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)

[Met5]-Enkephalin (ME) secretion and the expression of proenkephalin A (proENK) mRNA were studied following long-term exposure of bovine adrenal medullary chromaffin (BAMC) cells to pertussis toxin. Treatment with pertussis toxin for 24 h increased the secretion of ME in a concentration- and time-dependent manner. The magnitude of ME secretion continued to increase with time in the presence of pertussis toxin. The intracellular concentration of ME in the pertussis toxin-treated group was not significantly different from controls, suggesting that elevated levels of ME secretion result from increased biosynthesis of ME rather than from release of stored ME. Prolonged (24 h) stimulation of BAMC cells with pertussis toxin also increased proENK gene expression. Pretreatment with nimodipine (a calcium channel blocker) and calmidazolium (a calmodulin antagonist) inhibited both the secretion of ME and the increase in proENK mRNA levels induced by pertussis toxin, while the intracellular calcium antagonist dantrolene and the protein kinase C inhibitors sphingosine and H7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine] were ineffective in blocking pertussis toxin-induced responses. Forskolin (an adenyl cyclase activator) and isobutyl methyl xanthine (a phosphodiesterase inhibitor) increased both ME secretion and proENK mRNA levels; pertussis toxin synergistically increased the secretion of ME with these cyclic AMP-elevating agents but had only an additive effect with these agents on the level of proENK mRNA. Our results suggest that a pertussis toxin-sensitive G protein may tonically regulate the secretion of ME as well as the level of proENK mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pertussis toxin stimulates the secretion of [Met5]-enkephalin and the expression of proenkephalin A mRNA in bovine adrenal medullary chromaffin cells. 128 24

The psychoactive properties of Cannabis sativa and its major biologically active constituent, delta 9-tetrahydrocannabinol, have been known for years. The recent identification and cloning of a specific cannabinoid receptor suggest that cannabinoids mimic endogenous compounds affecting neural signals for mood, memory, movement, and pain. Using whole-cell voltage clamp and the cannabinomimetic aminoalkylindole WIN 55,212-2, we have found that cannabinoid receptor activation reduces the amplitude of voltage-gated calcium currents in the neuroblastoma-glioma cell line NG108-15. The inhibition is potent, being half-maximal at less than 10 nM, and reversible. The inactive enantiomer, WIN 55,212-3, does not reduce calcium currents even at 1 microM. Of the several types of calcium currents in NG108-15 cells, cannabinoids predominantly inhibit an omega-conotoxin-sensitive, high-voltage-activated calcium current. Inhibition was blocked by incubation with pertussis toxin but was not altered by prior treatment with hydrolysis-resistant cAMP analogues together with a phosphodiesterase inhibitor, suggesting that the transduction pathway between the cannabinoid receptor and calcium channel involves a pertussis toxin-sensitive GTP-binding protein and is independent of cAMP metabolism. However, the development of inhibition is considerably slower than a pharmacologically similar pathway used by an alpha 2-adrenergic receptor in these cells. Our results suggest that inhibition of N-type calcium channels, which could decrease excitability and neurotransmitter release, may underlie some of the psychoactive effects of cannabinoids.
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PMID:Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. 131 42

1. In the present study, the properties of glaucine (an aporphine structurally related to papaverine) were compared with those of papaverine, diltiazem, nifedipine and prazosin. The work includes functional studies on rat isolated aorta contracted with noradrenaline, caffeine or KCl, and a determination of the affinity of glaucine at calcium channel binding sites of alpha-adrenoceptors, by use of [3H]-(+)-cis-diltiazem, [3H]-nitrendipine and [3H]-prazosin binding to cerebral cortical membranes. The effects of glaucine on the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta were also determined. 2. Contraction evoked by noradrenaline (1 microM) or depolarizing solution (60 mM KCl) were inhibited in a concentration-dependent manner by all the compounds tested. As expected, prazosin showed a greater selectivity of action on NA-induced contraction, whereas nifedipine and diltiazem appeared more potent on KCl-induced contraction. Glaucine had a greater potency on the contraction elicited by noradrenaline whereas papaverine acted non specifically. 3. In Ca(2+)-free solution, prazosin (0.1 microM) and glaucine (0.1 mM) inhibited the contraction evoked by NA; diltiazem (0.1 mM) diminished this contraction whereas nifedipine (1 microM) had no effect. Preincubation of tissues with glaucine, diltiazem, nifedipine and prazosin did not modify the contractile response induced by caffeine. In contrast, papaverine (0.1 mM) significantly inhibited the contractions evoked by NA or caffeine in Ca(2+)-free medium. 4. Glaucine and papaverine show affinity at the [3H]-prazosin binding site and at the benzothiazepine binding site of the Ca(2+)-channel receptor complex, but have no effect at the dihydropyridine binding site in rat cerebral cortex. Glaucine exerts some selectivity as an inhibitor of [3H]-prazosin binding as opposed to [3H]-(+ )-cis-diltiazem binding while papaverine appears to have approximately equal affinity in this respect.5. This study confirms the presence of four phosphodiesterase (PDE) activities in bovine aorta: a calmodulin-activated PDE (CaM-PDE type I) which hydrolyzed preferentially guanosine 3':5'-cyclic monophosphate (cyclic GMP); a cyclic GMP selective form (cGMP-PDE type V); and two low Km adenosine 3':5'-cyclic monophosphate (cyclic AMP) PDEs that are insensitive to the stimulatory effect of CaM, one of which was inhibited by cyclic GMP (CGI-PDE, type III) and the other by rolipram (cAMP-PDE, type IV). Glaucine selectively inhibits one of the two forms of Ca2+-independent low Km cAMP-PDE, the type IV. In contrast, papaverine exerts a non-selective inhibitory effect upon all PDE forms.6. The present work provides evidence that glaucine, a benzyltetrahydroisoquinoline alkaloid, has interesting properties as an alpha l-adrenoceptor antagonist, calcium entry blocker (through the benzothiazepine recognition site in the calcium channel) and as a selective inhibitor of the rolipram-sensitive cAMP-PDE, type IV PDE.
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PMID:Multiple actions of glaucine on cyclic nucleotide phosphodiesterases, alpha 1-adrenoceptor and benzothiazepine binding site at the calcium channel. 132 80

