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 mode of action of E5510, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid, which has very potent anti-platelet activities, was investigated by examining its effects on the biochemical responses in the process of human platelet activation. In a whole-cell system, E5510 inhibited the increased turnover of inositol phospholipids arising from phospholipase C activation, arachidonic acid release from phospholipids by phospholipase A2, mobilization of intracellular free Ca2+, protein kinase C activation, and thromboxane A2 production. In a cell-free system, E5510 inhibited cyclooxygenase activity and cyclic AMP-dependent phosphodiesterase activity in a dose-dependent manner. An elevation of cyclic AMP in platelets was also observed at a relatively high concentration of E5510. It was suggested that receptor-mediated turnover of inositol phospholipids, intracellular Ca2+ increase, arachidonic acid release from phospholipids and protein kinase C activation might be indirectly inhibited by the increased cyclic AMP level in platelets. Thromboxane A2 production in the whole-cell system was very strongly inhibited by E5510, and the IC50 for this effect was 100 times lower than that of direct inhibition of cyclooxygenase in the cell-free system. It was concluded that although the primary mode of action of E5510 is the inhibition of the cyclooxygenase pathway of positive signal transduction in platelets, E5510 has another mode of action by increasing platelet cyclic AMP, which can act as a negative messenger in platelet signal transduction, and these multiple sites of action synergistically antagonize platelet cellular activation.
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PMID:A new anti-platelet drug, E5510, has multiple suppressive sites during receptor-mediated signal transduction in human platelets. 164 15

L-Histidine and imidazole (the histidine side chain) significantly increase cAMP accumulation in intact LLC-PK1 cells. This effect is completely inhibited by isobutylmethylxanthine (IBMX). Histidine and imidazole stimulate cAMP phosphodiesterase activity in soluble and membrane fractions of LLC-PK1 cells suggesting that the IBMX-sensitive effect of these agents to stimulate cAMP formation is not due to inhibition of cAMP phosphodiesterase. Histidine and imidazole but not alanine (the histidine core structure) increase basal, GTP-, forskolin-, and AVP-stimulated adenylate cyclase activity in LLC-PK1 membranes. Two other amino acids with charged side chains (aspartic and glutamic acids) increase AVP-stimulated but neither basal- nor forskolin-stimulated adenylate cyclase activity. This suggests that multiple amino acids with charged side chains can regulate selected aspects of adenylate cyclase activity. To better define the mechanism of histidine regulation of adenylate cyclase, membranes were detergent-solubilized which prevents histidine and imidazole potentiation of forskolin-stimulated adenylate cyclase activity and suggests that an intact plasma membrane environment is required for potentiation. Neither pertussis toxin nor indomethacin pretreatment alter imidazole potentiation of adenylate cyclase. IBMX pretreatment of LLC-PK1 membranes also prevents imidazole to potentiate adenylate cyclase activity. Since IBMX inhibits adenylate cyclase coupled adenosine receptors, LLC-PK1 cells were incubated in vitro with 5'-N-ethylcarboxyamideadenosine (NECA) which produced a homologous pattern of desensitization of NECA to stimulate adenylate cyclase activity. Despite homologous desensitization, histidine and imidazole potentiation of adenylate cyclase was unaltered. These data suggest that histidine, acting via an imidazole ring, potentiates adenylate cyclase activity and thereby increases cAMP formation in cultured LLC-PK1 epithelial cells. This potentiation requires an intact plasma membrane environment, occurs independent of a pertussis toxin-sensitive substrate and of products of cyclooxygenase, and is inhibited by IBMX. This IBMX-sensitive pathway does not involve either inhibition of cAMP phosphodiesterase activity or a stimulatory adenosine receptor coupled to adenylate cyclase.
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PMID:Histidine regulation of cyclic AMP metabolism in cultured renal epithelial LLC-PK1 cells. 168 53

Platelet-dependent occlusive thrombosis at sites of deep vessel wall injury elicited by electrical stimulation of rat carotid arteries was significantly reduced by thromboxane A2 (TXA2) synthetase inhibition and/or TXA2/prostaglandin endoperoxide receptor antagonism (ridogrel 1.25 mg/kg i.v.; dazoxiben 5 mg/kg i.v.; sulotroban 20 mg/kg i.v.), by inhibition of ADP-dependent platelet responses (ticlopidine 3 x 200 mg/kg orally) and by anticoagulation (heparin 250 U/kg i.v.; warfarin 1.25 mg/kg i.p.). This points to an involvement of arachidonic acid metabolites, ADP and thrombin as modulators of the thrombotic process. The antithrombotic effect of ridogrel (IC50 = 0.22 mg/kg i.v.) was abolished by cyclooxygenase inhibition (suprofen 5 mg/kg i.v.) but enhanced by cAMP phosphodiesterase inhibition (HL 725 6 micrograms/kg/min i.v.), demonstrating the importance of platelet inhibitory prostanoids such as PGD2, and prostacyclin formed after TXA2 synthetase inhibition. High doses of ridogrel (1.25 mg/kg i.v.) producing additional TXA2/prostaglandin endoperoxide receptor antagonism were more effective than lower doses (0.16 mg/kg i.v.) providing TXA2 synthetase inhibition alone. The antithrombotic effect of ridogrel, when combined with ticlopidine or heparin, exceeded that of the single compounds, pointing to interactions between arachidonic acid metabolites, ADP and thrombin in the formation of occlusive thrombosis at sites of arterial injury.
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PMID:Arachidonic acid metabolites, ADP and thrombin modulate occlusive thrombus formation over extensive arterial injury in the rat. 215 28

