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:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On the basis of the information presented in this review, it is difficult to reach any firm decision regarding the role of cyclic AMP (or cyclic GMP) in synaptic transmission in the brain. While it is clear that cyclic nucleotide levels can be altered by the exposure of neural tissues to various neurotransmitters, it would be premature to claim that these nucleotides are, or are not, essential to the transmission process in the pre-or post-synaptic components of the synapse. In future experiments with cyclic AMP it will be necessary to consider more critically whether the extracellularly applied nucleotide merely provides a source of adenosine and is thus activating an extracellularly located adenosine receptor, or whether it is actually reaching the hypothetical sites at which it might act as a second messenger. The application of cyclic AMP by intrcellular injection techniques should minimize this particular problem, although possibly at the expense of new diffulties. Prio blockade of the adenosine receptor with agents such as theophylline or adenine xylofuranoside may also assist in the categorization of responses to extracellularly applied cyclic AMP as being a result either of activation of the adenosine receptor or of some other mechanism. Utimately, the developement of highly specific inhibitor for adenylate cyclase should provide a firm basis from which to draw conclusions about the role of cyclic AMP in synaptic transmission. Similar considerations apply to the action of cyclic GMP and the role of its synthesizing enzyme, guanylate cyclase. The use of phosphodiesterase inhibitors in studies on cyclic nucleotides must also be approached with caution. The diverse actions of many of these compounds, which include calcium mobilization and block of adenosine uptake, could account for many of the results that have been reported in the literature.
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PMID:The role of cyclic nucleotides in the CNS. 1 46

A study was made on the force of spontaneous mechanical activity in the rat portal vein. Prostaglandin inhibitor, sodium meclofenamate, phosphodiesterase inhibitors, aminophylline and dipyridamole, adenosine and blockade of calcium entry by isoptin all reduced the force of spontaneous activity in a concentration-dependent manner, while imidazole enhanced it. Low concentration of aminophylline (10 microM), dipyridamole (6 microM) and meclofenamate (10 microM) depressed the spontaneous contraction of the vein by about 50% without modifying the response to noradrenaline. At higher concentration of these drugs, spontaneous mechanical contraction was reduced further and the response to noradrenaline antagonized. Low concentration of isoptin also reduced the mechanical activity without affecting maximum response to noradrenaline. A common mechanism of action for the drugs tested, namely the limiting of Ca2+ availability for muscular contraction, is discussed. Adenosine markedly reduced the spontaneous mechanical activity of the rat portal vein. Its relaxation effect could be due to the activation of a specific adenosine receptor.
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PMID:Effect of drugs on the force of spontaneous mechanical activity in rat portal vein. 26 64

The mechanism(s) underlying adenosine receptor-mediated modulation of cardiac cAMP levels has been investigated using detergent-permeabilized embryonic chick ventricular myocytes. The beta-adrenergic receptor agonist isoproterenol (ISO) stimulated adenylyl cyclase activity in detergent-permeabilized cells by 5-10-fold, with an EC50 value of 0.3 microM. Three adenosine receptor agonists, (R)-N6-phenylisopropyladenosine, N6-(3-iodo-4-aminobenzyl)adenosine, and 5'-N-ethylcarboxamidoadenosine, inhibited ISO (10 microM)-stimulated adenylyl cyclase activity in a concentration-dependent manner. The maximum inhibition of the ISO-stimulated adenylyl cyclase activity by (R)-N6-phenylisopropyladenosine (10 microM) was 30-40%. This inhibition was antagonized by the adenosine receptor antagonists xanthine amine congener and 8-cyclopentyl-1,3-dipropylxanthine and was abolished by pertussis toxin treatment, suggesting that the inhibition of adenylyl cyclase activity is mediated by A1 adenosine receptors acting via a pertussis toxin-sensitive guanine nucleotide-binding protein (G protein). Because the adenosine receptor agonists had no detectable effect on phosphodiesterase activity, the adenosine receptor-mediated inhibition of adenylyl cyclase activity appears to account for the cAMP-lowering effect of adenosine receptor agonists seen in intact cardiac myocytes. Moreover, two A1 adenosine receptor antagonists, 8-cyclopentyl-1,3-dipropylxanthine and 3-(4-amino)phenethyl-1-propyl-8-cyclopentylxanthine, stimulated basal adenylyl cyclase activity in the absence of an adenosine receptor agonist; this stimulation was abolished by pretreatment of the cells with pertussis toxin. We postulate that "precoupled" A1 adenosine receptor-G protein complexes, present in the cardiac myocytes, exert a tonic inhibitory influence on adenylyl cyclase activity and that some adenosine receptor antagonists remove this tonic inhibition by destabilizing these precoupled receptor-G protein complexes.
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PMID:Modulation of cardiac cyclic AMP metabolism by adenosine receptor agonists and antagonists. 133 65

