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)

1. beta-adrenoceptors on human alveolar macrophages obtained by bronchoalveolar lavage (BAL) from healthy smoking volunteers (n = 26) were characterized by studying cyclic AMP (cAMP) accumulation in intact macrophages evoked by adrenaline or isoprenaline, with or without appropriate antagonists and by radioligand binding to macrophage membranes, using [125I]-iodopindolol (125IPIN) as beta-adrenoceptor ligand. 2. In a second study, cAMP responses of alveolar macrophages to isoprenaline and PGE1 and of peripheral blood lymphocytes to isoprenaline were compared in smoking and non-smoking healthy volunteers (n = 9 + 9), as our initial studies were performed in smokers, due to their higher cell yield. 3. BAL yielded 47 +/- 23 x 10(6) cells in smokers and 12 +/- 6 x 10(6) cells in non-smokers with a recovery of 82 +/- 8% in the elutriation step (means +/- s.d.). The cell preparation consisted of 99.2 +/- 0.8% macrophages and their viability (trypan blue exclusion) was 97.5 +/- 5.2%. 4. Isoprenaline or adrenaline increased cAMP accumulation approximately 40-fold with or without the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX, 10(-4) M), which enhanced basal and stimulated cAMP accumulation approximately five-fold. Peak responses were seen after 2 min. EC50s for isoprenaline and adrenaline were 3-5 x 10(-7) M. Phentolamine did not alter responses to adrenaline, indicating absence of inhibitory alpha 2-adrenoceptors. Propranolol inhibited isoprenaline induced cAMP accumulation stereoselectively; pD2-values were 8.2 for (-)-propranolol, 5.6 for atenolol and 7.5 for ICI 118,551, suggesting a predominance of beta 2-adrenoceptors. 5. Specific 125IPIN binding to macrophage membranes was rapid and saturable. Non-specific binding was determined in the presence of 1 microM (-)-propranolol. KD values were 71 +/- 7 pM and the density of specific binding sites was 36 +/- 3 fmol mg-1 protein (three experiments on a membrane pool from 10 subjects; r values for Scatchard analyses = 0.98 +/- 0.01). Similar values were obtained when 200 microM isoprenaline (+ GTP) was used to assess non-specific binding. Competition experiments again showed stereoselectivity for propranolol and a predominance of beta 2-adrenoceptors, as judged by the displacement of specific 125IPIN binding by atenolol and ICI 118,551. 6. Macrophages from smokers responded with less marked cAMP accumulation upon stimulation with isoprenaline or PGE1 than did cells from non-smokers (difference approximately 30%; P less than 0.05 for both agonists) in the presence of IBMX. Thus macrophages from smokers may produce less cAMP due to post-receptor changes in responsiveness.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Beta-adrenoceptors in human alveolar macrophages isolated by elutriation. 170 82

1. In rat isolated islets of Langerhans the selective beta 2-adrenoceptor agonist, clenbuterol (1 to 20 microM), significantly increased the level of adenosine 3':5'-cyclic monophosphate (cyclic AMP) within 2 min of incubation. 2. The cyclic AMP response to clenbuterol was inhibited in the presence of the selective beta 2 adrenoceptor antagonist, ICI 118551 (0.1 or 10 microM) but remained unchanged when the beta 1-antagonist, atenolol (0.1 microM) was administered. 3. Despite causing an elevation in cyclic AMP, clenbuterol (up to 20 microM) failed to influence insulin secretion at any glucose concentration tested, even in the presence of a phosphodiesterase inhibitor. 4. By contrast, clenbuterol elicited a dose-dependent rise in the rate of glucagon secretion; the maximal agonist-induced increase in secretion was two fold, a response equivalent to that observed with 20 mM L-arginine. 5. ICI 118551 significantly inhibited the rise in glucagon secretion induced by clenbuterol (up to 20 microM). 6. The results indicate that the rat islet A cell population is equipped with functional beta 2-adrenoceptors which influence glucagon secretion via the second messenger cyclic AMP, but that the B cells are deficient in functional beta-receptors.
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PMID:Selective stimulation of glucagon secretion by beta 2-adrenoceptors in isolated islets of Langerhans of the rat. 171 26

