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 mixed inhibitory and excitatory effects of 5-HT on hippocampal pyramidal cells were studied on hippocampal slices perfused with a low-Ca2+/high Mg2+ solution that blocked synaptic activity and induced spontaneous pyramidal cell discharge. Extracellular recordings of the spontaneous discharge revealed that, in 65% of the cells, 5-HT (0.5-10 microM) initially inhibited and then, upon washout, facilitated spontaneous discharge. Sometimes the off-stimulation persisted for the duration of the experiment. In 17% of the cells the response to 5-HT was only stimulatory, and in 15% the response was exclusively inhibitory. The 5-HT1 agonists, 8-hydroxy-dipropylamino-tetraline, and 5-carboxamidotryptamine produced inhibition with no excitatory responses upon washout. The inhibition was blocked by spiroxatrine indicating it was mediated by 5-HT1A receptors. The 5-HT3 agonist, 2-methyl 5-HT, had no effect, and the 5-HT2 antagonist, ketanserin, did not alter the excitatory responses to 5-HT. This indicates the excitatory response is not mediated by 5-HT2 or 3 receptors. Cisapride, a 5-HT4 agonist increased pyramidal cell discharge. The 5-HT3 & 4 antagonist, ICS 205-930 antagonized the excitatory responses to 5-HT, alpha-methyl 5-HT, and cisapride, indicating the excitatory response is mediated, in part, by 5-HT4 receptors. The phosphodiesterase inhibitor, isobutyl-methyl-xanthine, stimulated pyramidal cell discharge and potentiated the response to cisapride. This further suggests 5-HT4 receptor involvement since these receptors are positively coupled to adenylyl cyclase.
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PMID:5-HT1A and 5-HT4 receptor colocalization on hippocampal pyramidal cells. 798 94

Zardaverine is a novel phosphodiesterase III/IV inhibitor, developed as a potential therapeutic agent for asthma. In this study we evaluated the effect of zardaverine in an in vivo animal model of airway inflammation and hyperresponsiveness. Endotoxin exposure in rats causes a transient increase in airway responsiveness and a neutrophilic inflammation of the bronchi, which are both at least partly mediated through the secondary release of tumour necrosis factor alpha (TNF alpha). Groups of 10 animals each were pretreated with placebo or zardaverine (1, 10, 30 mumol/kg) i.p., 30 min prior to exposure to aerosolized endotoxin (LPS) or saline. Ninety minutes later, airway responsiveness to 5-HT was assessed and bronchoalveolar lavage (BAL) performed. Zardaverine did not influence baseline lung resistance (RL), but inhibited dose dependently the 5-HT induced increase in RL in control animals. In placebo pretreated animals LPS exposure caused a significant decrease in PC50RL5-HT (provocative concentration of 5-HT causing a 50% increase in RL), compared to the saline exposed control group (1.1 +/- 0.1 vs 2.7 +/- 0.4 micrograms/kg) (P < 0.01). This decrease in PC50RL5-HT was significantly inhibited by zardaverine 30 mumol/kg (5.4 +/- 1.8 vs 1.1 +/- 0.1 micrograms/kg) (P < 0.05). Compared to placebo pre-treated, LPS exposed animals, zardaverine 30 mumol/kg also significantly inhibited to LPS induced neutrophil increase (193.0 +/- 50.0 vs 915.6 +/- 181.3 x 10(3)) (P < 0.01), increase in elastase activity (23 +/- 11 vs 54 +/- 9 nmol substrate/h/ml) (P < 0.05) and TNF alpha release in BAL fluid (93.1 +/- 19.5 vs 229.5 +/- 24.8 U/ml BAL fluid) (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of zardaverine, an inhibitor of phosphodiesterase isoenzymes III and IV, on endotoxin-induced airway changes in rats. 836 79

