Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0595921 (intraocular pressure)
 11,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stimulation of DP, but not TP or FP, prostanoid receptors has previously been shown to reduce intraocular pressure (IOP) in rabbits. However the role of EP receptors (EP1, EP2, and EP3 subtypes) has not been studied extensively. Sulprostone, RS-61565, and RS-20216 have been studied for effects on rabbit IOP, and their prostanoid-receptor profiles characterized. The data suggest that the EP3, but not EP2, FP, or TP activity of these agonists correlated with the intraocular hypotensive effects. Moreover, RS-20216 lowered IOP at a dose of 5 micrograms for up to 12 hr after administration. In contrast to PGE1 and PGE2, which elicited both hyper- and hypotensive responses, sulprostone, RS-61565, and RS-20216 elicited only a hypotensive responses with no signs of ocular irritation. Thus stimulation of the EP3 receptor results in a lowering of IOP in rabbits. Compounds specific for this receptor subtype may act as novel therapeutic agents for the treatment of glaucoma.
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PMID:EP3, but not EP2, FP, or TP prostanoid-receptor stimulation may reduce intraocular pressure. 217 84

The use of natural prostaglandins (PG), such as PGD2, PGE2, PGF2 alpha, and PGI2, for treating glaucoma is limited by their ocular side effects. One approach to achieve the required separation of ocular hypotensive activity from side effects is to employ ester prodrugs. From a novel series of 11- and 15-mono and 11,15-diacyl esters of PGF2 alpha we identified prodrugs where PGF2 alpha formation rates in the iris-ciliary body exceeded those in the conjunctiva, sclera, and corneal endothelium. Compared to PGF2 alpha-1-isopropyl ester the ocular tissue hydrolysis rates of the 11-monopivaloyl, the 11,15-dipivaloyl ester and the 1,11-lactone were up to 1000 fold less. Despite this large disparity in hydrolysis rates, the pivaloyl esters and the 1,11-lactone were potent ocular hypotensives in our animal models. In studying prostaglandin analogs, we found that a diverse variety of prostanoid receptor selective agonists lowered intraocular pressure in dogs and/or monkeys. These included DP-, EP1-, EP2-, EP3-, and FP-receptor selective compounds. These findings were surprising and prompted us to re-examine the receptor selectivity of these agonists by radioligand binding studies. Using radiolabelled PGE2, 17-phenyl PGF2 alpha, and sulprostone we were able to confirm the selectivity of the agonists currently used for receptor characterization directly by radioligand binding competition studies. It appears that multiple prostanoid receptor subtypes may be involved in regulating intraocular pressure.
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PMID:Studies on the ocular hypotensive effects of prostaglandin F2 alpha ester prodrugs and receptor selective prostaglandin analogs. 820 25

Prostaglandins can lower intraocular pressure when they are applied topically to the eye. This pressure-lowering effect is mediated by enhancement of uveoscleral outflow. Human ciliary muscle has binding sites (receptors) for prostaglandins and the EP2 receptor subtype is the predominant prostanoid receptor found in this muscle. Prostaglandins are thought to bind to these receptors located on the ciliary muscle, induce its relaxation, and promote the uveoscleral outflow. It is important to know the receptor type involved in the pressure reduction to design a new drug with less adverse effect and more potency.
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PMID:[Prostaglandins as ocular hypotensive drugs]. 831 45

The receptors involved in the ocular hypotensive activity of prostaglandins (PG) E2 and F2 alpha in dogs and monkeys was investigated by examining the effects of putative receptor selective agonists on intraocular pressure. A diverse variety of receptor selective agonists lowered intraocular pressure in these species. Thus, FP-receptor agonists (17-phenyl PGF2 alpha, fluprostenol), agonists with potent activity at the EP3 receptor (MB 28767, sulprostone) and a prostanoid with activity at the EP2 receptor (11-deoxy PGE1) were all potent ocular hypotensives when administered as a single dose to dogs and monkeys or b.i.d. for 5 days in monkeys. These findings were regarded as surprising and prompted us to re-examine some aspects of the current classification for prostanoid receptors. At present certain receptor subtypes, notably EP2, EP3 and FP receptors, are defined only according to the potency rank order for agonists. In these studies, we employed radioligand binding studies to determine the degree of competition between prostanoid agonists claimed to be selective on the basis of functional assays. Competition studies with a diverse variety of prostanoids at the binding site for PGE2 and sulprostone on the myometrial plasma membrane prepared from the rat uterus were consistent with the presence of an EP3 receptor. Thus, EP3-receptor agonists (MB 28767 and sulprostone) potently inhibited PGE2 and sulprostone binding, whereas FP agonists (17-phenyl PGF2 alpha, fluprostenol), a DP agonist (BW 245C), an EP1 antagonist (AH 6809), an EP2 agonist (AH 13205) and TP-receptor ligands (BM 13505, I-BOP) afforded little or no inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intraocular pressure effects of selective prostanoid receptor agonists involve different receptor subtypes according to radioligand binding studies. 835 15

