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)

ADP-induced platelet aggregation and shape change were monitored optically in citrated rabbit platelet-rich plasma (PRP) diluted with isotonic salt solutions. Lithium (Li) produced a concentration-dependent reduction in the rate of platelet aggregation but had no discernible effect on the shape change which precedes aggregation. When PRP was pre-incubated with Li, the inhibitory effect of the ion was independent of the duration and temperature of the treatment. The inhibitory effect of Li also was observed in heparinized PRP or when 5-HT was used as the aggregation-inducing agent. When Li was combined with aggregation inhibitors which enhance platelet cyclic AMP content either by activating adenylate cyclase or by inhibiting phosphodiesterase, only additive effects were observed. The inhibitory effect of Li was opposed by added calcium. Kinetic evaluation of the interaction between Li and Ca indicated that their antagonism was competitive. Added calcium also displayed competitive antagonism toward the aggregation inhibiting effect of increased hydrogen ion concentration in the pH range between 6 and 8.
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PMID:Competitive inhibition by lithium and hydrogen ions of the effect of calcium on the aggregation of rabbit platelets. 1 92

Serotonin (5-hydroxytryptamine) is known to influence glomerular function and may have an important role in the pathogenesis of glomerulopathies. Because serotonin acts in nonrenal tissues through mediation of cyclic nucleotides, we investigated in vitro its effect on cAMP and cyclic guanosine monophasphate (cGMP) in tissue slices and isolated glomeruli from rat kidney. Serotonin increased cAMP 161 +/- 35% but not cGMP in renal cortex; it had no effect on cyclic nucleotides in medulla and papilla. In isolated glomeruli, serotonin elicited a dose-dependent (in the range of 10-7 to 10-4 M) increase in cAMP; the maximum increase over basal values was 376 +/- 45%. Serotonin increased cAMP either in the presence or in the absence of a cAMP phosphodiesterase inhibitor. In tubular fraction, serotonin elevated cAMP to a much lesser degree (82 +/- 15%). Neither in glomeruli nor in tubules did cGMP concentrations change in response to serotonin, but carbamylcholine, a known cGMP agonist, significantly increased cGMP concentrations. The increase in cAMP in response to serotonin was blocked (greater than 85% inhibition) by equimolar concentrations of serotonin antagonists methysergide and cinanserine. Results of this study demonstrate that interaction of serotonin with receptors in the kidney, particularly in the glomeruli, cause a striking increase in cAMP concentrations without detectable changes in cGMP concentrations. These findings suggest that serotonin, either synthesized in the kidney or released locally from platelets aggregated in glomeruli (for example, in association with immunopathologic injury) may exert of modulate its physiologic or pathologic effects via mediation of cAMP.
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PMID:Action of serotonin (5-hydroxytryptamine) on cyclic nucleotides in glomeruli of rat renal cortex. 22 97

The efflux of radioactivity after loading with trace amounts of tritiated 5-hydroxytryptamine ([3H]5-HT) or 5-hydroxytryptophan ([3H]5-HTP) was studied in perifused beta-cell-rich pancreatic islets from ob/ob mice. Analysis of the effluent revealed that more than 90% of the radioactivity was released as [3H]5-HT after loading with [3H]5-HTP. Increasing the concentration of glucose in the perifusion medium from 3 to 20 mmol/l enhanced the efflux when islets from fed mice were used and this effect was potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). Whereas 20 mM-glucose alone did not stimulate the efflux of 5-HT from islets isolated from mice starved for 3 days, a stimulatory effect was observed in the presence of IBMX. Stimulation of the efflux of radioactivity by glucose was inhibited if calcium was omitted from or adrenaline added to the medium. The results are consistent with the concept of exocytotic release of 5-HT occurring in response to stimulation of insulin secretion, although basal non-exocytotic transport must also be occurring across the beta-cell membrane.
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PMID:Association between 5-hydroxytryptamine release and insulin secretion. 35 42