The inotropic vasodilator, ICI 153,110, a phosphodiesterase inhibitor intended for the treatment of congestive heart failure, was administered to Alderley Park Wistar-derived rats for periods of up to 182 days. Treatment produced hypertrophy of salivary glands, hyperplasia of intestinal mucosa, and dacryoadenitis of the harderian gland. As the functions of these glandular tissues can be modified by factors which alter cyclic nucleotide metabolism, it is postulated that the glandular alterations produced by ICI 153,110 occurred as a result of phosphodiesterase inhibition.
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PMID:Long-term effects of an inotropic phosphodiesterase inhibitor (ICI 153,110) on the rat salivary gland, harderian gland, and intestinal mucosa. 178 Jun 38

The aim of these studies was to determine whether phosphodiesterase inhibition by enoximone is able to regulate differentially beta 1- and beta 2-adrenoceptor (AR)-mediated inotropic effects. Strips of human right atrial myocardium were stimulated with noradrenaline plus ICI 118,551 (selective beta 1-AR stimulation) or adrenaline plus CGP 20,712A (selective beta 2-AR stimulation). Concentration-effect curves were determined in the absence or presence of enoximone. Enoximone alone was shown to produce dose-related positive inotropic effects. In tissues from beta 1-blocker-treated patients, enoximone potentiated the responses to both beta 1-AR and beta 2-AR stimulation. There was a fall in -log EC50 (mol/l) of 0.7 +/- 0.2 (mean +/- SEM; n = 6) for beta 1-AR stimulation and of 0.6 +/- 0.1 (n = 10) for beta 2-AR stimulation. The potentiation of beta 2-AR responses in non-beta-blocker-treated patients was similar with a fall in -log EC50 (mol/l) of 0.5 +/- 0.1 (n = 6). The extent of potentiation was not significantly different between beta 1-AR and beta 2-AR stimulation, nor between beta 1-blocker-treated patients and non-beta-blocker-treated patients. Further experiments showed that the potentiation by enoximone of the effects of catecholamines was unaltered by diazoxide (n = 6). Enoximone thus causes positive inotropic effects and potentiates the effects of catecholamines acting through both beta 1- and beta 2-AR. These actions are consistent with inhibition of cyclic AMP hydrolysis. The potentiation of the effects of catecholamines by phosphodiesterase inhibition appears unaltered by prior patient therapy with beta 1 blockers.
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PMID:Enoximone potentiates the positive inotropic effects of beta-1- and beta-2-adrenoceptor stimulation in human atrial myocardium. 197 34

The effect of intracellular increases of cyclic adenosine monophosphate (cAMP) on the accumulation of inositol phosphates (IPs) in response to various mitogens in vitro in human peripheral mononuclear leucocytes (MNL) was investigated. The beta-adrenoceptor agonists inhibited mitogen-induced IPs-accumulation by about 30-50% with a rank order of potency isoprenaline greater than adrenaline much greater than noradrenaline. This rank order corresponded with the order of potency of the beta-adrenoceptor agonists to generate cAMP. The beta-adrenoceptor agonist-induced inhibition of IPs-accumulation in response to mitogen could be completely prevented by the beta 2-adrenoceptor selective antagonist ICI 118,551, but not by the beta 1-adrenoceptor selective antagonist CGP 20712A. Furthermore, the isoprenaline-induced inhibition of IPs-accumulation in response to mitogen could be enhanced by the phosphodiesterase inhibitor IBMX. We conclude that cAMP antagonizes mitogen-induced IPs-accumulation in human peripheral MNL in vitro.
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PMID:Cyclic AMP antagonizes mitogen-induced accumulation of inositol phosphates in human peripheral mononuclear leucocytes in vitro. 198 77

