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 effects of cholinergic agents on hormone-stimulated cyclic AMP (cAMP) accumulation were investigated in iris-ciliary body segments, excised ciliary processes, and isolated ciliary epithelium from albino rabbit eyes. In all three tissue preparations, the cholinergic agonist carbamylcholine markedly inhibited the stimulation of cAMP biosynthesis by vasoactive intestinal peptide VIP--a potent activator of nonpigmented ciliary epithelial adenylate cyclase. Carbamylcholine also attenuated cAMP increases mediated by isoproterenol, prostaglandin E2, and forskolin. The effects of carbamylcholine on VIP-induced cAMP synthesis were concentration dependent (EC50 = 23 nM), mimicked by selective muscarinic cholinergic agonists (oxotremorine, pilocarpine), and antagonized by atropine. Carbamylcholine- and clonidine-mediated inhibition of VIP-stimulated cAMP accumulation in ciliary processes were nonadditive, indicating that inhibitory muscarinic and alpha 2-adrenergic receptors coexist on VIP-responsive target cells. These findings suggest that the cholinergic system may have a direct role in modulation of ciliary epithelial adenylate cyclase and aqueous humor secretion.
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PMID:Muscarinic cholinergic inhibition of adenylate cyclase in the rabbit iris-ciliary body and ciliary epithelium. 216 35

The inhibitory effect of neuropeptide Y (NPY) was studied on the adenylate cyclase (AC) activity in homogenates of rabbit ciliary processes and compared with that of the alpha 2-adrenergic agonist clonidine (CLN). NPY inhibited basal AC activity as well as AC activity stimulated by isoproterenol (ISO), vasoactive intestinal polypeptide (VIP) or forskolin (FSK). The extent of this inhibition corresponded well to the inhibition elicited by CLN. The inhibitory effects of NPY and CLN appeared to be nonadditive. AC activity stimulated by ISO was considerably more sensitive to the effects of either NPY or CLN than basal, VIP- or FSK-stimulated AC activity. It was inferred that NPY inhibitory effects were mediated by the activation of NPY receptors coupled negatively to the catalytic unit of AC via the inhibitory Gi protein. Moreover, involvement of NPY in physiological modulation of AC activity in ciliary processes and in the regulation of aqueous humor formation and intraocular pressure is suggested.
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PMID:Inhibitory effects of neuropeptide Y on adenylate cyclase of rabbit ciliary processes. 233 9

Pirbuterol and nylidrin, both purported sympathomimetic amines, reduced intraocular pressure (IOP) when given topically (50 microliter, 0.1%) to albino rabbits. Pirbuterol increased the cyclic-AMP concentration in aqueous humor by a factor of 3.25, while nylidrin had no effect on aqueous cyclic-AMP nor on adenylate cyclase activity of iris-ciliary body membranes assayed in vitro. Studies of the receptor affinity of pirbuterol, timolol and nylidrin were carried out on iris-ciliary body membranes by competition binding with radioactive ligands. Four ligands were used that appear to label separate subpopulations of adrenergic receptors; dihydroalprenolol (beta-receptors), WB-4101 (alpha 1-receptors) prazosin (alpha 1-receptor subpopulation) and yohimbine (alpha 2-receptors). Pirbuterol and timolol showed exclusive selectivity for beta-receptors with high affinities (Kd 12.6 and 0.48 nM, respectively) compared with other adrenergic receptor populations in iris-ciliary body. Nylidrin had high affinities for beta-receptors (Kd 22 nM) and for the subpopulation of alpha 1-receptors labelled by prazosin (Kd 6.5 nM), but showed 100-fold lower affinity and complex binding characteristics to the two other classes of alpha-adrenergic receptor sites labelled by WB-4101 and yohimbine, respectively. The results show that pirbuterol and timolol are highly beta-receptor selective and that hypotensive responses to these drugs are not mediated by the other classes of alpha-adrenergic receptor determined in this study. However, the hypotensive response to nylidrin may be related to its prazosin-like (alpha 1-receptor) antagonist properties with additional activity at beta-receptors.
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PMID:Ocular hypotension in the rabbit. Receptor mechanisms of pirbuterol and nylidrin. 285 89