In heart failure, the sympathetic nervous system is activated. The increased release of norepinephrine from the heart and the elevated levels of circulating catecholamines produce a downregulation of myocardial beta 1-adrenoceptors. In ischemic cardiomyopathy and mitral valve disease, a downregulation of beta 2-adrenoceptors has been observed also. The beta-adrenoceptor downregulation closely correlates to the reduced positive inotropic effects of beta-adrenoceptor agonists. In addition, an increase of the inhibitory guanine-nucleotide binding protein (Gi alpha) has been observed, while the levels of the stimulatory guanine-nucleotide binding protein (Gs alpha), the activity of the catalyst and the anti-adrenergic effects of A1-adenosine receptor- or m-cholinoceptor stimulation remain unchanged in the failing human heart. The increase of Gi alpha correlated closely to the reduced positive inotropic responses to the cAMP-phosphodiesterase inhibitor milrinone. In the failing human heart, the beta-adrenoceptor downregulation and the increased expression of Gi alpha represent pathobiochemical alterations which are involved in the reduced effects of cAMP-dependent positive inotropic agents. The therapeutic reversal of these pathobiochemical alterations is a future promise in the treatment of heart failure.
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PMID:[Adrenergic beta receptors and guanine nucleotide binding proteins (G-proteins) of the failing human heart]. 133 8

Activation of cAMP-dependent protein kinase (kinase A) has recently been shown to enhance responses evoked by stimulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in cultured hippocampal pyramidal neurons. Here we report results of experiments designed to determine if activation of the cAMP cascade potentiates synaptic strength in field CA1 of rat hippocampal slices. We find that bath application of the direct adenylate cyclase activator forskolin (50 microM) enhances the field excitatory postsynaptic potential (EPSP) slope and population spike amplitude evoked by stimulation of Schaffer/commissural afferents. This effect is potentiated by the phosphodiesterase inhibitor and adenosine receptor antagonist 3-isobutyl-1-methylxanthine (IBMX). The enhancement produced by forskolin is suppressed in the presence of adenylate cyclase inhibitors and is not mimicked by the inactive forskolin analogue 1,9-dideoxyforskolin, indicating that, indeed, activation of adenylate cyclase mediates the effects of forskolin in field CA1. Our observations support the idea that changes in intracellular cAMP levels can modulate synaptic efficacy of excitatory glutamatergic synapses in the mammalian hippocampus.
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PMID:Modulation of synaptic efficacy in field CA1 of the rat hippocampus by forskolin. 137 10

Cyclic AMP regulation by muscarinic and adenosine receptors was investigated in isolated canine ventricular myocytes. Both the muscarinic receptor agonist, carbachol, and the adenosine receptor agonist, phenylisopropyladenosine, decreased isoproterenol-stimulated cyclic AMP accumulation in a concentration-dependent manner. Carbachol was more potent than phenylisopropyladenosine and had a greater inhibitory effect. At 10(-6) M, carbachol reduced isoproterenol-stimulated cyclic AMP by 73 +/- 5% while 10(-3) M phenylisopropyladenosine was required to decrease cyclic AMP accumulation by 54 +/- 8%. Pretreatment of myocytes with pertussis toxin to inactivate the inhibitory guanine nucleotide binding protein, Gi, completely abolished the effect of phenylisopropyladenosine to reduce cyclic AMP stimulation. In comparison, pertussis toxin treatment blunted the response to carbachol and shifted the dose-effect curve to the right but did not eliminate the inhibitory action of carbachol. In toxin-treated myocytes, 10(-3) M carbachol produced a 26 +/- 6% reduction of isoproterenol-induced cyclic AMP accumulation. This pertussis toxin-insensitive action of carbachol was antagonized by atropine and pirenzepine and was prevented when either of two different phosphodiesterase inhibitors. RO-20-1724 or isobutylmethylxanthine, was included in the incubation medium. The results indicate that adenosine receptor-mediated inhibition of hormone-stimulated cyclic AMP accumulation in ventricular myocytes occurs by a single, Gi-dependent mechanism while muscarinic inhibition appears to involve both Gi-dependent and Gi-independent mechanisms. The Gi-independent mechanism may reflect enhanced phosphodiesterase activity which results from the activation of muscarinic receptors.
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PMID:Differential effect of pertussis toxin on adenosine and muscarinic inhibition of cyclic AMP accumulation in canine ventricular myocytes. 164 26