The effect of Cyclosporin A (CsA) on vascular vasomotor responses was determined in two isolated tissue preparations. The first preparation was the rat mesenteric vascular bed which was constricted by phenylephrine (EC80) and perfused with CsA (8.32 x 10(-8) to 8.32 x 10(-6) M). Vasodilation responses to acetylcholine, bradykinin and the calcium ionophore, A23187, were impaired, as was the response to sodium nitroprusside at high CsA concentrations. Indomethacin had no effect suggesting that the CsA effect is unrelated to the synthesis of cyclooxygenase products. In the second preparation, thoracic aortic rings from rats treated with CsA (5-10 and 20-50 mg/kg/daily for 3 and 1 weeks, respectively) were used. Aorta rings precontracted by phenylephrine (EC80) also showed impaired responses to both endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilators. Furthermore, a marked decrease of the guanosine 3',5'-cyclic monophosphate (cGMP) content in aortic preparations was found to accompany the in vivo effect of CsA on relaxation. In addition, exposure of aortic rings to CsA (8.32 x 10(-8) to 8.32 x 10(-6) M) in vitro, also inhibited markedly the cGMP response induced by acetylcholine or sodium nitroprusside. This effect of CsA was not modified by isobutyl methylxanthine, a phosphodiesterase inhibitor. We conclude that CsA acts directly on the vascular smooth muscle; and speculate that CsA may compromise the response to vasodilators by inhibiting cGMP formation.
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PMID:Attenuation of vascular relaxation and cyclic GMP responses by cyclosporin A. 215 99

Histamine stimulated large increases of cyclic adenosine monophosphate (cAMP) in freshly isolated human blood monocytes in the presence of R02-1724, a specific cAMP phosphodiesterase inhibitor. This was mediated by H2 receptors, since it was inhibited by cimetidine but not chlorpheniramine. Stimulation was attenuated in cells aged in culture 1-2 days. Indomethacin prevented the desensitization, suggesting that a cyclooxygenase product was responsible. Desensitization was heterologous, since the adenylate cyclase responses to 5'-(N-ethylcarboxamido)adenosine (A2 receptor agonist), isoproterenol (beta-adrenoceptor agonist), and prostaglandin E2 (PGE2) also declined during culture. The loss of sensitivity to histamine was restored by incubating monocytes with PGE2 in the presence of indomethacin. The results indicate that, while PGE2 inhibits monocyte functions via cAMP, its accumulation paradoxically permits cells to escape this regulation through a heterologous desensitization of the cAMP response to itself and other agonists.
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PMID:Prostaglandin-dependent desensitization of human monocyte cAMP responses. 217 33

We examined, in isolated blood perfused rat lungs, the effect of the cell permeable 8-bromo derivative of cGMP on pulmonary vasoconstriction induced by either alveolar hypoxia or angiotensin II. 8-Bromo cGMP dose-dependently reduced both hypoxia-(IC50 = 2.2 X 10(-5) M) and angiotensin-II-induced pulmonary vasoconstriction (IC50 = 5.0 X 10(-5) M). This effect of 8-bromo cGMP on pulmonary vasoconstriction was not affected by cyclooxygenase blockade. M & B 22948 (0.1 mM), an inhibitor of cGMP-phosphodiesterase, reduced synergistically with 8-bromo cGMP the hypoxia or angiotensin-II-induced vasoconstriction. The cGMP-phosphodiesterase inhibitor M & B 22948, by itself, selectively reduced hypoxia-induced vasoconstriction, suggesting a modulating effect of endogenous cGMP during hypoxic vasoconstriction.
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PMID:Effect of cyclic guanosine monophosphate on hypoxic and angiotensin-II-induced pulmonary vasoconstriction. 217 15

The possible roles of follicular cyclooxygenase and cAMP in the control of in vitro spontaneous brook trout (Salvelinus fontinalis) ovulation were investigated. Brook trout oocytes that had undergone germinal vesicle breakdown and follicular separation in vivo, were incubated in vitro in the presence of indomethacin. At 3 or 30 microM, indomethacin significantly reduced the levels of PGF and PGE (measured by radioimmunoassay) in the incubation medium but did not inhibit spontaneous ovulation in vitro. Follicular cAMP levels were measured by a competitive protein binding assay, prior to and during spontaneous ovulation. cAMP levels were approximately 3.2 pmol/mg protein prior to incubation and did not fluctuate significantly from this value throughout the 24-hr incubation period. The phosphodiesterase inhibitor, 3-isobutyl-l-methyl-xanthine, significantly increased follicular cAMP levels at 1.0 and 0.1 mM. The combined results suggest that cyclooxygenase metabolites or a decrease in cAMP are not involved in the control of spontaneous brook trout ovulation in vitro. The in vitro effects of primaquine, a putative phospholipase mediator, were also investigated. At lower concentrations (0.1-0.5 mM), primaquine significantly enhanced ovulation above that observed in spontaneous controls. However, at 1.0 mM, primaquine inhibited spontaneous ovulation. Indomethacin at 3 or 30 microM did not block the stimulatory effect of primaquine observed at lower concentrations, indicating that cyclooxygenase metabolites are not involved in the stimulatory effect of primaquine on ovulation.
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PMID:Investigations on the control of in vitro spontaneous brook trout (Salvelinus fontinalis) ovulation. 241 33