The calcium channel blocker nifedipine and the new phosphodiesterase (PDE) inhibitor enoximone are used in the treatment of cardiovascular diseases. Since both substances are acting on slow calcium channels and because systemic elimination of these two agents is dependent on oxidative drug metabolizing enzyme activity, this study was performed in order to investigate hemodynamic changes and effects on plasma levels when both substances are given simultaneously. Forty-five patients undergoing aortocoronary bypass grafting were randomly subdivided into three groups: (a) group (n = 15) received 0.3 micrograms/kg/min of nifedipine as an infusion (N patients); (b) group (n = 15) received 0.5 mg/kg of enoximone as a bolus (E patients); and (c) group (n = 15) received nifedipine and enoximone in the same dosages (E + N patients). In addition to various hemodynamic variables, plasma levels of nifedipine, enoximone, and enoximone sulfoxide were measured until the end of the operation. Injection of enoximone was followed by an increase in cardiac index and right ventricular ejection fraction, decrease in pulmonary artery pressure, pulmonary capillary pressure, and systemic vascular resistance, whereas heart rate and mean arterial pressure remained almost unchanged. These changes were comparable for E and E + N patients. Plasma concentrations of enoximone and enoximone sulfoxide were not affected by nifedipine infusion and showed a comparable course in E and E + N patients. Nifedipine plasma level dropped to values less than 15 ng/ml at the end of extracorporeal circulation in N and E + N patients. It can be concluded that enoximone improved hemodynamics even in patients pretreated with nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Drug interactions: the new phosphodiesterase inhibitor enoximone and the calcium channel blocker nifedipine in coronary surgery patients--influence on hemodynamics and plasma concentrations. 168 80

The effect of caffeine on inward current carried by barium ions through voltage-dependent calcium channels has been investigated in single rabbit ear artery cells using whole-cell voltage-clamp techniques. Caffeine (1-30 mM) caused a rapid and reversible concentration-dependent blockade of barium current and a related compound, 3-isobutyl-1-methylxanthine (IBMX), was a more potent inhibitor of barium current. Caffeine-induced inhibition of barium current showed no voltage- or use-dependence and caffeine did not alter the steady-state inactivation of barium current. The effect of caffeine was not blocked by extracellular or by intracellular ryanodine or inclusion of both 5 mM 1,2-bis(2-aminophenoxy)-ethane N,N,N',N',-tetraacetic acid (BAPTA) and 2 mM ethylene glycol-bis(beta-amino ethyl ether) N,N,N',N',-tetraacetic acid (EGTA) in the intracellular solution. Rolipram and M&B 22984, non-xanthine inhibitors of phosphodiesterase, did not diminish inward barium current. The data indicate that caffeine and IBMX block voltage-operated calcium channels and it is suggested that this is due to a direct interaction of methylxanthines with the calcium channel.
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PMID:The action of caffeine on inward barium current through voltage-dependent calcium channels in single rabbit ear artery cells. 169 46