The actions of a new type of ergolene derivative, MPME ((5R, 8R)-8-(4-p-methoxyphenyl-1-piperazinyl methyl)-6-methylergolene), have been evaluated on central catecholamine (CA) neurons in the rat by means of a combined biochemical, histochemical and behavioural analysis. The evidence suggests that this ergolene derivative is a preferential agonist at subcortical limbic dopamine (DA) receptors and at DA receptors belonging to the neostriatal DA islands. (1) MPME does not change the DA and noradrenaline (NA) levels 4 h after the injection in doses ranging from 0.1 to 5 mg/kg. MPME significantly reduced DA turnover in doses from 0.5 to 5 mg/kg, whereas the NA turnover was increased in the same dose range. (2) Histochemically, using quantitative microfluorometry, DA levels were unchanged, except in the islands of the nucleus caudatus following administration of MPME. The drug selectively reduced DA turnover in the subcortical limbic regions (tuberculum olfactorium and nucleus accumbens) and in the DA terminal islands of the nucleus caudatus in doses of 1-5 mg/kg, whereas the large diffuse DA terminal systems of the nucleus caudatus were unaffected. Using this ergolene derivative the islandic small neostriatal DA system can be excellently demonstrated also in the adult rat. The effects of MPME on DA turnover, are blocked by haloperiodol but not by methergoline (which blocks 5-HT receptors). (3) Studies on uptake of tritiated DA in the nucleus caudatus and tuberculum olfactorium reveal a weak inhibition of DA uptake and retention only in high concentrations (10(-5)-10(-6) M). Such actions therefore can probably not explain the changes in DA turnover observed. (4) Behavioural effects of MPME were evaluated in the rotometer model of Ungerstedt25. This model will reveal actions on supersensitive striatal DA receptors. MPME was found to mimic the action of apomorphine and cause a prolonged rotational behaviour towards the nonoperated side in doses of 0.25-0.5 mg/kg. A marked potentiation of the action of MPME was obtained by means of pretreatment with phosphodiesterase inhibitors suggesting that the effect of MPME might be mediated by cyclic AMP. Studies with the DA receptor blocking agent pimozide indicated a high affinity of MPME for the supersensitive striatal DA receptors, since only very high doses of pimozide (15 mg/kg) were capable of blocking the actions of MPME. (5) Studies on the effect of MPME on DA sensitive adenylate cyclase in the nucleus caudatus and the subcortical limbic system (mainly tuberculum olfactorium and nucleus accumbens) suggested that MPME is a partial DA receptor agonist with different intrinsic activity on the DA receptors of the subcortical limbic system and of the nucleus caudatus, the effects in the subcortical limbic system being considerably larger than in the nucleus caudatus. Thus, the present paper gives evidence that the various DA receptor populations in the brain are sufficiently different to allow their preferential activation by drugs.
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PMID:Dopamine receptors and ergot drugs. Evidence that an ergolene derivative is a differential agonist at subcortical limbic dopamine receptors. 64 92

In this study we have evaluated the second messenger system that might couple 5-HT1A receptor activation to produce peripheral hyperalgesia. The intradermal injection of the serotonin (5-hydroxytryptamine; 5-HT) receptor agonist for the 1A receptor subset (5-HT1A), (+/-)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthaline hydrobromide (8-OH DPAT) produces a dose-dependent hyperalgesia which was attenuated by a cAMP kinase inhibitor (the R-isomer of cyclic adenosine-3'-5'-monophosphate), but prolonged by the inhibition of endogenous phosphodiesterase by rolipram, supporting a role for the cAMP second messenger system. The 5-HT1A receptor agonist, 8-OH-DPAT, and the adenyl cyclase activator, forskolin administered together, produced an additive hyperalgesia, suggesting that the 5-HT1A receptor in peripheral terminals of the primary afferent neurons is positively coupled to the cAMP second messenger system in producing hyperalgesia. The inability of pertussis toxin to inhibit 8-OH DPAT-induced hyperalgesia further supports this hypothesis. The coupling of the 5-HT1A receptor to the cAMP second messenger system appears to be through guanine regulatory proteins since guanosine 5'-O-(3-thiotriphosphate) and cholera toxin both markedly enhanced 8-OH DPAT hyperalgesia. In further support of the role of guanine nucleotide regulatory proteins, guanosine 5'-O-(2-thiodiphosphate), as well as activators of inhibitory guanine regulatory proteins (the mu-opioid agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, and the adenosine A1 agonist, N6-cyclopentyladenosine, significantly attenuated 8-OH DPAT hyperalgesia.
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PMID:Mediation of serotonin hyperalgesia by the cAMP second messenger system. 131 16

