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)

Rolipram is a clinically effective antidepressant with selective cAMP phosphodiesterase (PDE) inhibiting properties. (+/-)-[3H]Rolipram binds with high affinity (Kd = 2.52 +/- 0.47 nM) to sections of rat brain (Hill number = 0.90 +/- 0.05). Binding is stereospecific. Association of (+/-) [3H]rolipram to sections is rapid (47% of specific binding in the first minute, kobs = 0.52 min-1). Dissociation of (+/-)-[3H]rolipram exhibits non first order kinetics (3 component model; t1/2 = 2.5 min, 50 min and 6 h, respectively). A number of PDE inhibitors reduce (+/-)-[3H]rolipram binding to the level of nonspecific binding ((-)-rolipram, IC50 = 0.9 nM; (+/-)-rolipram, IC50 = 1.5 nM; Ro 20-1724, IC50 = 11 nM; ICI 63.197, IC50 = 35 nM; medazepam, IC50 = 240 nM; diazepam, IC50 = 1200 nM; IBMX, IC50 = 3800 nM). In vitro autoradiography reveals high binding site densities in the cerebellum, olfactory bulb, lateral septal nucleus, frontal cortex, subiculum and CA1 of hippocampus. Most of the labeled structures are part of the limbic system. In vivo autoradiography of (+/-)-[3H]rolipram binding shows much more nonspecific binding than in vitro, nevertheless the distribution pattern of (+/-)-[3H]rolipram binding sites is similar. A comparison of the distribution pattern of (+/-)-[3H]rolipram binding sites with that of an antidepressant (monoamine oxidase inhibitor, monoamine uptake inhibitor) reveals no overlap. Limited, though significant correlations exist with the distribution of beta 1-adrenergic, adenosine1 and glutamate/quisqualate receptors as well as protein kinase C, but not with beta 2-adrenergic receptors and forskolin binding sites.
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PMID:Autoradiographic mapping of a selective cyclic adenosine monophosphate phosphodiesterase in rat brain with the antidepressant [3H]rolipram. 255 65

The aim of the present work was to demonstrate the presence of presynaptic beta-adrenoceptors in the rabbit isolated pulmonary artery by investigating the effect of isoprenaline on 3H-noradrenaline (3H-NA) release evoked by electrical field stimulation. (-)-Isoprenaline (10(-7)-10(-6) mol/l) had no effect on the 3H-overflow evoked by stimulation (3 Hz) of the pulmonary artery preloaded with 3H-NA. At 10(-5) mol/l, (-)-isoprenaline reduced the 3H-overflow by maximally 39%. (-)-Isoprenaline (10(-5) mol/l) caused an inhibition that remained almost constant with time. The same results were obtained with (-)-isoprenaline (10(-7)-3 X 10(-5) mol/l) in the presence of cocaine (3 X 10(-5) mol/l), corticosterone (4 X 10(-5) mol/l), and the catechol-O-methyltransferase inhibitor U-0521 (3',4'-dihydroxy-2-methylpropiophenone) (10(-4) mol/l). In the presence of cocaine plus corticosterone, (-)-isoprenaline (3 X 10(-10)-10(-7) mol/l) had no effect on the 3H-overflow evoked by stimulation at 1 Hz. At 10(-6) mol/l, (-)-isoprenaline slightly reduced the 3H-overflow. At 10 Hz, (-)-isoprenaline (10(-6)-3 X 10(-5) mol/l) decreased the 3H-overflow and had no effect at 10(-7) mol/l. In the presence of either rauwolscine (10(-6) mol/l), phentolamine (10(-6) mol/l) or the phosphodiesterase inhibitor ICI 63,197 (3 X 10(-5) mol/l), (-)-isoprenaline (10(-7)-10(-6) mol/l) did not enhance the stimulation-evoked 3H-overflow. (+/-)-Propranolol (10(-7)-10(-5) mol/l) did not alter the stimulation-evoked 3H-overflow.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of isoprenaline on noradrenaline release from sympathetic neurones in rabbit isolated pulmonary artery. 282 40

