Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The intracellular pathway by which beta-adrenergic agonists and antagonists affect aqueous humor dynamics involves the intracellular mediator, cyclic AMP. We have therefore tested the activity of forskolin, a direct activator of adenylate cyclase, in rabbits. Following a 15 min in vitro incubation in the presence of forskolin (15 microM) and isobutylmethylxanthine, a 10 fold increase in cyclic AMP was found in both rabbit iris-ciliary body and scleral-trabecular rings relative to controls. Following an intracameral injection of forskolin (10 micrograms) a time-dependent decrease in intraocular pressure was observed, which reached a mean decrease of 5 mm Hg at 4 hr in unanesthetized rabbits. Outflow facility was measured in anesthetized rabbits by constant pressure perfusion before injection and 1 hr after injection of either forskolin (10 micrograms) or control vehicle. Forskolin caused an approximate doubling of outflow facility (0.41 microliter/min/mm Hg) compared to the preinjection mean value. Control vehicle, ethyl alcohol, caused a statistically insignificant increase in outflow facility. At this concentration of forskolin, the integrity of the blood-aqueous barrier was normal as measured by protein and fluorescein entry into the aqueous humor. These results indicate that agents which directly activate adenylate cyclase are effective at increasing outflow facility and decreasing IOP.
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PMID:Forskolin stimulates cyclic AMP synthesis, lowers intraocular pressure and increases outflow facility in rabbits. 613 23

Adenylate cyclase activity was studied on the two epithelial cell types of bovine ciliary process after digestion by trypsin and purification by density gradient centrifugation. cAMP formation after isoproterenol stimulation showed that non pigmented cells were particularly enriched in adenylate cyclase activity. Furthermore pharmacological characteristics of this enzyme indicated that adenylate cyclase-associated beta adrenergic receptors were of beta 2 type in each kind of epithelial cells. These results support the hypothesis that beta adrenergic compounds modulate aqueous humor production through a direct effect on ciliary epithelium and enrichment of beta adrenergic sensitive adenylate cyclase activity in non pigmented epithelial cells suggests that these particular cells may play an important role in aqueous humor secretion.
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PMID:Pharmacological characteristics of beta-adrenergic-sensitive adenylate cyclase in non pigmented and in pigmented cells of bovine ciliary process. 615 85

Catecholamines, prostaglandins, and various hormones may influence aqueous humor dynamics via the second messenger, adenosine 3',5'-monophosphate (cyclic AMP). To test this hypothesis in rabbit ocular tissues, we have investigated the effects of cholera toxin (CTX), a specific, irreversible activator of adenylate cyclase. CTX (5 x 10(-4) to 5 x 10(2) microgram/ml) in both the presence and absence of isobutylmethylxanthine (IBMX) increased cyclic AMP production in the isolated iris-ciliary body. The effects of CTX were dependent on its concentration, duration of exposure, and presence of IBMX. Furthermore, iris-ciliary bodies and scleral-trabecular rings exercised after intravitreal injection of 10 microgram of CTX and incubated in vitro produced significantly more cyclic AMP than contralateral control tissues. Thus significant binding of CTX to both iris-ciliary body and scleral-trabecular ring occurred within 5 hr after intravitreal injection. Intraocular pressure (IOP) and outflow facility were measured by intraocular cannulation. Five hours after intravitreal injection of CTX, the IOP was lower than in control eyes. At this time, the outflow facility was threefold greater in the CTX-treated eyes than in control eyes. On the basis of these results, we conclude that (1) CTX stimulates cyclic AMP production in iris-ciliary body and scleral-trabecular ring of rabbits, (2) IOP decreases and outflow facility increases after intravitreal injection of CTX, and (3) the hypotensive effect of CTX is apparently mediated, at least partially, by outflow mechanisms.
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PMID:Effects of intravitreal cholera toxin on adenosine 3',5'-monophosphate, intraocular pressure, and outflow facility in rabbits. 625 77

To determine the site and possible mechanism of action of adrenergic agents in regulating intraocular pressure, experiments were undertaken to identify, localize, and characterize beta-adrenergic receptors associated with adenylate cyclase in various ocular tissues involved in secretion and reabsorption of aqueous humor. The ciliary process epithelium was found to be enriched in an adenylate cyclase with pharmacological characteristics indicative of a predominance of beta 2-adrenergic receptors. The results are consistent with the possibility that the adrenergic nervous system may regulate aqueous humor production through a direct effect on secretion. The data also are relevant to the potential development of drugs that can control increased intraocular pressure.
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PMID:Adrenergic regulation of intraocular pressure: identification of beta 2-adrenergic-stimulated adenylate cyclase in ciliary process epithelium. 626 Dec 57