5-Hydroxytryptamine (5-HT) stimulates corticosteroid secretion from adrenal cells through activation of 5-HT4 receptors positively coupled to adenylyl-cyclase. In the present study, we investigated in frog adrenocortical cells the effect of 5-HT4 receptor agonists on cytosolic calcium concentration ([Ca2+]i) and determined the sequence of events associated with 5-HT4 receptor agonist zacopride (10[-8] to 10[-5]M each in the vicinity of cultured adrenocortical cells caused a dose-dependent increase in [Ca2+]i. Preincubation of the cells with the selective 5-HT4 receptor antagonist [1-[2-(methylsulfonylamino)ethyl]-4- piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate maleate totally blocked the 5-HT-induced stimulation of [Ca2+]i. Chelation of extracellular calcium with ethylene glycol bis (beta-aminoethyl ether)-N,N,N', N'-tetraacetic acid (10 MM) suppressed the stimulatory effect of 5-HT on [Ca2+]i. Conversely, thapsigargin, an inhibitor of calcium ATPase activity, had no effect on the [Ca2+]i rise. The calcium influx induced by 5-HT4 receptor agonists was not affected by nifedipine and omega-conotoxin GVIA but was totally blocked by pimozide, a T-type calcium channel antagonist. The [Ca2+]i response to zacopride was potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine and markedly reduced by the protein kinase A inhibitor adenosine-3',5'-cyclic monophosphorothioate. We studied in perifused frog adrenal slices the involvement of [Ca2+]i rise and cAMP formation in the mechanism of action of 5-HT4 receptor agonists. Zacopride-induced steroidogenesis was significantly reduced in the presence of adenosine-3'5'-cyclic monophosphorothioate or after suppression of calcium in the perifusion medium. The stimulatory effect of zacopride on corticosteroid secretion was not affected by nifedipine and omega-conotoxin GVIA but was significantly inhibited by pimozide. Taken together, these data indicate that activation of 5-HT4 receptors in adrenocortical cells causes stimulation of adenylyl cyclase and subsequently increases calcium influx through a T-type calcium channel. Both the increased in cAMP formation and the calcium rise are involved in the stimulatory effect of 5-HT on corticosteroid secretion.
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PMID:Activation of 5-hydroxytryptamine4 receptors causes calcium influx in adrenocortical cells: involvement of calcium in 5-hydroxytryptamine-induced steroid secretion. 864 88

1. The nature of the receptor coupling mechanism of the 5-hydroxytryptamine4 (5-HT4) receptor in the circular smooth muscle of the human colon has been further investigated. 2. 5-HT stimulated cyclic AMP generation and caused a relaxation in a concentration-dependent fashion, with EC50 values of 175.5 and 274.9 nM respectively. DAU 6236 increased cyclic AMP formation and caused a relaxant effect but was a partial agonist relative to 5-HT. 3. The 5-HT4 receptor antagonist, GR 113808, inhibited cyclic AMP formation and relaxation induced by 5-HT with -log Ki values of 9.1 (cyclic AMP) and 8.9 (relaxation) and apparent pA2 values of 9.2 (cyclic AMP) and 9.5 (relaxation). 4. Ondansetron and methysergide failed to inhibit cyclic AMP formation or the relaxation induced by 5-HT. 5. The phosphodiesterase inhibitor, IBMX, produced a concentration-dependent relaxation (EC50 = 30 microM) and at 1 microM it enhanced the 5-HT-induced relaxation producing a leftward shift of the 5-HT concentration-effect curve with a concentration-ratio of 4.1. Rolipram caused a concentration-dependent relaxation (EC50 = 564.8 nM) and at 200 nm caused a leftward shift of the concentration-effect curve to 5-HT with a concentration-ratio of 5.5. 6. Application of the adenylyl cyclase inhibitor, SQ 22536 (0.1 mM), and the protein kinase inhibitors, H7 (100 nM) and H89 (200 nM), inhibited the relaxant effect of 5-HT inducing a rightward shift of the concentration-effect curve with concentration-ratios of 10.1, 2.7 and 4.2 respectively. 7. Forskolin stimulated cyclic AMP production and caused a relaxation. The maximum relaxant effect of forskolin (6 microM, 13.8 +/- 1.9 cm.s) was not significantly different from the maximum relaxant effect of 5-HT (10 microM, 12.7 +/- 4.9 cm.s). However, the cyclic AMP levels stimulated by forskolin (6 microM, 49.3 +/- 6.6 pmol mg-1) were markedly greater than those stimulated by 5-HT (10 microM, 7.6 +/- 2.0 pmol mg-1). 8. In conclusion, these results indicate that the 5-HT4 receptors of the circular smooth muscle of human colon mediate relaxation and inhibition of spontaneous contractions via activation of adenylyl cyclase, formation of cyclic AMP and activation of protein kinase A.
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PMID:Further investigation into the signal transduction mechanism of the 5-HT4-like receptor in the circular smooth muscle of human colon. 879 82

