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)

The activation of human platelets by 5-hydroxytryptamine (5-HT) is not accompanied by detectable release of ATP or TXB2. The process is unaffected by cyclooxygenase, thromboxane synthetase or combined cyclooxygenase/lipoxygenase inhibition (suprofen, indomethacin, R 19091, dazoxiben, N.D.G.A, BW755C, esculetin), indicating the absence of involvement of arachidonic acid metabolites. Transmembrane Ca2+-entry blockers (flunarizine, nifedipine, nimodipine) have no effect either, indicating that the activator calcium released by 5-HT comes from intracellular stores. The 5-HT-induced platelet activation is inhibited by stimulators of adenylate cyclase (PGE1, PGE2, isoprenaline, adenosine) and inhibitors of cAMP phosphodiesterase (papaverine, anagrelide, RA233), indicating that also for this type of platelet activation cAMP behaves as a unidirectional, inhibitory regulator.
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PMID:Biochemical mechanisms in 5-hydroxytryptamine-induced human platelet aggregation. 300 59

The phosphodiesterase inhibitor and putative antidepressant rolipram (0.3-30 mg/kg i.p.) stimulated the accumulation of dopa following inhibition of the aromatic amino acid decarboxylase with 3-hydroxybenzylhydrazine HCl dose-dependently in all brain regions investigated, suggesting that both dopamine and noradrenaline synthesis was enhanced. The stimulatory effect of rolipram on dopa accumulation in dopamine rich regions persisted even after pretreatment with gamma-butyrolactone which by itself increased dopa accumulation three fold. Following inhibition of catecholamine synthesis with alpha-amethyl-p-tyrosine rolipram accelerated the disappearance of noradrenaline and slowed the disappearance of dopamine. At low doses rolipram tended to reduce the pargyline-induced accumulation of 3-methoxytyramine. Rolipram attenuated the accumulation of 5-hydroxytryptophan in the neocortex and the diencephalon of 3-hydroxybenzylhydrazine HCl pretreated rats. The data suggest that rolipram enhances noradrenergic transmission by direct stimulation of tyrosine hydroxylase and by an increase of neuronal activity. Despite a stimulatory effect on tyrosine hydroxylase rolipram does not appear to alter dopamine release and metabolism to a large extent. In view of the occurrence of head-twitches the rolipram-induced reduction of 5-hydroxytryptamine metabolism may be due to feedback inhibition.
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PMID:Effects of rolipram, a novel antidepressant, on monoamine metabolism in rat brain. 403 44

1. Oxyfedrine (0.01-1.0 mug/ml), inhibited spontaneous myogenic activity in rat isolated portal vein and carbachol-induced contractions of rat isolated uterus, and relaxed the rabbit duodenum and the guinea-pig tracheal chain preparation. These actions were prevented by the beta-adrenoceptor blocking drug alprenolol. Oxyfedrine was a relatively weak beta-adrenoceptor stimulant (10-100 times less active than isoprenaline) but its actions were more prolonged.2. In the same concentrations, oxyfedrine reduced or prevented the inhibition of myogenic activity of the rat portal vein induced by isoprenaline and by repeated doses of oxyfedrine itself, acting as a partial agonist at beta-adrenoceptor sites.3. Oxyfedrine, 1-12 mug/ml increased myogenic activity in the rat portal vein. This effect was not due to direct or indirect stimulation of alpha-adrenoceptors (because it was unaffected by phentolamine) or to potentiation of acetylcholine or 5-hydroxytryptamine.4. Oxyfedrine (>20 mug/ml) inhibited spontaneous myogenic activity in the portal vein and relaxed the saphenous vein contracted with noradrenaline. This spasmolytic effect of the drug was not due to beta-adrenoceptor stimulation or to inhibition of phosphodiesterase since it was unaffected by alprenolol and by concentrations of imidazole which antagonized the effects of the active phosphodiesterase inhibitor, papaverine. In the portal vein this effect of oxyfedrine was similar to that of the calcium inhibitor iproveratril; some of the effects of oxyfedrine on venous smooth muscle may be mediated through effects on calcium transport.
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PMID:Effects of oxyfedrine on isolated portal vein and other smooth muscles. 414 43

