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)

In rat aorta, KT2-734 inhibited contractile responses to 5-hydroxytryptamine (5-HT) and KCl. KT2-734 inhibited the relaxing effect of verapamil, but not nifedipine. Similarly, verapamil, but not nifedipine, inhibited the vasorelaxing effect of KT2-734. KT2-734 relaxation was inhibited by endothelium removal but not by atropine and propranolol. Methylene blue, a guanylyl cyclase inhibitor, and NG-monomethyl arginine also inhibited the relaxation both in the presence and absence of endothelium. In the absence of endothelium, KT2-734 potentiated the relaxation induced by L-arginine, nitroglycerin and isoproterenol. In addition, M & B 22,948, a cGMP phosphodiesterase inhibitor, and theophylline inhibited and potentiated, respectively, KT2-734-induced relaxation. However, methylene blue inhibited the potentiation of isoproterenol relaxation by KT2-734 and that of KT2-734-relaxation by theophylline. KT2-734 caused increases in the level of cGMP without significantly affecting the cAMP level. These results suggest that KT2-734 may cause endothelium-independent relaxation mainly due to inhibition of cGMP-phosphodiesterase.
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PMID:Vasoinhibitory action of KT2-734, an antihypertensive agent, in isolated rat aorta. 813 65

The effects of 5-hydroxytryptamine (5-HT)2A receptor activation on cAMP formation were studied in a cell line derived from embryonic rat cortex (A1A1). 5-HT (EC50 = 0.87 microM) amplified the amount of cAMP formed in response to 5'-N-ethylcarboxamidoadenosine (an adenosine A2 receptor agonist), cholera toxin, and forskolin after 15 min of coincubation in the presence of the phosphodiesterase inhibitor rolipram. This effect of 5-HT was blocked by 10 nM ketanserin as well as by 10 nM spiperone, indicating a response mediated by the 5-HT2A receptor subtype. Similarly, cAMP accumulation was enhanced by coincubation with the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore A23187. After exposure to PMA for 24 hr (PKC-depleted cells), 5-HT and A23187 still enhanced cAMP formed in response to forskolin and 5'-N-ethylcarboxamidoadenosine, whereas the amplifying effects of PMA were abolished. Analysis by Western blots and PKC activity measurements revealed that, of three PKC isoforms detected in A1A1 cells (alpha, delta, and epsilon), only the calcium-independent isoform PKC-epsilon remained in membrane fractions after long term PMA treatment. In PKC-depleted cells, 5-HT-mediated amplification was greatly reduced after treatment with the calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (acetoxymethyl)-ester or the calmodulin antagonists calmidazolium and N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide hydrochloride. In addition, 5-HT-mediated amplification of cAMP accumulation was reduced by the PKC inhibitor staurosporine in normal cells but was unaffected in PKC-depleted cells. In conclusion, these data suggest that 5-HT2A receptor activation can amplify cAMP formation in A1A1 cells by two distinct pathways coupled to the hydrolysis of inositol phosphates, i.e., PKC and calcium/calmodulin.
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PMID:5-Hydroxytryptamine type 2A receptors regulate cyclic AMP accumulation in a neuronal cell line by protein kinase C-dependent and calcium/calmodulin-dependent mechanisms. 819 Jan