Serotonin (5HT) and ATP are simultaneously released from activated platelets at the site of vascular injury and are hypothesized to play a significant role in hemostasis. Our laboratory investigated the modulation of vascular contraction of arterial ring segments by 5HT plus ATP as a model of the potential regulation of localized vascular tone by platelet releasates in regions of arterial damage. This study expands our focus on how these two vasoactive components, released from platelet dense granules, regulate vascular tone. 5HT- and 5HT analog-induced vasoconstrictions were measured in the presence or absence of ATP and ATP analogs with intact or deendothelialized rat pulmonary arterial ring segments suspended in organ baths. The possible presence of 5HT2 and 5HT1A receptor types in the rat pulmonary artery was demonstrated by vasoconstrictions induced by 5HT and (+)-8-hydroxy-2-(di-N-propylamino) tetralin hydrobromide (DPAT). The DPAT response was only 30%-50% of that induced by comparable concentrations of 5HT. The 5HT-induced contraction was inhibited by the 5HT2 antagonist, ketanserin. ATP equally relaxed 5HT and DPAT contracted tissue while the P2X agonist, alphabeta-methylene ATP, increased the contracted state of DPAT-treated arteries to a significantly greater extent than observed with 5HT. The P2y agonist, 3'-O-(4-benzoyl)benzoyl ATP (BzATP), the P2X agonist betagamma-methylene ATP, and ATP all relaxed 5HT-induced contractions to similar levels under a number of physiological conditions. The final level of 5HT-induced tissue contraction was the same whether ATP was added prior to, after, or simultaneously with 5HT. ATP and the phosphodiesterase inhibitor, theophylline, inhibited 5HT-induced vasoconstriction in an additive fashion. The ATP effects were endothelium dependent, while the inhibition by theophylline was not. The distribution of 5HT and ATP receptor types, as indicated by these and numerous other studies, appears to vary within different regions of the cardiovascular system. Extracellular ATP can synergistically enhance or inhibit 5HT-contracted blood vessels differentially at localized regions, which would significantly impact on localized vascular tone, and this in turn may modulate hemostasis and thrombosis.
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PMID:ATP modification of serotonin-induced contraction of the rat pulmonary artery. 908 56

The role of Ca(2+)-activated K+ channel modulation and cyclic nucleotide second messenger signal transduction in the canine pulmonary vascular response to serotonin was determined in the isolated blood-perfused dog lung. Pulmonary vascular resistances and compliances were measured using vascular occlusion techniques. Serotonin (10(-5) M) significantly increased precapillary and postcapillary resistance and significantly decreased total vascular compliance by decreasing large vessel compliance and middle compartment compliance. Tetraethylammonium ions (TEA+; 1 mM), an inhibitor of Ca(2+)-activated K+ channels, significantly potentiated the pressor effect to serotonin on both the pulmonary arteries and pulmonary veins. Pretreatment with the guanosine 3',5'-cyclic monophosphate (cGMP)/adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10(-5) M), the cell membrane-permeable analog of cAMP, dibutyryl-cAMP (10(-5) M), or the cAMP-dependent vasodilator isoproterenol (10(-5) M) inhibited the serotonergic response on both the arteries and veins, which was reversed by TEA+. In contrast, the stable membrane-permeable analog of cGMP, 8-bromo-cGMP (10(-5) M), had no effect on serotonin. These results indicate that there is a basal level of vasorelaxation in canine pulmonary blood vessels that is mediated by Ca(2+)-activated K+ channel activity and that inhibition of these K+ channels increases pulmonary vascular tone and potentiates the pulmonary vasoactive response to serotonin. Also, these data suggest that cAMP-induced pulmonary vasodilation is mediated primarily by Ca(2+)-activated K+ channels and that activation of these specific K+ channels attenuates the pressor response to serotonin. Thus an important relationship appears to exist between the cAMP second messenger system and Ca(2+)-activated K+ channels in canine pulmonary vasoreactivity.
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PMID:Role of calcium-activated potassium channels and cyclic nucleotides on pulmonary vasoreactivity to serotonin. 925 51