Forskolin is a diterpene derivative of the plant Coleus forskohlii that stimulates adenylate cyclase activity without interacting with cell surface receptors. Forskolin lowers the intraocular pressure of rabbits, monkeys, and humans. In rabbits, net aqueous humor inflow decreases, outflow facility remains unchanged, and ciliary blood flow increases. Tolerance to the intraocular pressure lowering effect did not occur in rabbits after topical doses given every 6 hr for 15 days. In vitro forskolin activates adenylate cyclase of crude particulate homogenates prepared from cultured human ciliary epithelia or from dissected ciliary epithelial processes of rabbit or human eyes. This activation is not blocked by timolol. The stimulation of adenylate cyclase by isoproterenol in vitro is potentiated in the presence of forskolin. Forskolin represents a potentially useful class of antiglaucoma agents differing in molecular mechanism of action from previously used drugs.
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PMID:Forskolin lowers intraocular pressure by reducing aqueous inflow. 653 89

Prostaglandin E2 (PGE2) binding revealed that porcine ciliary epithelial membranes possess two subclasses of binding sites or receptors. Ciliary nonpigmented epithelial (NPE) membranes have two binding sites (Kd,1 = 35 x 10(-9) M, Bmax,1 = 485 x 10(-12) mol/mg protein; Kd,2 = 0.723 x 10(-6) M, Bmax,2 = 1473 x 10(-12) mol/mg protein), while pigmented epithelial (PE) membranes have one binding site (Kd = 82 x 10(-9) M, Bmax = 377 x 10(-12) mol/mg protein). The three sites of NPE/PE membranes were found to show the highest affinity for PGE2 by competitive binding assay; affinity for PGF2 alpha and PGD2 was several orders of magnitude less. PGE2 binding to the higher affinity site of NPE membranes induced inhibition of adenylate cyclase activity. Activation of the lower affinity site resulted in activation of the cyclase activity. PGE2 binding to PE membranes caused inhibition of adenylate cyclase activity. There is evidence that cyclic adenosine monophosphate (cAMP) affects transport of ions and water in the ciliary epithelium, hence modulates aqueous humor inflow. The present results, therefore suggest that aqueous humor production by the ciliary NPE cells may be influenced by changes in the concentration of PGE2 which binds to the receptor subtypes having opposing effects on adenylate cyclase and regulates intracellular cAMP level.
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PMID:Bimodal regulation of adenylate cyclase by prostaglandin E2 receptors in porcine ciliary epithelium. 825 73

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

Pituitary adenylate cyclase-activating peptide (PACAP)-like immunoreactivity was demonstrated by immunocytochemistry together with calcitonin gene-related peptide (CGRP)-like immunoreactivity in small to medium-sized neurons in the trigeminal ganglion and in nerve fibers in the iris, ciliary body, cornea, choroid and sclera of the rabbit eye. The regional distribution of PACAP-27- and PACAP-38-like immunoreactivity in the eye was studied by radioimmunoassay: the highest concentrations were found in the iris sphincter and ciliary body. The distribution pattern resembled that of CGRP-like immunoreactivity, which is a well-known constituent of sensory C-fibre neurons. Intravitreal injection of PACAP-27 or PACAP-38 induced conjunctival hyperemia, swelling of the anterior segment of the eye, miosis and breakdown of the blood-aqueous barrier, manifested as a marked aqueous flare response. Tetrodotoxin pretreatment inhibited the conjunctival hyperemia, the swelling of the anterior segment of the eye, and the miosis but not the aqueous flare response. The concentration of PACAP-like immunoreactivity in the aqueous humor was increased greatly following infrared irradiation of the iris, topical application of formaldehyde to the cornea, or intravitreal injection of endotoxin or bovine serum albumin. Also the concentration of CGRP-like immunoreactivity in the aqueous humor was increased greatly. Both in vivo and in vitro studies showed that capsaicin caused a parallel release of PACAP-like immunoreactivity and CGRP-like immunoreactivity from the uvea. Injection of PACAP-27 and PACAP-38 resulted in the release of CGRP-like immunoreactivity (and PACAP-like immunoreactivity) into the aqueous humor and PACAP-27 and PACAP-38 were also found to evoke tachykinin-mediated contractions of the isolated iris sphincter muscle, indicating that PACAP induces positive feedback on C-fibres. Thus, PACAP is a sensory neuropeptide in the eye. Since the PACAP-induced ocular responses mimicked the symptoms of inflammation, and since the PACAP-like immunoreactivity concentration in the aqueous humor was greatly increased following noxious stimulation, we suggest that it takes part in the inflammatory responses of the rabbit eye.
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PMID:Distribution and effects of pituitary adenylate cyclase-activating peptide in the rabbit eye. 863 27

