Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to elucidate the mechanisms by which arachidonic acid activates guanylate cyclase from guinea pig lung. Guanylate cyclase activities in both homogenate and soluble fractions of lung were examined. Guanylate cyclase activity was determined by measuring formtion of [32-P] cyclic GMP from alpha-[32-P] GTP in the presence of Mn2+, a phosphodiesterase inhibitor and a suitable GTP regenerating system. Arachidonic acid, and to a slight extent dihomo-gamma-linolenic acid, activated guanylate cyclase in homogenate but not soluble fractions. Similarly, phospholipase A2 activated homogenate but not soluble guanylate cyclase. Methyl arachidonate, linolenic, linoleic and oleic acids did not activate guanylate cyclase in either fraction. High concentrations of indomethacin, meclofenamate and aspirin inhibited activation of homogenate guanylate cyclase by arachidonic acid and phospholipase A2, without altering basal enzyme activity. These data suggested that a product of cyclooxygenase activity, present in the microsomal fraction, may have accounted for the capacity of arachidonic acid to activate homogenate guanylate cyclase. This view was supported by the findings that addition of the microsomal fraction to be soluble fraction enabled arachidonic acid to activate soluble guanylate cyclase, an effect which was reduced with cycloooxygenase inhibitors. Lipoxygenase activated guanylate cyclase in homogenate and soluble fractions. Arachidonic acid potentiated the activation of soluble guanylate cyclase by lipoxygenase, and this effect was inhibited with nordihydroguairetic acid, 1-phenyl-3-pyrazolidone and hydroquinone, but not with high concentrations of indomethacin, meclofenamate or aspirin. These data suggest that arachidonic acid activates guinea pig lung guanylate cyclase indirectly, via two independent mechanisms, one involving the microsomal fraction and the other involving lipoxygenase.
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PMID:Arachidonic acid activation of guinea pig lung guanylate cyclase by two independent mechanisms. 4 57

The antithrombotic effect of dipyridamole is through phosphodiesterase inhibition and depends on stimulation of platelet cyclic A.M.P. by circulating prostacyclin in the bloodstream. Low doses of aspirin selectively inhibit platelet cyclooxygenase and potentiate the antithrombotic effects of dipyridamole and theophylline. High doses of aspirin also prevent prostacyclin formation, thereby abolishing the effects of dipyridamole. Thus, the antithrombotic effectiveness of the combination of aspirin and dipyridamole depends critically on the doses used.
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PMID:Dipyridamole and other phosphodiesterase inhibitors act as antithrombotic agents by potentiating endogenous prostacyclin. 7 50

Prostacyclin (PGI2) generated by the vascular wall is a potent vasodilator, and the most potent endogenous inhibitor of platelet aggregation so far discovered. Prostacyclin inhibits platelet aggregation by increasing cyclic AMP levels. Prostacyclin is a circulating hormone continually released by the lungs into the arterial circulation. Circulating platelets are, therefore, subjected constantly to prostacyclin stimulation and it is via this mechanism that platelet aggregability in vivo is controlled. Moreover, phosphodiesterase inhibitors such as dipyridamole or theophylline exert their antithrombotic actions by potentiating circulating prostacyclin. The prostacyclin:thromboxane A2 ratio is important in the control of thrombus formation; manipulation of this ratio by small doses of aspirin (which will inhibit mainly platelet cyclooxygenase), a selective inhibitor of thromboxane formation, or the dietary use of a fatty acid like eicosapentaenoic acid (which would be the precursor for a delta17-prostacyclin (PGI3) but is transformed by the platelets into nonaggregating thromboxane A3) might have beneficial effects as antithrombotic therapies. Prostacyclin has interesting potential for clinical application in conditions where enhanced platelet aggregation is involved or to increase biocompatibility of extracorporeal circulation systems.
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PMID:The role of prostacyclin in vascular tissue. 21 63