The effect of glucagon was studied on the isolated gastric fundus from immature rats in comparison with histamine. Glucagon (10(-7) -3 X 10(-6) M) caused a concentration-dependent increase in acid output, being approximately 25 fold more potent than histamine (ED50 values were 6.38 X 10(-7) M and 2.42 X 10(-5) M for glucagon and histamine, respectively). These compounds, however, did not differ in regard to the maximum response. The stimulatory effect of glucagon was not enhanced by pretreatment with 3 X 10(-8) M forskolin or 10(-7) M ICI 63197, a phosphodiesterase (PD) inhibitor. Conversely, both forskolin and ICI 63197 shifted to the left the concentration-response curve to histamine. The increase in acid secretion by glucagon was reduced by PGE1 (10(-5) M) and PGE2 (10(-5) M) but only PGE2 inhibited the response to histamine. From these data it can be concluded that glucagon stimulated acid production in the stomach from immature rats, and this effect does not seem to involve the same adenylate cyclase activated by histamine.
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PMID:Effect of glucagon on gastric acid secretion by the isolated fundus from immature rats. 283 65

The relationship of hepatic ornithine decarboxylase (ODC) activity to cyclic AMP levels and nutritional status was studied in the pre-weanling rat. Previous studies demonstrated that 2 hr without food causes a loss of hepatic ODC induction after glucagon or catecholamine injection. Isoproterenol or glucagon administration produced increased hepatic cyclic AMP and tyrosine aminotransferase activity which were not prevented by nutritional deprivation. Blockade of hepatic beta 2 receptors by the selective antagonist ICI 118,551 prevented increased cAMP levels and ODC activity after isoproterenol administration. Blockade of beta 1 receptors by atenolol did not prevent increased cAMP levels or ODC induction by isoproterenol although it did block activation of cardiac ODC. The phosphodiesterase inhibitor RO20-1724 increased hepatic cAMP levels as well as ODC and TAT activities, although the increase in ODC activity was attenuated by nutritional deprivation. RO20-1724 also potentiated the induction of hepatic ODC after glucagon or isoproterenol administration. Administration of 8-bromo cAMP elevated hepatic ODC activity regardless of nutritional status but also elevated serum levels of growth hormone and corticosterone. Hepatic ODC induction by glucagon or beta 2 agonists can be dissociated from changes in cAMP levels during nutritional deprivation.
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PMID:Hepatic cyclic AMP generation and ornithine decarboxylase induction by glucagon and beta adrenergic agonists. 286 May 51

In rabbit isolated pulmonary artery previously incubated with [3H]-noradrenaline, isoprenaline (0.3 microM) had no effect on the stimulation-induced outflow of radioactivity. However, if the phosphodiesterase inhibitor ICI 63,197 (30 microM) or the alpha-adrenoceptor blocker phentolamine (1 microM) was present, then isoprenaline significantly enhanced the stimulation-induced outflow, an effect blocked by propranolol (0.1 microM). ICI 63,197 (30 microM) but not phentolamine significantly enhanced the stimulation-induced outflow of radioactivity. In mouse isolated atria previously incubated with [3H]-noradrenaline and stimulated at a frequency of 10 Hz, isoprenaline had no effect on the stimulation-induced outflow of radioactivity; this is in contrast to its release-enhancing effects at stimulation frequencies of 4 Hz and 2 Hz. The facilitation of stimulation-induced outflow by isoprenaline at 4 Hz was blocked by propranolol (0.08 microM) which, by itself, had no effect on the stimulation-induced outflow. At a stimulation frequency of 2 Hz in mouse atria the facilitatory effect of isoprenaline (0.01 microM) was significantly greater in the presence of ICI 63,197 (30 microM) which, by itself, had no effect on the stimulation-induced outflow. Similarly, the facilitatory effect of isoprenaline was significantly greater in the presence of phentolamine (1 microM) but, in this case, phentolamine significantly enhanced the stimulation-induced outflow. These results suggest that facilitatory prejunctional beta-adrenoceptors are present in both rabbit pulmonary artery and mouse atria. The effects of the phosphodiesterase inhibitor ICI 63,197 suggest that they are linked to adenylate cyclase in both tissues and we propose that the ability of phentolamine to facilitate the release and enhance the effect of isoprenaline may be due to the blockade of alpha-adrenoceptor inhibition of adenylate cyclase. This latter proposition needs further investigation.
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PMID:Prejunctional beta-adrenoceptors in rabbit pulmonary artery and mouse atria: effect of alpha-adrenoceptor blockade and phosphodiesterase inhibition. 287 84