Prostaglandin F2 alpha (PGF 2 alpha) and its analog latanoprost are effective in lowering intraocular pressure (IOP) in both animal and human subjects. There is mounting experimental evidence now which indicates that the IOP-lowering effect of these PGs occurs through an increased uveoscleral outflow of aqueous humor. The ciliary muscle constitutes the main resistance in this pathway. Work from several laboratories, including our own, has shown that in this smooth muscle PGF 2 alpha has little effect on cAMP accumulation or on Ca2+ mobilization. In the present study, we hypothesized that some of the effects of PGF2 alpha and its analogs may be mediated through the release of endogenous PGs. The purpose of this work was to determine whether or not PGF2 alpha and its analogs can enhance the release of endogenous PGs in iris and ciliary muscles isolated from different species. This report documents for the first time that exogenous PGF2 alpha and its analogs, PhXA85 and latanoprost, stimulate the formation of PGE2, PGD2 and PGF2 alpha in iris and ciliary muscles isolated from cat, bovine, rabbit, dog, rhesus monkey and human. PG-induced PG release was demonstrated by means of both radioimmunoassay and radiochromatography. Kinetic studies on cat iris revealed that PGF2 alpha-induced PGE2 release is time (t 1/2 = 1.7 min) and dose-dependent (EC50 = 45 nM). The increase in PGE2 release was blocked by indomethacin (Indo) and by dexamethasone in a dose-dependent manner with IC50 s of 9.2 nM and 2.6 microM, respectively. Furthermore, dexamethasone inhibited arachidonic acid (AA) release, suggesting the involvement of phospholipase A2 in PGF2 alpha-induced PG release. The data presented demonstrate that PGF2 alpha and its analogs interact with the PG receptor to stimulate phospholipase A2 and release AA for PG synthesis. Relaxation of ciliary muscle by PGF2 alpha and its analogs, via release of endogenous PGE2, a potent activator of the adenylate cyclase system, could in part explain how these PGs may increase uveoscleral outflow and consequently lower IOP.
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PMID:Prostaglandin F2 alpha and its analogs induce release of endogenous prostaglandins in iris and ciliary muscles isolated from cat and other mammalian species. 894 3

The aim of this study was to investigate the influence of substances that increase intracellular cAMP levels on the aqueous humor outflow facility (C) of isolated bovine anterior segments. Anterior segments were perfused in vitro at a constant pressure of 10 mmHg for 270 min with a general protocol as follows: 90 min control perfusion with DMEM, 90 min of experimental perfusion with DMEM containing the test drug(s), and 90 min of postdrug-perfusion with DMEM. C was calculated as the ratio between the rate of medium inflow (microliter/min) and the perfusion pressure (mmHg). Anterior segments can be perfused in vitro for up to 5 hr without significantly modifying their C. The addition of epinephrine, forskolin, dibutyryl-cAMP or isobutylmethylxanthine to the control perfusion medium elicited a significant increase of C. If, during isobutylmethylxanthine perfusion, forskolin or epinephrine was added, C increased significantly. Finally, perfusion with indomethacin prior to addition of epinephrine prevented the increase of C induced by epinephrine. Epinephrine, the adenylate cyclase activator forskolin, the cAMP analog dibutyryl-cAMP, and the phosphodiesterase inhibitor isobutylmethylxanthine all increase aqueous facility. It seems reasonable to suspect that the cAMP system is involved in epinephrine's effects on bovine trabecular meshwork cells. Moreover, the complete inhibition by indomethacin of the outflow facility increase induced by epinephrine suggests that prostaglandins may be involved in the outflow facility mechanisms related to adrenoreceptor stimulation of trabecular meshwork cells.
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PMID:Facility changes mediated by cAMP in the bovine anterior segment in vitro. 906 27


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