ECL cells are numerous in the acid-producing part of the rat stomach. They are rich in histamine and pancreastatin, a chromogranin A-derived peptide, and they secrete these products in response to gastrin. We have examined how isolated ECL cells respond to a variety of neuromessengers and peptide hormones. Highly purified (85%) ECL cells were collected from rat stomach using repeated counter-flow elutriation and cultured for 48 h before experiments were conducted. The ECL cells responded to gastrin, sulphated cholecystokinin-8 and to high K+ and Ca2+ with the parallel secretion of histamine and pancreastatin. Glycine-extended gastrin was without effect. Forskolin, an activator of adenylate cyclase, induced secretion, whereas isobutylmethylxanthine, a phosphodiesterase inhibitor, raised the basal release without enhancing the gastrin-evoked stimulation. Maximum stimulation with gastrin resulted in the release of 30% of the secretory products. Numerous neuromessengers and peptide hormones were screened for their ability to stimulate secretion and to inhibit gastrin-stimulated secretion. Pituitary adenylate cyclase activating peptide (PACAP)-27 and -38 stimulated secretion of both histamine and pancreastatin with a potency greater than that of gastrin and with the same efficacy. Related peptides, such as vasoactive intestinal peptide, helodermin and helospectin, stimulated secretion with lower potency. The combination of EC100 gastrin and EC50 PACAP produced a greater response than gastrin alone. None of the other neuropeptides or peptide hormones tested stimulated secretion. Serotonin, adrenaline, noradrenaline and isoprenaline induced moderate secretion at high concentrations. Muscarinic receptor agonists did not stimulate secretion, and histamine and selective histamine receptor agonists and antagonists were without effect. This was the case also with GABA, aspartate and glutamate. Somatostatin and galanin, but none of the other agents tested, inhibited gastrin-stimulated secretion. Our results reveal that not only gastrin but also PACAP is a powerful excitant of the ECL cells, that not only somatostatin, but also galanin can suppress secretion, that muscarinic receptor agonists fail to evoke secretion, and that histamine (and pancreastatin) does not evoke autofeedback inhibition.
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PMID:Neurohormonal regulation of histamine and pancreastatin secretion from isolated rat stomach ECL cells. 941 89

The transduction of the serotonin (5-HT) signal in Fundulus heteroclitus ovarian follicles leading to the inhibition of oocyte meiosis reinitiation (oocyte maturation) in vitro induced by the naturally occurring maturation-inducing steroid 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one (17,20 beta P) was investigated. Steroid-induced oocyte maturation was inhibited by 5-HT in a dose-dependent manner; maximum inhibition (90%) was observed with 10(-4) M 5-HT. Groups of follicle-enclosed oocytes were cultured in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) and treated with increasing doses of 5-HT. Serotonin was found to slightly increase the levels of follicular 3',5'-cyclic adenosine monophosphate (cAMP) in a dose-dependent manner; 10(-4) M 5-HT induced approximately a 3-fold increase in cAMP with respect to the controls. The changes in cAMP were then evaluated in follicles treated with 17,20 beta P in IBMX-free culture media in the presence or absence of 10(-4) M 5-HT. The exposure of follicles to 17,20 beta P alone produced a small and transient reduction in cAMP (40%) within 1-3 hr of steroid stimulation, and these early changes in cAMP appeared associated with a high incidence of germinal vesicle breakdown (80% GVBD) by 24 hr of incubation. Under these conditions, treatment of follicles with 5-HT also increased significantly the production of cAMP, and when 5-HT was combined with 17,20 beta P, the steroid-mediated reduction in cAMP was prevented and the levels of GVBD inhibited by 95%. Meiosis also was reinitiated with either the protein kinase A (PKA) inhibitor H8 or the protein kinase C (PKC) activator PMA, and the 5-HT inhibitory action on GVBD was found to be 100-fold reduced or completely ineffective, respectively. Preincubation of follicles with the PKC inhibitor GF109203x abolished PMA-induced GVBD in a dose-dependent manner, whereas this inhibitor had no effect on 17,20 beta P-triggered meiotic maturation, indicating that activation of PKC is apparently sufficient but not necessary to reinitiate meiosis. Taken together, these findings suggest that 5-HT may inhibit 17,20 beta P-induced meiotic reinitiation through the activation of a cAMP-PKA transduction pathway and that PKC possibly induces oocyte maturation by a different pathway than the steroid and thus is not affected by 5-HT.
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PMID:Serotonin inhibition of steroid-induced meiotic maturation in the teleost Fundulus heteroclitus: role of cyclic AMP and protein kinases. 949 86