The time course of the effects of isoprenaline (3 X 10(-7) mol/l) on contractile force and on the cyclic AMP level was studied in the electrically driven isolated muscle strip of the human right atrium. Isoprenaline produced a rise in cyclic AMP content (maximum increase after 60 s) preceding the increase in contractile force. The effects of isoprenaline on contractile force and on the intracellular level of cyclic AMP were enhanced in the presence of the phosphodiesterase inhibitor papaverine (10(-5) mol/l). On the other hand, the beta-adrenoceptor antagonist propranolol (10(-7) mol/l) suppressed isoprenaline-induced cyclic AMP increases, but reduced the increase in force of contraction by only 35%. In addition, both the beta 1-selective antagonist bisoprolol (3 X 10(-9)-3 X 10(-8) mol/l) and the beta 2-selective antagonist ICI 118,551 (3 X 10(-9)-3 X 10(-8) mol/l) inhibited the isoprenaline-induced cyclic AMP increase concentration-dependently; ICI 118,551 produced more pronounced inhibition than bisoprolol. It is concluded that cyclic AMP is involved in the positive inotropic action of isoprenaline evoked by beta 1- and beta 2-adrenoceptor stimulation in isolated human right atrium; however, an additional cyclic AMP independent mechanism cannot be ruled out.
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PMID:The role of cyclic AMP in the positive inotropic effect mediated by beta 1- and beta 2-adrenoceptors in isolated human right atrium. 288 23

The antidepressant potential of rolipram and inhibitors of phosphodiesterase (PDE) which are selective for cyclic AMP has previously been ascribed to enhancement of central noradrenergic transmission by the combination of two mechanisms of action: increase of synthesis of noradrenaline and release (presynaptic component) and concomitant potentiation of noradrenaline signals due to inhibition of phosphodiesterase (postsynaptic component). To examine the contribution of the latter component to the antidepressant action, rolipram, ICI 63 197 or Ro 20-1724 were given to mice which were depleted of monoamines in the brain by combined pretreatment with reserpine, alpha-methyl-p-tyrosine and p-chlorophenylalanine. Rolipram, ICI 63 197 and Ro 20-1724 dose-dependently reversed the hypothermia and hypokinesia induced by this pretreatment. Imipramine and pargyline were inactive in this respect, indicating that their antidepressant effect depends on the availability of endogenous monoamines. The antihypothermic and antihypokinetic action of rolipram was not prevented by blockade of central beta-adrenergic or dopaminergic receptors. It is concluded that an action of rolipram, beyond postsynaptic receptors, essentially contributes to its antidepressant effect. The postsynaptic adenylate cyclase/cyclic AMP phosphodiesterase system is thought to be the most likely target. The unique properties of rolipram to stimulate both presynaptic and postsynaptic components of central neurotransmission should enable more efficient transduction of postsynaptic signals by circumventing presynaptic inhibitory feedback mechanisms, responsible for the delay in the therapeutic action of conventional antidepressant drugs.
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PMID:Rolipram, a novel antidepressant drug, reverses the hypothermia and hypokinesia of monoamine-depleted mice by an action beyond postsynaptic monoamine receptors. 294 76