The electrically excitable salivary cells of the giant Amazon leech, Haementeria, display a time-dependent inward rectification. Under voltage clamp, hyperpolarizing steps to membrane potentials negative to about -70 mV were associated with the activation of a slow inward current (Ih) which showed no inactivation with time. The time course of activation of Ih was described by a single-exponential function and was strongly voltage dependent. The activation curve of Ih ranged from -72 to -118 mV, with half-activation occurring at -100 mV. Ion-substitution experiments indicated that Ih is carried by both Na+ and K+ ions. 5-Hydroxytryptamine (5-HT) increased the amplitude of Ih and its rate of activation. It also produced a positive shift of the activation curve of the conductance underlying Ih (Gh) without altering the slope factor, thus indicating that the voltage dependence of Ih was modulated by 5-HT. Cs+ blocked both Ih and the 5-HT-potentiated current in a voltage-independent manner, whereas Ba2+ had little effect. It is concluded that 5-HT increases Ih by modulating the inwardly rectifying Na(+)-K+ channels in the salivary cells. The effect of 5-HT may be mediated by an increase in adenylate cyclase activity since Ih was increased by 8-bromo-cyclic AMP and by the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine. In contrast, Ih was reduced by 8-bromo-cyclic GMP and by zaprinast (an inhibitor of cyclic GMP-sensitive phosphodiesterase). Cyclic GMP itself also reduced Ih, and the effect was specific to the 3',5' form; 2',3'-cyclic GMP was inactive. The results suggest that the inward-rectifier channel may be modulated in opposite directions by cyclic AMP and cyclic GMP.
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PMID:Modulation of inwardly rectifying Na(+)-K+ channels by serotonin and cyclic nucleotides in salivary gland cells of the leech, Haementeria. 132 43

To study the contribution of cAMP to the spike broadening produced by serotonin (5-HT) in the pleural sensory neurons of the tail withdrawal reflex, we utilized two phosphodiesterase-resistant cAMP analogs: the Sp diastereomer of cyclic adenosine 3',5'-monophosphothioate (Sp-cAMP[S]), which activates protein kinase A, and the antagonist Rp diastereomer of cyclic adenosine 3',5'-monophosphothioate (Rp-cAMP[S]), agonist Sp-cAMP[S] was injected into the sensory neurons, it caused spike broadening comparable to that induced by 5-HT. In turn, the cAMP antagonist Rp-cAMP[S] blocked approximately 50% of the 5-HT-induced spike broadening. We next examined the K+ currents that are modulated by 5-HT and determined how these currents are affected by cAMP. Confirming Baxter and Byrne [(1989) J. Neurophysiol. 62, 665-679], we found that 5-HT modulated two currents, an S-type K+ current (IKS) as well as a transient and voltage-dependent K+ current (IKV). Rp-cAMP[S] blocked the reduction by 5-HT of the early phase of IKV in parallel with, and to the same degree (60%), as this inhibitor blocked the IKS and spike broadening. These results support the idea that in the pleural sensory neurons cAMP mediates a significant part of the spike broadening that accompanies short-term facilitation produced by 5-HT and that cAMP can produce spike broadening by modulating both IKV and IKS.
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PMID:Modulation of a transient K+ current in the pleural sensory neurons of Aplysia by serotonin and cAMP: implications for spike broadening. 133 11

Early passaged bovine pulmonary artery smooth muscle cells (SMC) respond to serotonin (5-HT) by developing a reversible change in configuration. (Lee et al. J. Cell. Physiol. 138:145, 1989). This configurational change does not occur in pulmonary artery endothelial cells (EC) subjected to 5-HT and is adenosine triphosphate (ATP) dependent, lost with passage of SMC, and inhibited by various agents that block high-affinity 5-HT uptake. We now report a second configurational change (also dendritic formation) of SMC produced by 5-HT only in the presence of isobutylmethylxanthine (IBMX), an inhibitor of phosphodiesterase. This configurational change was also ATP dependent, but unlike the first response, (Lee et al., 1989), it occurred in both first and later passaged SMC and was not inhibited by blockade of 5-HT uptake. Also, unlike the response with 5-HT alone that failed to elevate cAMP, this one was associated with a large elevation of cAMP (eight fold above control values), similar to the response to the beta-agonist isoproterenol, plus IBMX. The second response was not blocked by a variety of 5-HT receptor antagonists but was reproduced by (+/-)-8-hydroxy-DPAT HBr (8-OH-DPAT), a reputed 5-HT1A agonist. The response was not dependent upon Ca2+ and was blocked by 1-2 mM n-phenylanthranilic acid or anthracene-9-carboxylic acid, electrically conductive Cl- channel inhibitors. Hence, 5-HT in the presence of IBMX causes a marked elevation of cAMP of SMC and this elevation in cAMP likely results in a cellular configurational change through a Cl- channel-dependent mechanism similar to that we previously described for EC in the presence of beta-adrenergic agonist stimulation (Ueda et al. Circ. Res. 66:951, 1990). EC do not show a similar response to 5-HT possibly because cAMP is not adequately elevated, even in the presence of IBMX, to enhance Cl- channel activity. We propose that our observations indicate the presence of two sites of action of 5-HT on the smooth muscle cell, one intracellularly and another at a cell surface receptor.
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PMID:Serotonin produces a configurational change of cultured smooth muscle cells that is associated with elevation of intracellular cAMP. 137 Aug 41