Nicorandil is an antianginal vasodilator having a hybrid property between nitrates and potassium channel openers, and cromakalim is a relatively specific potassium channel opener. We investigated whether or not the vasorelaxant actions of the two drugs would be selective for certain vasoconstrictor agonists (simply agonists hereafter), and the underlying mechanisms in isolated porcine large coronary arteries. Both nicorandil and cromakalim produced a complete relaxation in the arteries precontracted with seven agonists, i.e., Bay-K-8644, endothelin, histamine, 5-hydroxytryptamine (5-HT), phenylephrine, PGF2 alpha, and U 46619. The EC50 values (-log M) of nicorandil and cromakalim were 5.20-5.44 and 6.43-6.87, respectively, toward the seven agonists, indicating that the vasorelaxant actions of the two drugs were agonist nonselective. In the arteries precontracted with Bay-K-8644, endothelin, 5-HT, and U 46619, the vasorelaxant action of cromakalim was antagonized by glibenclamide, an antagonist of potassium channel openers, and Schild analysis of these antagonisms yielded pA2 values of 7.10-7.41 for glibenclamide. The vasorelaxant actions of nicorandil in the arteries precontracted with the four agonists each were not antagonized by glibenclamide. Instead, the vasorelaxant action of nicorandil was antagonized by methylene blue (10 microM), an inhibitor of guanylate cyclase, and slightly potentiated by M&B 22,948 (10 microM), an inhibitor of cyclic-GMP phosphodiesterase, in the arteries precontracted with U 46619. These results indicate that the vasorelaxant actions of nicorandil and cromakalim in the porcine large coronary artery are agonist nonselective and that nicorandil exerts such an action entirely as a nitrate, whereas cromakalim does so entirely as a potassium channel opener.
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PMID:Nicorandil as a nitrate, and cromakalim as a potassium channel opener, dilate isolated porcine large coronary arteries in an agonist-nonselective manner. 824 Oct 13

Vascular smooth muscle cells derived from bovine basilar artery by the explant method were grown in culture. In the presence of 1 microM forskolin and the phosphodiesterase inhibitor rolipram, 5-hydroxytryptamine (5-HT) agonists inhibited by 90 to 100% the accumulation of intracellular cyclic AMP (cAMP) with a rank order of potency 5-carboxamidotryptamine (5-CT) > or = 5-HT > 5-benzyloxytryptamine = sumatriptan > RU24969 [5-methoxy-3(1,2,3,6-tetrahydro-4-pyridinyl)-1H indole succinate] > (+/-)-8-hydroxydipropylaminotetralin. In suspensions of cells loaded with the calcium-sensitive probe fura-2, 5-CT and 5-HT caused a biphasic increase in the concentration of intracellular free calcium ([Ca++]i) that consisted of both transient and sustained phases. The transient phase was reduced and the sustained phase abolished in the absence of extracellular calcium. The EC50 for 5-CT-induced increase in [Ca++]i (6 nM) was similar to that for inhibition of cAMP accumulation (1.3 nM). Both the inhibition of cAMP accumulation and increase in [Ca++]i were inhibited by the antagonist methiothepin (pA2 = 8.9), but not by the antagonists ketanserin, spiperone and pindolol. Both the inhibition of cAMP accumulation and increase in [Ca++]i were attenuated by greater than 85% in cells that were pretreated with pertussis toxin. PI turnover was not stimulated by 5-CT. The rank order of agonist potency, as well as the antagonist sensitivity, indicates responses mediated by one or more 5-HT1-like-type receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:5-Hydroxytryptamine1-like receptors linked to increases in intracellular calcium concentration and inhibition of cyclic AMP accumulation in cultured vascular smooth muscle cells derived from bovine basilar artery. 839 13

The effects of chronic treatment (6-8 days) with a phosphodiesterase inhibitor, rolipram, on the expression of voltage-dependent Ca2+ channels, nicotinic acetylcholine (ACh) receptors and 5-hydroxytryptamine (5-HT) receptors were investigated in PC12 cells. The results were compared with the effects of nerve growth factor (NGF), 8-bromo-cyclic AMP (8-Br-cAMP) and phorbol 12-myristate 13-acetate (PMA). In the morphological study rolipram, at a high concentration (100 microM) induced the extension of neurites. A similar result was obtained in 8-Br-cAMP (1 mM)-treated cells. Rolipram, at a low concentration (10 microM) or PMA (10(-7) M) did not induce obvious morphological change. NGF (100 ng/ml) induced the extension of long neurites and the formation of neural networks. Rolipram (100 microM) increased the current density (pA/pF) of voltage dependent Ca2+ current (ICa). Both NGF and 8-Br-cAMP also increased the current density of ICa, whereas PMA did not. NGF increased the current density of the nicotinic ACh response whereas rolipram, 8-Br-cAMP and PMA decreased. Rolipram (100 microM), NGF (100 ng/ml), and 8-Br-cAMP (1 mM) increased the current density of the 5-HT response whereas the effect of PMA (100 nM) was slight. The results suggest that rolipram is able to contribute to the neuronal development by increasing intracellular cAMP as well as 8-Br-cAMP. Consequently, rolipram behaves like a neurotrophic factor in cultured PC12 cells.
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PMID:Rolipram enhances the development of voltage-dependent Ca2+ current and serotonin-induced current in rat pheochromocytoma cells. 840 99