To investigate the possible role of cyclic nucleotides and [Ca2+]i in non-adrenergic non-cholinergic (NANC) relaxations evoked by electrical field stimulation (EFS) in the cat airway, we studied the effects of specific phosphodiesterase (PDE) type IV or V inhibitors on the biphasic-NANC relaxations, the correlation between NANC relaxation and changes in intracellular levels of cAMP and cGMP ([cAMP]i and [cGMP]i), and measured changes in [Ca2+]i during the NANC relaxation. EFS (repetitive stimuli at 20 Hz, 1 or 4 ms pulse duration, 50 V) applied to the bronchial smooth muscle during contraction induced by 5-HT (10(-5) M) in the presence of atropine (10(-6) M) and guanethidine (10(-6) M) elicited biphasic NANC relaxations. Zaprinast (> 3 x 10(-7) M), a specific PDE type V inhibitor, preferentially enhanced the amplitude of the first component of the NANC relaxations. However, rolipram (> 3 x 10(-7) M) enhanced both the first and second component of the NANC relaxation to a similar extent. In the trachea, EFS evoked monophasic NANC relaxation accompanied by a concomitant accumulation of [cAMP]i and [cGMP]i. Pretreatment with rolipram (3 x 10(-6) M) enhanced the accumulation of [cAMP]i and amplitude of NANC relaxation evoked by EFS. However, zaprinast did not affect the amplitude of NANC relaxation although it significantly increased the levels of [cGMP]i. Nomega-Nitro-L-arginine methylester (L-NAME; 10(-5) M) completely suppressed the accumulation of [cGMP]i but only partly suppressed the NANC relaxation evoked by EFS. In contrast, EFS significantly enhanced [cAMP]i in the presence of L-NAME. During NANC relaxation, time-dependent decrease in [Ca2+]i occurred, which was partly suppressed by L-NAME. These results indicate that NANC relaxation is associated with concomitant accumulation in both [cAMP]i and [cGMP]i, and decrease in [Ca2+]i. However, the timing of the action of [cGMP]i and [cAMP]i in NANC relaxations differs in the central and peripheral airway.
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PMID:Possible role of cAMP, cGMP and [Ca2+]i during NANC relaxation in the cat airway smooth muscle. 953 40

Nociceptive sensory neurons (SNs) in Aplysia provide useful models to study both memory and adaptive responses to nerve injury. Induction of long-term memory in many species, including Aplysia, is thought to depend on activation of cAMP-dependent protein kinase (PKA). Because Aplysia SNs display similar alterations in models of memory and after nerve injury, a plausible hypothesis is that axotomy triggers memory-like modifications by activating PKA in damaged axons. The present study disproves this hypothesis. SN axotomy was produced by (1) dissociation of somata from the ganglion [which is shown to induce long-term hyperexcitability (LTH)], (2) transection of neurites of dissociated SNs growing in vitro, or (3) peripheral nerve crush. Application of the competitive PKA inhibitor Rp-8-CPT-cAMPS at the time of axotomy failed to alter the induction of LTH by each form of axotomy, although the inhibitor antagonized hyperexcitability produced by 5-HT application. Strong activation of PKA in the nerve by coapplication of a membrane-permeant analog of cAMP and a phosphodiesterase inhibitor was not sufficient to induce LTH of either the SN somata or axons. Furthermore, nerve crush failed to activate axonal PKA or stimulate its retrograde transport. Therefore, PKA activation plays little if any role in the induction of LTH by axotomy. However, the expression of LTH was reduced by intracellular injection of the highly specific PKA inhibitor PKI several days after nerve crush. This suggests that long-lasting activation of PKA in or near the soma contributes to the maintenance of long-term modifications produced by nerve injury.
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PMID:Activation of protein kinase A contributes to the expression but not the induction of long-term hyperexcitability caused by axotomy of Aplysia sensory neurons. 995 2


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