The characteristics for the binding of the selective cAMP phosphodiesterase inhibitor and antidepressant agent rolipram to brain and peripheral organs were investigated. (+/-)-[3H]Rolipram equilibrium binding and Scatchard analysis revealed saturable, reversible, stereospecific, Mg2+-dependent and heat-sensitive binding with an apparent Hill number of 1. Binding was detected both to membrane-bound and soluble sites, with dissociation constants Kd of 1.2 and 2.4 nM, respectively, and binding site concentrations (Bmax) of 19.3 and 23.6 pmol/g rat forebrain. The (-)-enantiomer of rolipram was ca. 20 times more effective than the (+)-enantiomer in displacing (+/-)-[3H]rolipram from membranes. Rolipram bound to brain tissue of all mammalian species tested including man, while tissue from bird and fish showed less binding. Organs other than brain exhibited only negligible binding. Only specific cAMP phosphodiesterase inhibitors (ICI 63.197, Ro 20-1724) were potent competitors, while rolipram itself was inactive in a variety of receptor binding assays of neuroactive ligands. The kinetics of (-)-[3H]rolipram binding to the particulate fraction revealed a complex association and dissociation behaviour. The nature of the rolipram binding protein(s) is not clear, but the low affinity binding site evident from binding kinetics may represent a rolipram-sensitive phosphodiesterase isoenzyme also common to some peripheral organs, while the high affinity binding site(s) may be related to PDE isoenzymes more confined to the central nervous system.
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PMID:Stereospecific binding of the antidepressant rolipram to brain protein structures. 301 21

The effects of systemically administered forskolin, a direct activator of the catalytic subunit of adenylate cyclase, on locomotor activity, rectal temperature and the incidence of grooming and head twitches were studied in rats. Forskolin, 0.1-25 mg/kg, decreased locomotor activity and lowered rectal temperature. The incidence of grooming and head twitches increased dose-dependently after forskolin, 6.25 25 mg/kg. The combination of a threshold dose of forskolin with a threshold dose of the cAMP-selective phosphodiesterase (PDE) inhibitor rolipram resulted in a marked, statistically significant enhancement of the behavioral, hypothermic and brain cAMP elevating effect. The present findings support the assumption that enhanced brain cAMP availability is associated with a characteristic behavioral syndrome in rats as was previously shown with dibutyryl cAMP or neurotropic cAMP-selective PDE inhibitors like rolipram. Ro 20-1724 or ICI 63 147.
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PMID:Effects of forskolin on spontaneous behavior, rectal temperature and brain cAMP levels of rats: interaction with rolipram. 303 38

1 In mouse isolated atria previously incubated with [3H]-noradrenaline, 8-bromo-cyclic AMP (3-270 microM) produced a concentration-dependent increase in the fractional stimulation-induced outflow of radioactivity. 8-Bromo-cyclic GMP induced a lesser increase in the stimulation-induced outflow. 2 The phosphodiesterase inhibitors: M&B 22948 (90 microM); ICI 63197 (30 and 90 microM) and 3-isobutyl-1-methylxanthine (90 microM) increased the fractional stimulation-induced outflow. Together these results indicate that cyclic AMP may have a modulatory effect on noradrenaline release. 3 The inhibition of the stimulation-induced outflow produced by clonidine (0.03 microM) and its facilitation produced by phentolamine (1 microM) were unaltered in the presence of 8-bromo-cyclic AMP (90 microM). However, in the presence of 8-bromo-cyclic AMP (270 microM), the facilitatory effect of phentolamine was enhanced, but the inhibitory effect of clonidine (0.03 microM) was unaltered. In the presence of ICI 63197 (30 microM) the inhibitory effect of clonidine (0.03 microM) was unaltered, but the facilitatory effect of phentolamine (1 microM) was slightly enhanced. 4 Isoprenaline (0.003-0.1 microM) enhanced the fractional stimulation-induced outflow, an effect blocked by propranolol (0.1 microM). In the presence of 8-bromo-cyclic AMP (90 microM), the facilitatory effect of isoprenaline (0.01 microM) was blocked. In the presence of ICI 63197 (30 microM) the facilitatory effect of isoprenaline (0.003 microM) was potentiated. 5 These results suggest that whereas beta-adrenoceptor-mediated enhancement of noradrenaline release is linked to the stimulation of adenylate cyclase and enhanced formation of cyclic AMP, alpha-adrenoceptor-mediated inhibition of noradrenaline release is not linked to inhibition of adenylate cyclase activity.
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PMID:Involvement of cyclic nucleotides in prejunctional modulation of noradrenaline release in mouse atria. 366 78


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