The cyclic adenosine-3',5'-monophosphate (cAMP) elevation caused by exposure of human neutrophils to the Ca2+ ionophore A23187 was prevented when endogenously produced adenosine was either removed by preincubation with adenosine deaminase or blocked from binding to the adenosine receptor by antagonists [theophylline or (E)-4-(1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-9H-purin-8-yl)cinnamic acid]. In the absence of endogenous adenosine, A23187 potentiated the neutrophil cAMP response to 2-chloroadenosine, prostaglandin E1, and isoproterenol. When neutrophil suspensions were preincubated with concentrations of Ro 20-1724, which appeared to maximally inhibit cAMP phosphodiesterase, A23187 was still able to substantially elevate cAMP levels, suggesting that A23187 increases cAMP by amplifying adenylate cyclase responsiveness to the agonist rather than by inhibiting cAMP phosphodiesterase. The ability of A23187 to augment the cAMP elevation caused by 2-chloroadenosine was persistent over a 10-min period. The neutrophil cAMP elevations caused by chemoattractants leukotriene B4, C5a, and N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) were all prevented when endogenously produced adenosine was eliminated from the cell suspensions by the addition of adenosine deaminase. The A23187-induced cAMP elevation was inhibited completely by the calmodulin inhibitors chlorpromazine, trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, whereas cAMP levels induced by FMLP, leukotriene B4 and C5a were less affected. It appears that A23187 raises cAMP in human neutrophils by a calmodulin-dependent potentiation of adenylate cyclase responsiveness to endogenously produced adenosine while the chemoattractant-induced cAMP elevations (FMLP), leukotriene B4, and C5a), although possibly Ca2+ dependent, are less sensitive to calmodulin inhibitors and may involve additional biochemical events.
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PMID:Ca2+ ionophore-induced cyclic adenosine-3',5'-monophosphate elevation in human neutrophils. A calmodulin-dependent potentiation of adenylate cyclase response to endogenously produced adenosine: comparison to chemotactic agents. 166 48

Mechanisms responsible for the reductions in renal blood flow (RBF) and glomerular filtration rate (GFR) in response to acute infusions of amphotericin B were investigated in vivo in rats. The influence of salt status and the roles of adenosine, cyclic AMP, and calcium influx were examined. Amphotericin B was infused into the renal artery in seven groups of rats at 0.025 mg/kg of body weight per min for 15 min. RBF and GFR were measured over 15 min before, during, and after the infusion. Control rats were maintained on a normal salt diet; a second group of rats received a salt-depleted diet, and a third group received a high-salt intake. Four other groups were kept on a normal diet and received theophylline (0.5 mumol/kg/min into the renal artery, intra-arterially [i.a.]), dibutyryl cyclic AMP (85 micrograms/min, i.a.), the 5'-nucleotidase inhibitor adenosine alpha,beta-methylene diphosphate (4 mg/kg, intramuscularly), or diltiazem (20 micrograms/kg/min, i.a.). Control rats had a prompt 50% decrease in RBF in response to amphotericin B. This was sustained over the 15-min infusion period and was accompanied by a decrease in creatinine clearance (CLCR) (from 0.83 +/- 0.08 to 0.40 +/- 0.09 ml/min; P less than 0.05). On stopping the infusion, RBF returned quickly to baseline but CLCR continued to decrease further (to 0.35 +/- 0.07 ml/min; P less than 0.05). Salt loading, theophylline, and diltiazem administration prevented the decreases in both RBF and CLCR. Both RBF and CLCR responses in the remaining groups were not significantly different from those in controls. The results of this study reveal a protective effect of salt loading and theophylline against amphotericin B nephrotoxicity in the rat but deny a role for adenosine in mediating these effects. They further suggest that theophylline inhibits the acute responses by a mechanism unrelated to either adenosine receptor blockade or phosphodiesterase inhibition and that calcium influx into the cells is probably responsible for the acute changes in RBF and GFR in response to amphotericin B.
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PMID:Mechanisms of amphotericin B-induced decrease in glomerular filtration rate in rats. 166 54