Vasoactive intestinal peptide (VIP)-responsive adenylate cyclase and VIP binding sites were investigated in membranes prepared from ciliary processes dissected from albino rabbit eyes. High-affinity binding sites for VIP (Kd, 0.95 nM; 607 fmol/mg of protein), in addition to beta adrenergic sites labeled by dihydroalprenolol (Kd, 0.48 nM; 123 fmol/mg of protein), were present. Activation of adenylate cyclase by VIP had a Ka of 65 nM, and the maximal response was 3.3-fold greater than that for I-isoproterenol (Ka, 102 nM). A peptide fragment of VIP (sequence 10-28) was inactive in all assays and did not inhibit VIP-stimulated adenylate cyclase at 10 microM. Responses to VIP and isoproterenol in combination were additive at lower doses but less than additive at maximal doses. Responses to VIP in combination with a low dose of forskolin (0.1 microM) were potentiated at all dose levels, whether assays were done in presence of MgCl2 or MnCl2. VIP- and forskolin-activated adenylate cyclase was associated with the nonpigmented epithelial cell fraction and not with pigmented epithelial cells separated on Percoll density gradients after dissociation of cells from processes by collagenase digestion. Intravitreous injection of 10 nmol of VIP into the rabbit eye caused a maximal reduction in intraocular pressure at 40 to 50 hr lasting beyond 72 hr. VIP-responsive and beta adrenergic-responsive adenylate cyclase are present on the same cell type (nonpigmented epithelial cells) and appear to share components of the adenylate cyclase system in the same membrane. VIP may participate in the physiologic regulation of aqueous humor secretion at the level of the epithelial cell membrane.
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PMID:Vasoactive intestinal peptide and intraocular pressure: adenylate cyclase activation and binding sites for vasoactive intestinal peptide in membranes of ocular ciliary processes. 303 1

Some biochemical factors of the iris-ciliary body of the rabbit have been examined for effects induced by water-soluble marihuana-derived material (MDM). Adenylate cyclase activity and sensitivity to beta-adrenergic agonists were unchanged, as measured 4 hours after MDM administration in vivo. Magnesium-dependent and anion-sensitive, but not sodium-potassium, ATPase activities were inhibited 6 hours after MDM administration in vivo, although they were unaffected by in vitro incubation. Topical administration of a potent substance P antagonist had no effect on the time course or magnitude of intravenous MDM-induced ocular effects in rabbit. Intravenously administered sugars antagonized the effects of MDM on intraocular pressure. A variety of drugs which display a range of biochemical effects varying from beta-adrenergic receptor agonism, to alteration of glycoprotein residues were employed. None of the agents employed, ranging from cAMP modifiers to protein synthesis blockers, had any effect on the MDM-induced response. It is apparent that the mechanism underlying the ocular hypotensive effect of MDM does not reside in mediation through adenylate cyclase, ATPase or substance P, but rather through a mechanism mediated by terminal sugar moieties on the molecule. The data suggest that modification of the surface membrane glycoprotein residues on the ciliary epithelium can induce marked alterations in aqueous humor flow rate.
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PMID:Marihuana-derived material: biochemical studies of the ocular responses. 316 May 44

The influence of compound IS-35 on intraocular pressure of unanesthetized rabbits was studied. In some cases intraocular pressure was measured with either the tonometer of Schiotz and was calculated in mmHg according to Leydhecker's scale (1973), or with the tonometer of Maclakov. Intraocular pressure was measured before and at 30, 60, 120, 180, 240 and 360 min after topical application of IS-35, timolol and trimetoquinol. It was established that IS-35 applied locally in the eye as 0.5% solution or collyrium decreases statistically significantly intraocular pressure. This effect was similar to that of timolol and exceeded significantly the effect of trimetoquinol. The experimental study on the beta-adrenergic adenylate cyclase showed that the mechanism of action of IS-35 on ophthalmotonus most probably is similar to the effect of timolol and is due to the suppression of aqueous humor formation.
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PMID:Effects of compound IS-35 on intraocular pressure. 341 49