The effects of papaverine and isoprenaline on smooth muscle cells of the dog basilar artery were investigated using radioimmunoassay, electrophysiological and isometric tension recording methods. For comparative purposes, the actions of these drugs on the guinea-pig basilar artery were also examined. Papaverine and isoprenaline (1 microM and 10 microM) increased the amount of cyclic AMP in both dog and guinea-pig basilar arteries. Papaverine (up to 100 microM) and isoprenaline (up to 1 microM) had no effect on the membrane potential and membrane resistance measured by recording the amplitudes of the electrotonic potentials in smooth muscle cells of the dog and guinea-pig basilar arteries. The action potential evoked by outward current pulses after pretreatment with tetraethylammonium chloride (5-10 mM) was inhibited by papaverine (greater than 1 microM) but not by isoprenaline (up to 10 microM) in smooth muscle cells of the dog and guinea-pig basilar arteries. In the dog basilar artery, papaverine (greater than 1 microM) consistently inhibited the contractions evoked by excess concentrations of [K]o (greater than 20.2 mM) or 5-hydroxytryptamine (10 nM-10 microM), dose-dependently. Isoprenaline (1 microM) had only slight effects on the contraction evoked by low concentrations of 5-hydroxytryptamine (10 nM). In the Ca2+-free solution containing EGTA (2 mM), the contraction evoked by 5-hydroxytryptamine (10 microM) or caffeine (10 mM) was dose-dependently inhibited by papaverine (greater than 1 microM). However, isoprenaline (1 microM) had no effect on these contractions. These results indicate that the vasodilator actions of papaverine on the dog basilar artery are mainly due to inhibition of the voltage-dependent influx of Ca2+ and also to inhibition of the receptor-activated release of Ca2+ stored in the cell. Since isoprenaline increased the cyclic AMP to the same extent as papaverine but had no effect on the electrical and mechanical responses, the inhibitory actions of papaverine on this tissue may not be causally related to the increased levels of cyclic AMP induced by inhibition of phosphodiesterase.
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PMID:Lack of a causal relationship between the vasodilator effect of papaverine and cyclic AMP production in the dog basilar artery. 609 22

Protein I is a neuronal phosphoprotein associated primarily with synaptic vesicles. Regulation of its state of phosphorylation has been investigated in slices of rat facial nucleus. This brainstem motor nucleus has a facilitatory serotonergic input and contains no interneurons. Serotonin (5-hydroxytryptamine, 5-HT, 10(-4) M), in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX, 4 x 10(-5) M), converted approximately 26% of Protein I in these slices from the dephospho-form to the phospho-form. This effect was partially inhibited using two classical 5-HT antagonists, mianserin added to the slices during in vitro incubation and metergoline administered in vivo. The effect of 5-HT appeared to be Ca2+-dependent, unlike that of IBMX (10(-3) M). Adenosine, its analog 2-chloroadenosine, and ATP also increased the phosphorylation of Protein I in facial nucleus slices. 2-Chloroadenosine (5 x 10(-4) M) caused a 29% phosphorylation of Protein I, and this effect was not dependent on extracellular Ca2+. The phosphorylation of Protein I caused both by 2-chloroadenosine and by ATP was inhibited by the adenosine antagonist 2'-deoxyadenosine. Results of additional experiments suggest that the great majority of the Protein I in the facial nucleus is present in presynaptic terminals other than the serotonergic afferents. It is concluded that the stimulation by 5-HT and adenosine of Protein I phosphorylation results largely from a direct action of these compounds on those Protein I-containing terminals.
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PMID:Neurotransmitter- and neuromodulator-dependent alterations in phosphorylation of protein I in slices of rat facial nucleus. 616 92

1 The possibility that cyclic adenosine 3',5'-monophosphate (cyclic AMP) mediates a voltage-dependent inward current elicited by 5-hydroxytryptamine (5-HT) in RB and LB cells of the abdominal ganglion of Aplysia was tested. 2 Intracellular injection of cyclic AMP elicited an inward current with a similar time course, potential dependence and ionic sensitivity as the response to 5-HT. 3 Intracellular injection of guanylyl imidodiphosphate (GMP-PNP), which activated adenylate cyclase, neither mimicked nor enhanced the 5-HT-evoked current. On the contrary, it reduced the current. 4 The phosphodiesterase inhibitors, Ro20-1724, isobutyl methylxanthine (IBMX) and theophylline, each antagonized the voltage-dependent response to 5-HT. To varying degrees they each induced an inward current. 5 The adenylate cyclase antagonist, dithiobisnitrobenzoic acic (DTNB), had no effect on the response to 5-HT when applied either intracellularly or extracellularly. Intracellular injection of the phosphodiesterase activator imidazole also had no effect. 6 Tubocurarine and neostigmine did not reduce the voltage-dependent inward current evoked by 5-HT; methysergide elicited an inward current. 7 Although the observations that cyclic AMP and 5-HT can evoke similar voltage-dependent inward currents in RB and LB neurones of Aplysia might suggest a second messenger role for the cyclic nucleotide, the pharmacological data are inconsistent with this hypothesis.
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PMID:Does cyclic 3' ,5'-adenosine monophosphate act as second messenger in a voltage-dependent response to 5-hydroxytryptamine in Aplysia? 617 22