L-Histidine and imidazole (the histidine side chain) significantly increase cAMP accumulation in intact LLC-PK1 cells. This effect is completely inhibited by isobutylmethylxanthine (IBMX). Histidine and imidazole stimulate cAMP phosphodiesterase activity in soluble and membrane fractions of LLC-PK1 cells suggesting that the IBMX-sensitive effect of these agents to stimulate cAMP formation is not due to inhibition of cAMP phosphodiesterase. Histidine and imidazole but not alanine (the histidine core structure) increase basal, GTP-, forskolin-, and AVP-stimulated adenylate cyclase activity in LLC-PK1 membranes. Two other amino acids with charged side chains (aspartic and glutamic acids) increase AVP-stimulated but neither basal- nor forskolin-stimulated adenylate cyclase activity. This suggests that multiple amino acids with charged side chains can regulate selected aspects of adenylate cyclase activity. To better define the mechanism of histidine regulation of adenylate cyclase, membranes were detergent-solubilized which prevents histidine and imidazole potentiation of forskolin-stimulated adenylate cyclase activity and suggests that an intact plasma membrane environment is required for potentiation. Neither pertussis toxin nor indomethacin pretreatment alter imidazole potentiation of adenylate cyclase. IBMX pretreatment of LLC-PK1 membranes also prevents imidazole to potentiate adenylate cyclase activity. Since IBMX inhibits adenylate cyclase coupled adenosine receptors, LLC-PK1 cells were incubated in vitro with 5'-N-ethylcarboxyamideadenosine (NECA) which produced a homologous pattern of desensitization of NECA to stimulate adenylate cyclase activity. Despite homologous desensitization, histidine and imidazole potentiation of adenylate cyclase was unaltered. These data suggest that histidine, acting via an imidazole ring, potentiates adenylate cyclase activity and thereby increases cAMP formation in cultured LLC-PK1 epithelial cells. This potentiation requires an intact plasma membrane environment, occurs independent of a pertussis toxin-sensitive substrate and of products of cyclooxygenase, and is inhibited by IBMX. This IBMX-sensitive pathway does not involve either inhibition of cAMP phosphodiesterase activity or a stimulatory adenosine receptor coupled to adenylate cyclase.
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PMID:Histidine regulation of cyclic AMP metabolism in cultured renal epithelial LLC-PK1 cells. 168 53

Isobutylmethylxanthine (IBMX), a phosphodiesterase/adenosine receptor inhibitor, was combined with norepinephrine (nE), epinephrine (Epi) and isoproterenol, respectively, to evaluate their effect on intraocular pressure (IOP). Application of topical IBMX alone had no measurable effect on IOP. When IBMX was combined with nE or Epi the ocular hypotension in rabbits and beagles increased. The Emax for nE alone was 2.9 +/- 0.4 mmHg, for Epi alone 7.3 +/- 0.5 mmHg and for isoproterenol alone 5.1 +/- 0.3 mmHg. The EC50 was 0.2 +/- 0.05% (nE), 0.05 +/- 0.01% (Epi) and 0.003 +/- 0.001% for isoproterenol. When given in combination with 1% IBMX the Emax for nE was 7.4 +/- 1.7 mmHg, for Epi 9.0 +/- 0.8 mmHg and for isoproterenol 6.1 +/- 0.3 mmHg. The corresponding values for EC50 were 0.07 +/- 0.03% (nE), 0.02 +/- 0.006% (Epi) and 0.002 +/- 0.001% for isoproterenol. Combining 1% IBMX with 0.1% Epi increased the aqueous humour cyclic AMP-levels at 1, 3 and 5 hr in rabbits. The results of this study demonstrate that a phosphodiesterase/adenosine receptor inhibitor such as IBMX enhances the reduction in IOP induced by adrenergic agonists.
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PMID:Isobutylmethylxanthine enhances adrenergic-induced ocular hypotension in rabbits and beagles. 171 10


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