To gain information on the role of cyclic AMP (cAMP), ion transport and cell membrane permeability on aqueous humor formation, agents with well-known effects on transport properties in other epithelia were tested on the isolated rabbit iris-ciliary body. Forskolin stimulated the short-circuit current (SCC) by 37.5% when added to the aqueous-side solution. Forskolin was ineffective when added to the blood-side solution or when HCO3- was absent from the bathing solutions. The effect of forskolin confirms the presence of adenylate cyclase in the ciliary epithelium and the involvement of cAMP in ion transport. In HCO3- -rich media, 5 X 10(-5) M prostaglandin F2 alpha (PGF2 alpha), produced a prompt 25% increase in the SCC when added to the aqueous-side, and a small stimulatory SCC response when added to the blood-side. No change in SCC occurred when PGF2 alpha was added to either side of a HCO3- -free bathing solution. It is implied that cAMP acts on a HCO3- dependent transport system. These results are consistent with the previously observed stimulation of the SCC by 8Br-cAMP. BaCl2, 2.5 mM, on the aqueous-side increased the SCC by 240.5%, but reduced the SCC by 26% when added to the blood-side solution. The Ba2+ effects indicate the presence of high conductance K+ channels in the basolateral membranes of both the pigmented and non-pigmented cell layers.
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PMID:Effects of forskolin, prostaglandin F2 alpha, and Ba2+ on the short-circuit current of the isolated rabbit iris-ciliary body. 346 15

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) adrenergic agonists and antagonist that affect both aqueous humor formation and outflow, and 3) carbonic anhydrase inhibitors that decrease aqueous humor formation. Several new classes of drugs are being tested for efficacy and mechanism of action. They include: 1) the D-isomer of timolol that reduces aqueous humor formation without producing adrenergic blockade, 2) dopaminergic agonists and antagonists, including bromocriptine and butyrophenones that reduce intraocular pressure, and 3) cannabinoids that reduce aqueous humor formation and increase outflow. In addition, several other types of drugs, such as prostaglandins, diuretics, Na+,K+-ATPase inhibitors, and adenyl cyclase stimulators are just now beginning to be studied.
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PMID:A synopsis of recent developments in antiglaucoma drugs. 391 48

The secretory tissue of the eye, the ciliary processes, contains an enzyme receptor complex, composed of membrane proteins, the catalytic moiety of the enzyme adenylate cyclase, a guanyl nucleotide regulatory protein (or N protein), and other features. The enzyme can be activated by well-known neurohumoral or humoral agents, catecholamines, glycoprotein hormones produced by the hypothalamic pituitary axis, and other related compounds, including placental gonadotropin, organic fluorides, and forskolin, a diterpene. These compounds cause the ciliary epithelia to produce cyclic AMP at an accelerated rate. Cyclic AMP, as a second messenger, causes, either directly or indirectly, a decrease in the net rate of aqueous humor inflow that may be modulated by cofactors. Clinical syndromes fit the experimental data so that an integrated explanation can be given for the reduced intraocular pressure witnessed under certain central nervous system and adrenergic influences. The molecular biology of this concept provides important leads for future investigations that bear directly both upon the regulation of intraocular pressure and upon glaucoma.
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PMID:The adenylate cyclase receptor complex and aqueous humor formation. 609 93

To better understand the nature of interaction of various amines with adrenergic receptors in te human ciliary process, beta-adrenergic-stimulated adenylate cyclase activity was characterized in broken cell preparations of this tissue from donor eyes. Among various agonists, isoproterenol was the most potent activator of enzyme activity (Ka = 3.4 x 10(-7)M), followed in order by epinephrine (Ka = 2.7 x 10(-6)M), norepinephrine (Ka = 2.1 x 10(-5)M), and phenylephrine (Ka greater than 10(-4)M). Isoproterenol-stimulated enzyme activity was blocked by timolol (Ki = 3.4 x 10(-9)M), IPS 339 (Ki = 4.4 x 10(-9)M), H35/25 (Ki = 6.9 x 10(-7)M), and atenolol (Ki = 1.4 x 10(-5)M). These pharmacological characteristics indicate that the human ciliary processes contain a predominance of beta2-adrenergic receptors. The findings are relevant to physiological studies of aqueous humor secretion and to the potential development of adrenergic agents with greater specificity for the beta-adrenergic receptor.
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PMID:Human ciliary process adrenergic receptor: pharmacological characterization. 611 46


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