Prostaglandins can reduce intraocular pressure by increasing uveoscleral outflow. We have previously demonstrated that the human ciliary muscle was a zone of concentration for binding sites (receptors) for prostaglandin F2 alpha and for prostaglandin E2. Here, we try to elucidate the types of prostanoid receptors in the ciliary muscle using competitive ligand binding studies in human eye sections and computer assisted autoradiographic densitometry. Saturation binding curves showed that the human ciliary muscle had a large number of binding sites with a high affinity for prostaglandin E2 compared with prostaglandin D2 and F2 alpha. The binding of tritiated prostaglandin E2 and F2 alpha in the ciliary muscle was displaced most effectively by prostaglandin E2 and 11-deoxy prostaglandin E1 (a selective EP2 prostanoid receptor agonist), whereas the binding of prostaglandin D2 was displaced most effectively by prostaglandin E2 and D2. These results indicate that the dominant prostanoid receptor in the human ciliary muscle is the EP2 subclass and that there is also a small number of DP receptors.
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PMID:The EP2 receptor is the predominant prostanoid receptor in the human ciliary muscle. 843 10

The cloning of the genes that encode for prostaglandin (PG) receptors has resolved much of the complexity and controversy in this area by confirming the classification proposed by Coleman, et al. Two issues that remained unresolved were (1) the inability of the EP2 agonist butaprost to interact with the cloned putative EP2 receptor and (2) molecular biological confirmation of a fourth PGE2-sensitive receptor, which was pharmacologically designated EP4. In order to provide clarification, we attempted to clone further PGE2-sensitive receptors. By using a cDNA probe that encodes for the human EP3A receptor, a cDNA clone that encoded for a novel PGE2-sensitive receptor was obtained by screening a human placenta library. This cDNA clone was transfected into COS-7 cells for pharmacological studies. The cDNA clone obtained from human placenta had only about 30% amino acid identity with cDNAs for other PG receptors, including those that encode for the previously proposed murine and human EP2 receptors. Radioligand binding studies on the novel EP receptor expressed in COS-7 cells revealed that selective EP2 agonists such as butaprost, AH 13205, AY 23626 and 19(R)-OH PGE2 all competed with 3H-PGE2 for its binding sites, whereas selective agonists for other PG receptor subtypes had minimal or no effect. This receptor was coupled to adenylate cyclase and EP2 agonists caused dose-related increases in cAMP. It appears that the cDNA described herein encodes for the pharmacologically defined EP2 receptor. Ocular studies revealed that AH 13205 decreased intraocular pressure in normal and ocular hypertensive monkeys by a mechanism that does not appear to involve inhibition of aqueous humor secretion.
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PMID:Molecular characterization and ocular hypotensive properties of the prostanoid EP2 receptor. 859 Feb 76

The purpose of this work is to investigate the effect of prostaglandins (PGs) on the contraction of ciliary muscle cells. It has been proposed that PGs induce relaxation of ciliary muscle and facilitate uveoscleral outflow, and reduce intraocular pressure (IOP). The ocular response to PGs is complicated because the relative contributions of uveoscleral flow and the conventional outflow to lowering IOP and the type of PG receptors associated with ciliary muscle may vary depending on animal species. In order to obtain insights into prostaglandin receptors of ciliary muscle, ciliary muscle cells from porcine eye were grown in culture and characterized immunocytochemically with antibodies against smooth muscle-alpha-actin and PGE2 receptor subtypes. As in ciliary muscle tissues, positive immunostaining for alpha-actin and EP2 and EP3 subtypes was observed in cultured cells. Time-dependent contraction of cultured cells induced by 10(-4) M carbachol was recorded by taking sequential photographs and analyzed. Using this assay method, the effect of prostaglandins E2 and F2 alpha to inhibit the carbachol-induced contraction was studied. PGE2 showed potent inhibition of cell contraction; 10(-7) approximately 10(-8) M PGE2 inhibited 50% of full contraction in 15 min. PGF2 alpha at 10(-4) M neither caused cell contraction by itself nor blocked carbachol-induced contraction. The EP2 agonist 11-deoxy-16, 16-dimethyl PGE2 at 10(-4) M inhibited cell contraction but the EP3 agonist sulprostone had no effect. Dibutyryl cAMP at 3 x 10(-5) M inhibited contraction by 50%. In the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), less than 10(-7) M dibutyryl cAMP caused 50% inhibition. In support of the cAMP effect, the addition of 10(-4) M PGE2 to cultured cells in the presence of indomethacin and IBMX was shown to cause an 80% increase in intracellular cAMP concentration compared with the basal (i.e. unstimulated) level of cAMP. Stimulation of cells with 10(-4) M PGF2 alpha caused no increase in cellular cAMP. These results indicate that PGE2 receptor EP2 subtype, but not PGF2 alpha receptor, is involved in the inhibition (hence relaxation by inference) of carbachol-induced porcine ciliary muscle cell contraction. It awaits further studies to determine whether cultured ciliary muscle cells of other species respond similarly to different PGs.
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PMID:The effects of prostaglandins E2 and F2 alpha on porcine ciliary muscle cells in culture. 897 45