Acetylsalicylic acid (ASA) and three structurally related benzoic acid derivatives, 2-acetylbenzoic acid (ABA), 3-methylphthalide (3-MP), and 3-hydroperoxy-3-methylphthalide (3-HMP), were tested for inhibitory effects on three human blood platelet cyclic nucleotide phosphodiesterase (PDE) activities. 3-MP caused a dose-dependent inhibition of the high and low affinity cyclic AMP PDE activities and the cyclic GMP PDE activity. 3-HMP had some inhibitory effects but only on the low affinity cyclic AMP PDE activity. ASA and ABA had no effects. This study shows that progressive structural changes in the ASA molecule can shift the pharmacological profile from a cyclooxygenase inhibitor (ASA) to an inactive compound (ABA) to a PDE inhibitor (3-MP) and back again to a cyclooxygenase inhibitor (3-HMP). It is proposed that the potent anti-inflammatory effects of 3-MP, which differ from those of ASA, are mediated through the inhibition of the cyclic nucleotide PDE system.
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PMID:Cyclic nucleotide phosphodiesterase inhibition by a benzoic acid derivative. 242 Jan 62

Bradykinin (10(-6) and 10(-5) M) stimulated ACTH-IR release from rat anterior pituitary tissue in vitro concentration-dependently. The onset of this effect was delayed in comparison to that of AVP or CRF. The combined treatment of bradykinin with AVP or CRF produced additive effects of ACTH-IR release. Bradykinin may represent another candidate involved in the regulation of ACTH release. In contrast to AVP, bradykinin did not stimulate prostaglandin E2 synthesis in the pituitary tissue. Bradykinin-induced ACTH-IR release remained unchanged following cyclooxygenase inhibition by indomethacin. It can be concluded that prostaglandins are not involved in the action of bradykinin on the anterior pituitary. Bradykinin did stimulate cyclic AMP accumulation in pituitary tissue. Inhibition of phosphodiesterase by 3-isobutyl-l-methylxanthine (IBMX) potentiated the ACTH-IR release evoked by bradykinin. From the results obtained, we concluded that cyclic AMP appears to be involved as a second messenger in the bradykinin-evoked ACTH-IR release.
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PMID:Bradykinin-induced ACTH release from rat pituitary tissue in vitro. 242 24

The effect on cyclic AMP levels and bone resorption by two methylxanthine cyclic AMP phosphodiesterase (PDE) inhibitors, isobutyl-methylxanthine (IBMX) and theophylline, and two non-xanthine PDE inhibitors, Ro 20-1724 and rolipram, was studied in cultured mouse calvarial bones. Cyclic AMP accumulation in calvarial bones increased when Ro 20-1724 (0.1 mmol/l) or rolipram (30 mumol/l) was present in culture medium in 2 h incubations, and when IBMX (0.3 mmol/l) or theophylline (3 mmol/l) was present in 4 h incubations. The cyclic AMP response to PDE-inhibitors could be completely abolished by the cyclooxygenase-inhibitor indomethacin (1 mumol/l). In 120 h cultures, IBMX, theophylline, Ro 20-1724 and rolipram stimulated the release of 45Ca from calvarial bones prelabelled in vivo with 45Ca. This stimulatory effect could not be seen when the endogenous production of prostaglandins was reduced by adding indomethacin (1 mumol/l), hydrocortisone (1 mumol/l) or meclofenamic acid (1 mumol/l) to culture medium. These concentrations of indomethacin, hydrocortisone and meclofenamic acid did not reduce PTH- (10 nmol/l) or choleratoxin-stimulated (0.1 micrograms/ml) 45Ca release from mouse calvarial bones cultured for 120 h. The stimulation of 45Ca release in long-term cultures by the PDE inhibitors could be demonstrated in the presence of indomethacin, provided adenylate cyclase was stimulated by forskolin (1-10 nmol/l). The stimulatory effect of 1 alpha (OH)D3 on 45Ca release could not be potentiated by the PDE-inhibitor rolipram. These results suggest that basal adenylate cyclase activity in cultured murine calvaria is very low and that therefore PDE inhibitors are inactive unless a stimulator of adenylate cyclase is present. The adenylate cyclase stimulator may be an endogenous autacoid such as a prostaglandin.
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PMID:Delayed stimulation of bone resorption in vitro by phosphodiesterase inhibitors requires the presence of adenylate cyclase stimulation. 246 48


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