Beta adrenergic antagonists have been demonstrated to show stereoselective affinity for serotonin (5-HT) receptors in the central nervous system, and competitively inhibit 5-HT transport of platelets, but have not previously been evaluated for their influence on either 5-HT receptors or 5-HT transport systems of vascular cells. We have reported stimulation of 5-HT uptake by subjection of endothelial (EC) and smooth muscle cells (SMC) to anoxia. We now report that (+/-)-propranolol inhibits 5-HT uptake by both room air- and anoxia-exposed EC and SMC in culture. The effect on SMC was more marked than that on EC and showed a similar inhibition as ketanserin. The relative inhibitory potencies of beta adrenergic antagonists and ketanserin on uptake of 5-HT by SMC were as follows: (+/-)-propranolol = ketanserin greater than alprenolol = pindolol greater than oxprenolol = atenolol. The beta adrenergic receptor agonist, isoproterenol, in the presence of isobutylmethylxanthine, an inhibitor of phosphodiesterase, produced a high elevation of cyclic AMP in SMC along with a cellular configurational change and partially inhibited uptake of 5-HT. Propranolol inhibited 5-HT uptake both in the presence and absence of isoproterenol plus isobutylmethylxanthine, suggesting that its inhibitory effect was not mediated through its interaction at the beta adrenergic receptor. Kinetic analyses of the effect of propranolol on 5-HT uptake indicated that propranolol reduced 5-HT uptake by noncompetitive inhibition. We conclude that beta adrenergic antagonists block vascular cell uptake of 5-HT through an action other than interaction with the beta adrenergic receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Beta adrenergic antagonists inhibit serotonin uptake by pulmonary vascular cells in culture. 167 37

Synapses between the sensory and motor cells of Aplysia can be enhanced by heterosynaptic or homosynaptic stimulation. We have used the isolated sensorimotor synapse of Aplysia in cell culture to explore short- and long-term heterosynaptic facilitation produced by 2 facilitatory transmitters and compared these to homosynaptic facilitation produced by posttetanic potentiation. We found that brief application of 5-HT or small cardioactive peptide (SCP) evokes comparable short-lasting enhancement of nondepressed sensorimotor synapses. The effect evoked by SCP diverges from that of 5-HT when the sensorimotor synapse is first depressed by low-frequency homosynaptic stimulation. Whereas 5-HT facilitates sensorimotor synapses whether or not they are depressed, SCP has little or no effect on synapses that have been depressed by more than 75%. The 2 transmitters also differ in producing long-term facilitation. Whereas repeated applications of 5-HT evoke long-term facilitation of the synapses, SCP applications do not. To determine whether these failures to facilitate could be overcome by increasing levels of cAMP, we applied SCP in the presence of phosphodiesterase inhibitors, which resulted in SCP evoking both short- and long-term changes comparable to that of 5-HT. Homosynaptic facilitation by post-tetanic potentiation differed from heterosynaptic facilitation in that tetanic stimulation failed to evoke long-lasting changes in the synapse. These results support recent findings that 5-HT is a critical neuromodulator in behavioral sensitization and dishabituation and suggest that critical levels of cAMP may be required for long- and short-term facilitation of depressed synapses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective short- and long-term effects of serotonin, small cardioactive peptide, and tetanic stimulation on sensorimotor synapses of Aplysia in culture. 169 45


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