The positive inotropic action of the phosphodiesterase inhibitor zardaverine was investigated in guinea-pig heart muscle. In right papillary muscles, 1-30 microM zardaverine reversibly increased the force of contraction in a concentration-dependent manner. This effect was accompanied by a shortening of contraction and relaxation times. Resting membrane potential was unchanged, whereas action potential amplitude was significantly increased and duration was reduced. In papillary muscles partially depolarised with 22 mM K+, zardaverine (10 and 30 microM) restored slow action potentials, which were not influenced by cimetidine, propranolol or prazosin but were blocked by the calcium channel blocker (+)-nitrendipine or the muscarinic agonist carbachol. cAMP-specific phosphodiesterase III, isolated from guinea-pig ventricular muscle was inhibited by zardaverine as was cAMP-specific phosphodiesterase IV, isolated from dog trachea (IC50s: 0.5 and 0.8 microM, respectively). The results suggest that the observed positive inotropic and electrophysiological effects result from an inhibition of cellular phosphodiesterase.
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PMID:Actions of the phosphodiesterase inhibitor zardaverine on guinea-pig ventricular muscle. 170 Mar 9

In previous studies we have determined that both cultured neuronal and astrocyte glial cells prepared from the hypothalamus and brain stem of 1-day-old rats contain specific receptors for angiotensin II (ANG II). Astrocyte glial receptors are coupled to inositol phospholipid hydrolysis, but there is little indication of the intracellular messengers or signal transduction mechanisms coupled to the neuronal ANG II receptors. In the present study, we have determined that ANG II decreases cellular guanosine 3',5'-cyclic monophosphate (cGMP) levels in neuronal but not in astrocyte glial cultures. This effect is both time and concentration dependent and is inhibited by the ANG II-receptor antagonist [Sar1,Ile8]ANG II, showing the involvement of specific ANG II receptors. ANG II has no effects on particulate or soluble guanylate cyclase activities or on efflux of cGMP from neuronal cultures. However, the effects of ANG II on cellular cGMP content are abolished by pretreatment with the calcium channel blockers cadmium and nifedipine, and by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. These results suggest that calcium entry and possibly activation of a phosphodiesterase enzyme are involved in this ANG II-induced effect. This represents the first demonstration of a receptor-mediated effect of ANG II on an intracellular messenger in neuronal cultures. The functional role of cGMP as an intracellular messenger coupled to ANG II receptors in cultured neurons remains to be determined.
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PMID:Angiotensin II decreases cGMP levels in neuronal cultures from rat brain. 170 34

Interleukin-1 (IL-1) has been previously shown to stimulate prostaglandin E2 (PGE2) production by osteoblastic cells. This IL-1 effect has also been shown to be potentiated by parathyroid hormone (PTH), which activates both the calcium and the cAMP signal transduction pathways in osteoblastic cells. In the present study, the role of calcium, calmodulin, and cAMP in potentiating the IL-1 effect was examined. The calcium channel blocker verapamil (100 microM) completely inhibited the IL-1 effect. Similarly, the calmodulin antagonist W-7 (50 microM) inhibited the IL-1-induced stimulation. Conversely, the calcium ionophore A23187 (0.1 microM) potentiated the IL-1 effect. The phosphodiesterase inhibitor isobutyl-methylxanthine (IBMX; 100 microM), which elevates cAMP levels in the cells, had a strong potentiating effect on the IL-1-induced PGE2 production. These results suggest that both the calcium and the cAMP second messenger systems can modulate the IL-1 effect on osteoblastic cells.
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PMID:Recombinant interleukin-1 (IL-1) stimulates prostaglandin E2 production by osteoblastic cells: role of calcium, calmodulin, and cAMP. 171 74

Intracellularly perfused neurons of Helix pomatia in which serotonin-induced increase of calcium current (Ica) is mediated by cAMP were studied by the voltage clamp technique. It was established that an increase of the calcium intracellular concentration ([Ca2+]i) caused inhibition of the serotonin (5-HT) effect. The 5-HT effect value at 10(-6) and 10(-7) mol/l [Ca2+]i was 60 and 32% of the control one, respectively. Addition of the calmodulin antagonist (5.10(-5) M trifluoperasine) and phosphodiesterase blockers (5 mM theophylline or 10(-4) mol/l IBMX) sharply reduced the Ca2+ ability to inhibit the 5-HT effect. It is concluded that the Ca(2+)-calmodulin-dependent phosphodiesterase is a key link in the interaction between two signal transduction pathways--Ca2+ and cAMP in modulation of the calcium channel activity.
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PMID:[The effect of intracellular calcium on an increase in the cAMP-mediated calcium current]. 171 24

This paper describes the methods of prevention of delayed neurological deficit (DND) in patients with subarachnoid haemorrhage (SAH) due to ruptured intracranial aneurysm. To prevent the decrease in the cerebral flow, vasodilators, inhibitors of platelet aggregation and synthesis of endogenous prostaglandins, stimulators of prostacyclin synthesis of its analogue should be applied. It is also recommended to use the inhibitors of phosphodiesterase, blockers of serotonin and of calcium channel (particularly nimodipine). Therapy with the immunosuppressive drugs helps to prevent DND. With all those therapeutical methods DND is still a serious complication following SAH.
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PMID:[Management of intracranial vasospasm in rupture of cerebral aneurysm]. 181 Nov 86


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