The aim of the present investigation was to examine whether or not presynaptic facilitatory beta-adrenoceptors are detectable on the postganglionic nerves in the rabbit isolated ear artery. Strips of rabbit central ear artery were incubated with 3H-noradrenaline (10(-7) mol/l; 30 min or 10(-6) mol/l; 60 min). Subsequently, they were washed repeatedly with physiological salt solution. The strips were subjected to electrical-field stimulation (S1-S8) and the resultant 3H-overflow was determined. When the ear artery was stimulated with 150 pulses (0.5 ms; 3 Hz; 225 mA), isoprenaline (10(-9)-10(-6) mol/l) either alone or in the presence of either rauwolscine (10(-6) mol/l) or phentolamine (10(-6) mol/l) did not alter the stimulation-evoked 3H-overflow. This was also the case in the presence of rauwolscine (10(-6) mol/l) plus either the selective phosphodiesterase inhibitor ICI 63 197 (3 x 10(-5) mol/l) or forskolin (10(-6) mol/l). When the ear artery was stimulated with 300 pulses (1 ms; 5 Hz; 225 mA), isoprenaline had no effect on the stimulation-evoked 3H-overflow. This was also the case when phentolamine (10(-6) mol/l) was present. Propranolol (10(-7)-10(-5) mol/l) did not alter the stimulation-evoked 3H-overflow. In some experiments, the stimulation current was reduced to 175 mA in order to obtain similar reference release (S3) values despite the presence of rauwolscine (150 pulses; 0.5 ms; 3 Hz). Even then, isoprenaline (10(-9)-10(-6) mol/l) did not change stimulation-evoked 3H-overflow. The results suggest that postganglionic sympathetic nerves in rabbit central ear artery do not possess presynaptic facilitatory beta-adrenoceptors.
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PMID:Lack of presynaptic modulation by isoprenaline of 3H-noradrenaline release from rabbit isolated ear artery. 206 90

Homogenization of rat kidney under isotonic conditions and in the presence of protease inhibitors showed that some 92% of the cyclic AMP phosphodiesterase activity and some 83% of the cyclic GMP phosphodiesterase activity was released into the soluble fraction. Analysis of soluble phosphodiesterase activity by FPLC on a Mono-Q column resolved four distinct fractions expressing cyclic nucleotide phosphodiesterase activity. Lineweaver-Burk plots for the hydrolysis of both cyclic GMP and cyclic AMP yielded linear results. The first two peaks (KPDE-MQ-II, KPDE-MQ-III) showed higher activities towards cyclic GMP than cyclic AMP with the ratio of their Vmax values for the hydrolysis of cyclic AMP/cyclic GMP being 0.66 and 0.16, respectively. For the second two peaks (KPDE-MQ-IV, KPDE-MQ-V) the Vmax ratios for the hydrolysis of cyclic AMP/cyclic GMP were 6.4 and 16.7, respectively. All enzymes exhibited similar low Km values for both cyclic AMP and cyclic GMP but had very different Vmax values. KPDE-MQ-II was activated by Ca2+/calmodulin. The cyclic AMP phosphodiesterase activity of KPDE-MQ-III was augmented by the presence of low concentrations of cyclic GMP. Thermal denaturation studies showed that the phosphodiesterase activity of each fraction decayed as a single exponential indicating that each phosphodiesterase fraction contained but a single phosphodiesterase activity. The inhibitors IBMX, zaprinast, milrinone, amrinone, buquineran, carbazeran, ICI 118233, ICI 63197 exerted selective effects on the activities of these enzymes. We compared the action of these compounds on cyclic GMP phosphodiesterases from bovine retina. Over the concentration ranges used, the bovine retinal enzyme was only inhibited by IBMX, zaprinast and carbazeran. The cytosolic isoenzymes of cyclic AMP phosphodiesterases play a much more important role in metabolizing cyclic AMP in kidney compared with liver, where the activity of membrane-bound isoenzymes predominate.
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PMID:Identification and selective inhibition of four distinct soluble forms of cyclic nucleotide phosphodiesterase activity from kidney. 216