1. We have assessed the effects of adenosine receptor agonists and antagonists on collagen-induced 5-hydroxytryptamine (5-HT) release and cyclic AMP generation in human platelets. 2. 5'-N-ethylcarboxamidoadenosine (NECA) and CGS 21680 elicited accumulations of cyclic AMP with mean EC50 values of 2678 and 980 nM, respectively. The maximal response to CGS 21680 was approximately half that of the response to 10 microM NECA. 3. NECA and CGS 21680 inhibited collagen-induced 5-hydroxytryptamine release with mean EC50 values of 960 and 210 nM, respectively. The maximal response to CGS 21680 was approximately 25% of the response to 10 microM NECA. 4. The A1/A2a-selective adenosine receptor antagonist PD 115,199 was more potent as an inhibitor of NECA-elicited responses than the A1-selective antagonist DPCPX with calculated Ki values of 22-32 nM and > 10 microM, respectively. 5. In the presence of a cyclic AMP phosphodiesterase inhibitor, the effects of CGS 21680 on cyclic AMP accumulation and 5-HT release were enhanced to levels similar to those elicited by 10 microM NECA. In the absence of phosphodiesterase inhibition, CGS 21680 did not antagonise the effects of NECA. Furthermore, endogenous adenosine did not contribute to the effects of CGS 21680 when phosphodiesterase was inhibited. 6. We conclude that an A2a adenosine receptor appears to be involved in the NECA-elicited increases in cyclic AMP levels and inhibition of 5-HT release in human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Adenosine receptor-induced cyclic AMP generation and inhibition of 5-hydroxytryptamine release in human platelets. 852 67

1. Two-electrode voltage clamp was used to study the effects of adenosine 3':5'-cyclic monophosphate (cyclic AMP) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) on voltage-dependent ion channels in salivary gland cells of the leech, Haementeria ghilianii. 2. Intracellular cyclic AMP specifically blocked delayed rectifier K+ channels. This was shown by use of 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor), forskolin (an activator of adenylyl cyclase) and intracellular injection of cyclic AMP and its dibutyryl and 8-bromo analogues. Cyclic AMP appeared to be the second messenger for the putative neuroglandular transmitter, 5-hydroxytryptamine. 3. Intracellular injection of cyclic GMP specifically potentiated high-voltage-activated (HVA) Ca2+ current and the effect was mimicked by zaprinast, an inhibitor of cyclic GMP-dependent phosphodiesterase. 4. Extracellularly, cyclic GMP and cyclic AMP specifically decreased the amplitude and increased the rate of inactivation of HVA Ca2+ current. These effects of the cyclic nucleotides are identical to those known for extracellular ATP, which activates a presumed purinoceptor. The pyrimidine nucleotide, UTP, was almost equipotent to ATP (threshold dose < 10(-6) M), indicative of a vertebrate-type nucleotide receptor. However, suramin (5 x 10(-5) M), a non-specific P2-receptor antagonist, failed to block the effects of 5 x 10(-6) M ATP (higher suramin doses could not be reliably tested because of the depolarization and increase in membrane conductance produced by the drug). 5. Activation of the putative purinoceptor by ATP did not affect inward rectifier Na+/K+ current which is known to be potentiated by intracellular cyclic AMP and reduced by intracellular cyclic GMP. 6. The preparation may provide a useful model for study of nucleotide actions, and interactions, in channel modulation. It has technical advantages such as large cells (1200 microns in diameter) which lack intercellular coupling and may be individually dissected for biochemical studies.
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PMID:Differential modulation of voltage-activated conductances by intracellular and extracellular cyclic nucleotides in leech salivary glands. 852 70

