomers with respect to their ocular hypotensive and mydriatic effects have been determined after topical administration to conscious rabbits. The relative order of potency was found to be, iris: 1-epinephrine >>> d-epinephrine ≃ 1-norepinephrine ≃ dl-alpha-methyl-norepinephrine > dl-alpha-methyl-epinephrine > d-norepinephrine; intraocular pressure (IOP): 1-epinephrine > dl-alpha-methyl-epinephrine > d-epinephrine > dl-alpha-methyl-norepinephrine > d-norepinephrne ≃ 1-norepinephrine. The pupil and the initial ocular hypertensive responses clearly demonstrated the phenomenon of stereoselectivity of adrenergic stimulants, in that the 1-form was relatively more potent than the d-form. However, such order of potency does not seem to hold for IOP....
TL;DR: The corneal epithelial fraction of albino rabbits with butyrylcholinesterase-like activity was studied with respect to its susceptibility to substrate and product inhibition using a pH-stat method, and the neuropeptides enkephalins and their hydrolytic fragments were found to inhibit the hydrolysis of 1-naphthyl acetate, albeit less effectively than compounds such as 1- and 2- naphthol.
Abstract: The corneal epithelial fraction of albino rabbits with butyrylcholinesterase-like activity, which was purified by gel filtration chromatography, was studied with respect to its susceptibility to substrate and product inhibition using a pH-stat method 1- and 2-Naphthyl acetates were used as model ester prodrugs It was found that the hydrolytic rate of 1- and 2-naphthyl acetates at 12 mM was only 53% and 42% of that at 006 mM, respectively, suggesting that increasing the dose of an ester prodrug does not necessarily result in a proportional increase in its hydrolytic rate Product inhibition (by 1- and 2-naphthol) was evident only at a product concentration at least equal to the substrate concentration, suggesting that, at the therapeutic concentrations of an ester prodrug, product inhibition is probably insignificant Substrate and product inhibition did not appear to occur at the enzyme's active site Moreover, the neuropeptides enkephalins and their hydrolytic fragments were found to inhibit
TL;DR: Findings support previous findings suggesting that hydroxylation of the terpene portion of the delta 9-THC molecule significantly reduces intraocular pressure lowering activity and suggest that structural requirements for tension lowering effects, ocular toxicity, and neurotoxicity, may well be distinctively different.
Abstract: Both acute and chronic effects on intraocular pressure of 11-hydroxy- delta 9-tetrahydrocannabinol (11-OH-delta 9-THC; a metabolite of delta 9-THC) and 1-nantradol (a synthetic cannabinoid) have been examined in the cat. Acute effects of these cannabinoids on ocular tension have also been determined in the monkey. Single dose effects of several other hydroxylated delta 9-THC metabolites have been evaluated in either the cat or the monkey. Results indicated that 11-OH-delta 9-THC and 1-nantradol produced similar acute effects in both species, with 1-nantradol significantly lowering intraocular pressure and 11-OH- delta 9-THC producing no change. Neither 11-OH- delta 9-THC nor 1-nantradol lowered ocular tension chronically when delivered for nine days to cats eyes via osmotic minipumps and connecting extraocular cannulas. Neither cannabinoid likewise produced ocular toxicity, although both produced neurotoxicity, as assessed by evaluation of electroencephalograms recorded from rats. Both 8-beta-OH- delta 9-THC and 8-beta-11-diOH- delta 9-THC were inactive with regard to acute effects on ocular tension. These results support previous findings suggesting that hydroxylation of the terpene portion of the delta 9-THC molecule significantly reduces intraocular pressure lowering activity. In addition, results from these and earlier studies suggest that structural requirements for tension lowering effects, ocular toxicity, and neurotoxicity, may well be distinctively different.
TL;DR: The clinical interaction of 0.5% timolol maleate and 400 mg of oral caffeine on the intraocular pressure of 20 normotensive volunteers was studied and an antagonism, however, was observed in the fellow Timolol untreated eyes with caffeine.
Abstract: The clinical interaction of 0.5% timolol maleate and 400 mg of oral caffeine on the intraocular pressure of 20 normotensive volunteers was studied. Caffeine administration did not significantly alter the reduction in intraocular pressure in timolol treated eyes. An antagonism, however, was observed in the fellow timolol untreated eyes with caffeine. The crossover reduction in intraocular pressure noted in the control group was significantly depressed in the caffeine group. A proposed mechanism for these observations is discussed.
TL;DR: It seems likely that somatostatin and the som atostatin analog attenuate the miotic response to nociceptive stimuli by preventing the release of a substance, presumably substance P, from sensory nerves.
Abstract: The effects of somatostatin, cyclo(D-Trp-Lys-Thr-Phe-Pro-Phe) acetate, a somatostatin analog, neurotensin, and met-enkephalin were studied in the rabbit eye by measuring the intraocular pressure (IOP), aqueous humor protein concentration, ocular blood flow and the pupil diameter. Somatostatin or the analog injected intracamerally (10 micrograms/eye) and infused intra-arterially (0.6-4 micrograms/min) had no significant effect on the parameters studied in normal eyes. However, somatostatin and, particularly, the analog attenuated the miotic response to a standard nociceptive stimulus consisting of topical application of 1% neutral formaldehyde. The other component parts of the irritative response were not attenuated. Intracameral injection of 1-2 micrograms neurotensin caused vasodilation in the anterior segment of the eye, a slight increase in aqueous humor protein concentration, and some decrease in IOP. Intracameral injection of 1-50 micrograms met-enkephalin had no effect on the blood-aqueous barrier, IOP or the pupil diameter. Neither did this dose of met-enkephalin attenuate the miotic response to exogenous substance P. It seems likely that somatostatin and the somatostatin analog attenuate the miotic response to nociceptive stimuli by preventing the release of a substance, presumably substance P, from sensory nerves.