Using experimentally derived data for the activities and kinetic constants of hepatocyte cyclic AMP phosphodiesterase isoenzymes together with the derived changes in adenylate cyclase activity, due to stimulation and subsequent desensitization by glucagon, a computer model was established to simulate hepatocyte cyclic AMP metabolism. The established ability of glucagon to activate the 'dense-vesicle' cyclic AMP phosphodiesterase by eliciting its cyclic AMP-dependent phosphorylation was shown on the model to be capable of eliciting a profound reduction in the glucagon-stimulated increase in intracellular cyclic AMP. This was consistent with experimentally derived observations using the compound ICI 118233 which was used to inactivate the 'dense-vesicle' enzyme selectively. The non-hydrolysable adenosine agonist N6 (phenylisopropyl)-adenosine (PIA), which prevents glucagon pre-treatment of hepatocytes blocking the ability of insulin to stimulate the peripheral plasma membrane cyclic AMP phosphodiesterase, is shown here to accentuate the ability of insulin to decrease glucagon-elevated intracellular cyclic AMP concentrations. This effect was obliterated using the compound ICI 63197, a selective inhibitor of the peripheral plasma membrane phosphodiesterase. Computer modelling studies, taking into account experimentally derived actions in insulin in activating the peripheral plasma membrane phosphodiesterase, confirmed the potential of this enzyme to decrease intracellular cyclic AMP concentrations. Modelling of the putative effect of an insulin 'mediator' in activating the two cyclic GMP-stimulated cyclic AMP phosphodiesterase isoenzymes was shown to elicit a decrease in intracellular cyclic AMP concentrations which was comparable to that caused by insulin's action on intact hepatocytes. The relative contribution of each phosphodiesterase form to the metabolism of hepatocyte intracellular cyclic AMP, together with an assessment of the potential effect of inhibition and activation of specific species, was evaluated using the computer model. These experimental and stimulation studies indicate that alterations in the phosphodiesterase activity of the 'dense-vesicle' enzyme, the peripheral plasma membrane enzyme, the cyclic GMP-stimulated cyclic AMP isoforms and the IBMX-insensitive PDE-MQ-II can elicit profound effects upon hepatocyte intracellular cyclic AMP concentrations.
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PMID:The use of selective inhibitors and computer modelling to evaluate the role of specific high affinity cyclic AMP phosphodiesterases in the hormonal regulation of hepatocyte intracellular cyclic AMP concentrations. 217 3

The effects of single and chronic doses of rolipram on the sensitivity of alpha 2-adrenoceptors have been compared with the phosphodiesterase inhibitors, isobutylmethylxanthine (IBMX) and ICI 63,197, and the antidepressant, desipramine. While pretreatment with a single dose of rolipram, ICI 63,197 or IBMX administered either 1 or 24 h prior to clonidine (0.1 mg/kg) enhanced clonidine-induced hypothermia and hypoactivity, chronic dosing (twice daily for 14 days) with desipramine (10 mg/kg) or rolipram (5 mg/kg) antagonized these behavioural effects. In contrast, chronic dosing with IBMX or ICI 63,197 failed to antagonize clonidine-induced hypothermia and hypoactivity. In binding studies neither ICI 63,197, IBMX, rolipram nor desipramine induced changes in the binding of 3H-labelled clonidine to rat cerebral cortical membranes following chronic administration. The failure of ICI 63,107 and IBMX to antagonize clonidine-induced hypothermia and hypoactivity suggests that the antidepressant effect of rolipram is independent of its phosphodiesterase inhibitor property.
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PMID:Effect of long-term rolipram administration on the sensitivity of alpha 2-adrenoceptors in rat brain. 245 98

We examined regulation of histamine release from canine hepatic and fundic mucosal mast cells in short-term culture. We found that beta- but not alpha-adrenergic agonists markedly inhibited concanavalin A (ConA)-stimulated histamine release. Inhibition by epinephrine was reversed by the beta-antagonist propranolol, but not by the alpha-adrenergic antagonists phentolamine or yohimbine. The beta 2-selective antagonist ICI 115881 reversed the effects of epinephrine, whereas the beta 1-antagonists practolol and betaxolol had little effect. Prostaglandin E2 (PGE2), but not its analogue enprostil, inhibited ConA-stimulated histamine release. This difference may relate to the ability of PGE2, but not enprostil, to stimulate adenosine 3',5'-cyclic monophosphate (cAMP) production. Forskolin, cAMP analogues, and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also effectively inhibited ConA-stimulated histamine release. Neither adrenergic agonists nor PGE2 inhibited histamine release stimulated by the combination of phorbol 12-myristate-13-acetate plus the calcium ionophore A23187. These data suggest that inhibition was mediated via cAMP-dependent mechanisms and was exerted on primary cell activation, rather than on postreceptor activating events.
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PMID:Beta-adrenergic and prostanoid inhibition of canine fundic mucosal mast cells. 246 93


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