We examined responses to the 5-hydroxytryptamine 1D (5-HT1D)-receptor agonist sumatriptan in bovine pulmonary artery rings (2-3 mm ID). The effects of agonist-induced tone and agents that alter intracellular cyclic AMP [cyclic AMP]i or [cyclic GMP]i on responses to sumatriptan were investigated. At resting tension, responses to sumatriptan were slight or not evident. In the presence of tone induced by U46619, responses to sumatriptan (1 nM-30 mM) were greatly potentiated, as were responses to the alpha2-adrenoceptor agonist UK14304. Responses to the alpha 1-adrenoceptor agonist phenylephrine (PE) were potentiated only slightly. In the presence of U46619, addition of the adenylyl cyclase activator, forskolin (1 nM-0.1 microM or isoprenaline (ISO 1 microM) induced relaxations and increases in [cyclic AMP]i and resulted in further potentiation of the contractile response to sumatriptan. Addition of 0.1 microM sodium nitroprusside (SNP) inhibited sumatriptan-induced contractions. Whereas sumatriptan alone did not significantly affect [cyclic AMP]i, in the presence of U46619 it decreased [cyclic AMP]i. This effect of sumatriptan was further enhanced in the presence of forskolin. Sumatriptan increased [cyclic GMP]i. Using a nitric oxide (NO) synthase inhibitor and vessels denuded of endothelium, we showed that the increased [cyclic GMP]i in response to sumatriptan was endothelium-dependent and mediated by NO. This increase in [cyclic GMP]i was not observed in the presence of U46619. By measuring cyclic AMP and cyclic GMP phosphodiesterase (PDE) levels, we demonstrated that the point of "cross-talk" between cyclic nucleotides may not be at the level of total PDE activity. These results highlight the important role of [cyclic AMP], [cyclic GMP]i, and endothelium function in the control of 5-HT1D receptor-mediated vasoconstriction, which is dependent on a decrease in [cyclic AMP]i in the absence of an increase in [cyclic GMP]i.
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PMID:Contractile responses to sumatriptan in isolated bovine pulmonary artery rings: relationship to tone and cyclic nucleotide levels. 863 90

The mechanisms through which presynaptic 5-HT1A receptors cause inhibition of acetylcholine release from the guinea pig myenteric plexus were investigated. The selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) and 5-hydroxytryptamine (5-HT) caused concentration-dependent inhibitions of the electrically evoked release of [3H]acetylcholine from myenteric plexus preparations that had been preincubated with [3H]choline. The inhibitory effects were not modified by the activator of adenylyl cyclase, forskolin (10 microM), the phosphodiesterase inhibitor, AH 21-132 (100 microM), or after pretreatment of the guinea pigs with pertussis toxin (60 micrograms/kg). In contrast, the protein kinase C activator 4 beta- phorbol-12,13-dibutyrate (0.1 microM) prevented the release-inhibiting effect of 8-OH-DPAT, whereas the inactive isomer 4 alpha-phorbol-12,13-dibutyrate (0.1 microM) was without effect. The results suggest that the presynaptic 5-HT1A receptor is not coupled to a pertussis toxin sensitive G protein or to adenylyl cyclase. However, protein kinase C seems to be involved in the mechanism of inhibition of acetylcholine release by presynaptic 5-HT1A receptors.
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PMID:5-HT1A receptor-mediated inhibition of acetylcholine release from guinea pig myenteric plexus: potential mechanisms. 879 11

We have used a Mus domesticus/spretus congenic animal and two interspecific backcross panels to map genetically 30 sequence-tagged sites (STSs) and 13 genes to the vicinity of the pearl locus on mouse chromosome 13. The STSs defining the mapped region are from D13Mit9 to D13Mit37, spanning 10.6 cM. Genes mapped to this region include Versican (Cspg2), GTPase activating protein (Rasa), dihydrofolate reductase (Dhfr), arylsulfatase (As-1), thrombin receptor (Cf2r), hexosaminidase b(Hexb), 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr), microtubule associated protein 5/1b (Mtap5), phosphodiesterase (Pde), phosphatidylinositol 3' kinase (Pik3rl), rat integrin a1-subunit (Itga1), collagen receptor a2-subunit (Itga2), and 5-hydroxytryptamine 1a receptor (Htr1a). This high resolution genetic map of the pearl region of chromosome 13 establishes the order of multiple markers, including genes whose human homologs are located within a limited region of human chromosome 5, with respect to the phenotypic anchor marker pearl.
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PMID:An integrated genetic map of the pearl locus of mouse chromosome 13. 882 42


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