TL;DR: Oxidative drug metabolism in intraocular tissues (choroid, cornea, iris-ciliary body and retina) plus conjunctiva and liver was determined in rabbits and Iris- ciliary body showed the highest enzyme activity and cornea showed the lowest.
Abstract: Oxidative drug metabolism in intraocular tissues (choroid, cornea, iris-ciliary body and retina) plus conjunctiva and liver was determined in rabbits. 7-Ethoxycoumarin deethylase activity was found in all the intraocular tissues, but enzyme activities in these tissues were fairly low compared to activities in the conjuctiva and liver. Iris-ciliary body showed the highest enzyme activity and cornea showed the lowest. Relatively high activities were found in conjunctiva: 21 and 120 times as high as those in iris-ciliary body of young and adult rabbit eyes, respectively. The administration of phenobarbital or 3-methylcholanthrene (3-MC) to young rabbits caused marked induction of enzyme activity only in choroid tissues. Phenobarbital, but not 3-MC, also induced enzyme activities in conjunctiva and liver.
TL;DR: The concentration of vitamin A in various anterior segment tissues of the albino rabbit eye following topical instillation of a 1 mg/ml drug solution in peanut oil was determined using radiotracer techniques and it was found that 50-80% of the vitamin A absorption was in the corneal epithelium and the conjunctiva.
Abstract: The concentration of vitamin A in various anterior segment tissues of the albino rabbit eye following topical instillation of a 1 mg/ml drug solution in peanut oil was determined using radiotracer techniques. It was found that 50-80% of the vitamin A absorbed into the albino rabbit eye was in the corneal epithelium and the conjunctiva and that over 50% of the vitamin A in the cornea was in its epithelial layers. While trace amounts of topically applied peanut oil remained in the precorneal area as late as 2 hours post-dosing, the vitamin A dissolved in it did not appear to play a major role in sustaining vitamin A concentration within the eye. Rather, solubilization of vitamin A by the proteins in tears as well as by the cellular lipids and retinol-binding proteins in the corneal epithelium appear to play a more important role. It is suggested that further work is necessary to delineate the specific involvement of retinol-binding proteins in ocular vitamin A pharmacokinetics.
TL;DR: It is shown that corneal endothelial cells not only respond to β-adrenergic stimuli, but can also regulate the magnitude and duration of their response to the hormone.
Abstract: Corneal endothelial cells in primary culture responded to isoproterenol (Iso), epinephrine (Epi), nor-epinephrine (NE), Prostaglandins E1 and E2 (PGE1, PGE2) and forskolin by increasing cyclic AMP 61, 52, 28, 14, 10, and 176-fold, respectively, over control within a 10 minute incubation period. However, when cells were preincubated with Iso for one hour, they lost 76% of their responsiveness to a subsequent Iso challenge. Iso preincubation also decreased the effectiveness of other β-adrenergic agonists (Epi and NE), but responses to PGE1, PGE2 and forskolin remained unchanged. The decreased cyclic AMP response was associated with a loss of β-adrenergic binding sites. The affinity of the remaining receptors was unchanged as determined by propranolol displacement of [ 125I ] pindolol binding. This study shows that corneal endothelial cells not only respond to β-adrenergic stimuli, but can also regulate the magnitude and duration of their response to the hormone.
TL;DR: A model of Type I hypersensitivity in the conjunctiva of guinea pigs sensitized to normal rabbit serum was used to test the efficacy of 2-deoxy-D-glucose or a combination of isoproterenol and diethylcarbamazine in inhibiting conjunctival hypersensitivity.
Abstract: The release of histamine and other mediators from an immediate hypersensitivity reaction is energy dependent and cyclic AMP dependent. Drugs which inhibit the active secretion of mediators, or which may change cyclic AMP are effective in inhibiting mediator release. We used a model of Type I (immediate) hypersensitivity in the conjunctiva of guinea pigs sensitized to normal rabbit serum to test the efficacy of 2-deoxy-D-glucose or a combination of isoproterenol and diethylcarbamazine in inhibiting conjunctival hypersensitivity. After topical challenge with rabbit serum, edema was evaluated in five areas of the guinea pig conjunctiva. Controls were compared to conjunctiva pretreated with 2-deoxy-D-glucose or isoproterenol and diethylcarbamazine. Pretreatment with 2-deoxy-D-glucose or a combination of isoproterenol and diethylcarbamazine was found to inhibit the immediate hypersensitivity reaction.
TL;DR: The results with timolol suggest that this drug may decrease phosphoinositide hydrolysis, and the effects of these ocular hypotensive, non-selective beta blocking drugs on phospholipid turnover may ultimately limit the accumulation of breakdown products which could serve as cellular messengers.
Abstract: The effects of antiglaucoma drugs on [32P]-orthophosphate incorporation into phospholipids of iris and ciliary process were investigated. Both iris and ciliary process rapidly incorporated 32Pi into the major phospholipids, with the acidic phosphoinositides demonstrating a greater labelling than phosphatidylcholine, indicating a greater turnover. The muscarinic agonists, carbachol and pilocarpine, stimulated 32Pi-labelling of phosphatidylinositol (PI) and phosphatidic acid (PA) in both iris and ciliary process. These effects were blocked by atropine, suggesting that the response was mediated through muscarinic receptors. The beta blocking ocular hypotensive drugs, propranolol, timolol and atenolol, produced varying effects on 32P incorporation into phospholipids of iris and ciliary process. Propranolol stimulated 32Pi-labelling into phosphatidylinositol 4′, 5′ bisphosphate (PIP2), phosphatidylinositol 4′ phosphate (PIP), PI and PA. Timolol decreased 32Pi-incorporation into PIP2 and PI, whereas at...