Enormous progress has been made in the characterization of prostanoid receptors during the past five years. Molecular biological studies have enabled structural identification of all the human prostanoid receptors that had been proposed according to pharmacological criteria. The pharmacological classification proposed different receptor subtypes for prostaglandins D2, E2, F2 alpha, I2 and thromboxane A2 which were termed DP, EP, FP, IP and TP, respectively. Further subdivision for only the EP receptor has been reported and EP1, EP2, EP3, and EP4 subtypes have been unequivocally identified. The molecular structure of all prostanoid receptors is typical of that for G protein-coupled receptors and consists of seven alpha-helical transmembrane domains, three extracellular loops and an amino terminus, and three intracellular loops and a carboxyl terminus. Interestingly, mRNA alternative splice variants of the carboxyl termini have been found to determine G protein interactions for the EP3 receptor. Application of molecular biological techniques is beginning to make an impact in ocular research, where precise localization of receptors is difficult by more traditional methods because of the diminutive size of most ocular tissues. In situ hybridization and immunohistochemical studies using antibodies against the cloned human FP receptor have already suggested an unexpectedly wide distribution in the monkey eye. Transgenic studies involving FP receptor knock-out animals may provide future insight into the role of this receptor in glaucoma. However, since prostaglandins are extraordinarily effective in reducing intraocular pressure, it follows that traditional physiological and pharmacological studies retain a key role in glaucoma research. Studies in perfused human anterior segment organ culture have revealed that although prostaglandin F2 alpha does not facilitate trabecular aqueous humor outflow, prostaglandin E1 does increase trabecular outflow. Thus, different prostanoids may lower intraocular pressure by distinctly different mechanisms of action. Recent studies also indicate that prostanoids may exert a beneficial effect on retinal blood perfusion and may even act as neuroprotective agents.
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PMID:The molecular biology and ocular distribution of prostanoid receptors. 915 72

Prostaglandins (PGs) lower intraocular pressure by increasing uveoscleral outflow, presumably via a receptor-mediated mechanism coupled to a second messenger pathway in the ciliary muscle. In the present study, we examined the effect of prostanoids on cyclic AMP production in cultured human ciliary muscle cells. Cells were identified based on their expression of smooth muscle specific alpha-actin and monoclonal antibody against desmin. Cyclic AMP production in confluent cells incubated with buffer solution containing various concentrations of prostanoids was analyzed by radioimmunoassay. PGE2 caused a time-dependent increase in cyclic AMP concentrations which reached a maximum after 10 mins. With the exception of PGD2, all prostanoids produced a concentration-dependent increase in cyclic AMP levels with the following rank order of activity: PGE2 > 11-deoxy-PGE1 > 16,16-dimethyl PGE2 > sulprostone > PGF2alpha. PGE2-induced increase on cyclic AMP levels was unaffected by AH6809, an antagonist at both PGD2 (DP) and E2 (EP1) receptors. Flurbiprofen decreased basal cyclic AMP concentrations suggesting that intramurally-generated PGs stimulate the formation of the nucleotide in ciliary smooth muscle cells. PGE2-induced increases in cyclic AMP production was synergistic with those induced by the diterpene activator of adenylyl cyclase, forskolin. We conclude that prostanoids active at EP2-receptors can stimulate cyclic AMP production in cultured human ciliary muscle cells.
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PMID:Effect of prostaglandins on cyclic AMP production in cultured human ciliary muscle cells. 949 82

Prostaglandin E2 (PGE2) markedly reduces intraocular pressure (IOP) when applied topically and induces strong relaxation of pre-contracted isolated ciliary muscle through PGE2 receptor. Because the ciliary muscle relaxation reduces IOP by enhancing uveoscleral aqueous outflow, the ciliary muscle where the existence of PGE2 receptors has been demonstrated is thought to be one of the target tissues for PGE2-induced IOP reduction. To investigate the subtypes of PGE2 receptors in the ciliary muscle, the regional distribution of four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) in the mouse ciliary body was investigated by in situ hybridization using specific probes. Consistent messenger RNA signals for EP1 and EP4 receptors were expressed in the ciliary muscle, although signal levels for these subtypes were less potent as compared with the kidney, which was used as a reference organ. EP2 and EP3 signals were not detected. Stimulation of the EP4 receptor activates adenylate cyclase, which should induce ciliary muscle relaxation. Therefore, the IOP reduction induced by PGE2 analogs may be mediated by the EP4 receptor. In contrast, stimulation of the EP1 receptor is believed to promote intracellular Ca2+ mobilization, and hence should cause ciliary muscle contraction. Thus, the coexistence of EP1 and EP4 receptors in the ciliary muscle suggests that the regulation of ciliary muscle tone by PGE2 is based on a complex mechanism involving multiple receptor subtypes.
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PMID:Localization of prostaglandin E receptor subtypes in the ciliary body of mouse eye. 1087 May 20


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