We studied the action of the following phosphodiesterase inhibitors (PDEIs): rolipram (4-[3-cyclopentoxy-5-methoxyphenyl]-2-pyrrolidione), Ro 20-1724 (4-[3-butoxy-4-methoxybenzyl]-2-imidazolidione), 1-methyl-3-isobutylxanthine (IMBX) and theophylline on flexor reflex activity of the hind limb in the spinal rat. Potentiation of this reflex is thought to be due to enhancement of either 5-hydroxytryptaminergic or alpha-adrenergic transmission in the spinal cord. All the inhibitors potentiated flexor reflex activity in a dose-dependent manner in the following order of potency: rolipram greater than Ro 20-1724 greater than IBMX greater than theophylline. Their stimulatory action in this model paralleled their known potency in inhibiting phosphodiesterase (PDE). Neither the 5-hydroxytryptamine (5-HT) antagonist cyproheptadine nor the alpha-adrenoceptor blocker phenoxybenzamine prevented potentiation of flexor reflex activity by PDEIs. It is suggested that (1) the PDEIs potentiate flexor reflex activity through a novel spinal mechanism which does not involve alpha-adrenoceptors of 5-HT receptors in the spinal cord but rather is related to the inhibition of PDE localized postsynaptically; (2) flexor reflex activity in the spinal rat can be a useful experimental preparation to estimate the in vivo effects of known PDEIs.
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PMID:The stimulatory action of phosphodiesterase inhibitors on the flexor reflex of the hind limb in the spinal rat. 618 70

One model of synaptic transmission suggests that transmitters modify postsynaptic permeability through the intermediary of cyclic AMP. Thus, serotonin (5-hydroxytryptamine) evokes in molluscan neurones a decrease in a voltage-dependent K+ conductance which in turn generates a slow inward current when studied in steady voltage-clamp conditions. The serotonin-induced increase of the plateau phase of the spike of an Aplysia sensory neurone can be mimicked by both intracellularly injected cyclic AMP and extracellularly applied phosphodiesterase inhibitors, suggesting that cyclic AMP mediates the effect. We have tested whether a similar mechanism could account for the serotonin slow inward current in identified snail neurones and have found that the intracellular injection of cyclic AMP, but not of cyclic GMP or 5'-AMP, evokes a slow inward current showing similar voltage dependence, inversion potential and ionic properties to the serotonin slow inward current. Phosphodiesterase inhibitors at low concentrations (1-20 microM) potentiate the serotonin slow inward current and at higher concentrations evoke by themselves an inward current, partially or totally occluding the serotonin and cyclic AMP currents. Finally, we have found that in homogenates of pooled identified snail neurones serotonin stimulates the adenylate cyclase, increasing its activity by 50-100%.
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PMID:Role of cyclic AMP in a serotonin-evoked slow inward current in snail neurones. 626 Nov 54

Salivary glands from adult blowflies (Calliphora erythrocephala Meigen) were studied in vitro. The time course of changes in cyclic AMP content of the glands was followed at different concentration of 5-hydroxytryptamine. There was an immediate biphasic rise and fall in cyclic AMP content, following by a slower rise and subsequent gradual decline. The initial rise preceded the onset of fluid secretion by the glands. Rises in cyclic AMP content were inhibited by compound RMI 12330 A (an adenylate cyclase inhibitor) and were halted after about 15-20s if the glands were deprived of Ca2+. Theophylline (a phosphodiesterase inhibitor) abolished the decline phase of the fast response, Losses of cyclic AMP from the glands either to the bathing medium or to the saliva were small and could not account for the rapid fall found. Evidence is presented that cyclic GMP is not involved in the process of initiating secretion in the blowfly salivary gland.
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PMID:Changes in cyclic AMP and cyclic GMP concentrations during the action of 5-hydroxytryptamine on an insect salivary gland. 627 97

Serotonin (5-hydroxytryptamine, 5-HT) shifts the phase of the circadian rhythm in the eye of Aplysia. We have examined the role of cAMP in mediating the effects of 5-HT on the rhythm. The phase shifts produced by 5-HT are mimicked by treatments that should increase intracellular levels of cAMP. An analogue of cAMP-8-benzylthio-cAMP, advanced and delayed the rhythm at phases in which 5-HT had similar effects on the rhythm. In addition, two phosphodiesterase inhibitors, Ro-20-1724 and papaverine, caused advance phase shifts where 5-HT advances the rhythm. The phosphodiesterase inhibitors Ro-20-1724 and 3-isobutyl-1-methylxanthine each potentiated the effect of subthreshold doses of 5-HT on the rhythm. The effects of 5-HT and 8-benzylthio-cAMP on the rhythm were nonadditive, indicating that 5-HT and 8-benzylthio-cAMP affect the rhythm through a common pathway. Finally, 5-HT produced large changes (13-fold) in the levels of cAMP in the eye. These results indicate that cAMP mediates the effect of 5-HT on the rhythm. There are two possible roles for cAMP in the circadian system. Either the cAMP system is an intracellular step in an entrainment pathway or it is part of the biological clock. Because 5-HT, 8-benzylthio-cAMP, and three phosphodiesterase inhibitors inhibit impulses from the eye, cAMP may also mediate the inhibition produced by 5-HT, or it might be involved in regulating the frequency of spontaneous impulses throughout the day.
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PMID:Mechanism for shifting the phase of a circadian rhythm by serotonin: involvement of cAMP. 628 77


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