Triflusal is a new antithrombotic agent, structurally similar to acetylsalicylic acid (ASA), which has been shown to possess a different pharmacological profile, suggesting a different mechanism of action for both compounds. To confirm this hypothesis we have studied, comparatively, the inhibition by triflusal and ASA of the activity of several enzymes involved in the equilibrium of platelet haemostasis, namely, prostaglandin-synthetase system (PG-synthetase), cyclo-oxygenase, thromboxane-synthetase and cAMP-phosphodiesterase. Results indicate that trilfusal is 60% less potent as inhibitor of cyclooxygenase (biological method) and of prostaglandin biosynthesis (spectrophotometric method ) than ASA. On the contrary, triflusal is five times more potent than ASA as inhibitor of cAMP phosphodoesterase. Inhibition of thromboxane-synthetase by both compounds is negligible and without physiological significance. These results suggest a mechanism of action of trifusal that might explain the different pharmacological profile between triflusal and ASA as antithrombotic agents.
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PMID:Comparison of the inhibitory effects of acetylsalicylic acid and trifusal on enzymes related to thrombosis. 22 20

Thrombin rapidly induces the formation of labeled phosphatidic acid from platelets prelabeled with [17C]arachidonate or 32PO34- and specifically decreases by 50--75% the content of phosphatidylinositol. Ionophore A23187 also stimulates phosphatidate labeling, but less effectively than thrombin. This effect on phosphatidic acid is blocked by increasing the levels of cyclic AMP by preincubation with dibutyryl cyclic AMP, cyclic AMP-phosphodiesterase inhibitors or prostacyclin. Indomethacin and eicosatetraynoic acid do not alter the production of phosphatidate, indicating independence from cyclooxygenase or lipoxygenase products. Increased turnover of [14C]- or [32P]phosphatidate occurs within 2--5 s after platelet activation by thrombin and is observed before endogenous, 14C-labeled arachidonate can be detected. The rate of phosphatidate formation parallels the induced rate of serotonin release. Release of [3H]serotonin is not affected by eicosatetraynoic acid. Phosphatidate production reflects the generation of diacylglycerol by C-type phospholipase degradation of phosphatidylinositol. Diacylglycerol and phosphatidic acid may participate in the membrane modification related to the early changes in platelet shape, release reactions or aggregation which occur on stimulation.
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PMID:Stimulation of phosphatidic acid production in platelets precedes the formation of arachidonate and parallels the release of serotonin. 37 88

The uptake of immune complexes by macrophages (MP) may be important in disease states in which circulating immune complexes are increased. We undertook the present study to determine the effects of prostaglandin E2 (PGE2) and adenosine 3',5'-cyclic monophosphate (cAMP) on the uptake of immunoglobulin G complexes (IgG complexes) by MP. The uptake of 125I-IgG-gold particles (IgG-gold) was measured in the established MP cell line J774.16 following pretreatment with PGE2, the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), PGE2 plus IBMX, the cyclooxygenase inhibitor indomethacin (IM), and dibutyryladenosine 3',5'-cyclic monophosphate (DBcAMP). Preincubation with PGE2 at concentrations from (10(-12)) to (10(-5) M) revealed significantly diminished uptake of IgG-gold at (10(-6)) and (10(-5) M) (in counts per min per well, PGE2 [10(-6) M], 5,401 +/- 140; control, 17,150 +/- 493, p less than 0.001); (PGE2 [10(-5) M], 3,835 +/- 172; control, 17,150 +/- 493, p less than 0.001). IBMX (10(-3) M) alone did not significantly alter IgG-gold uptake (IBMX, 14,450 +/- 1938; control, 14,840 +/- 995, p less than 1.0). PGE2 (10(-6) M) plus IBMX (10(-3) M) significantly suppressed IgG-gold uptake (in counts per min per well, PGE2 plus IBMX, 3,659 +/- 129; control 18,296 +/- 486, p less than 0.001). PGE2 (10(-6) M) alone also suppressed IgG-gold uptake versus control (PGE2, 4,578 +/- 105; control, 18,296 +/- 486, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of prostaglandin E2 and cyclic AMP on uptake of immunoglobulin G complexes by cultured macrophages. 128 Apr 54

Pharmacological modulation of the in vivo induction of plasminogen activator inhibitor type-1 (PAI-1) synthesis was studied in rats using the induction of PAI-1 by endotoxin as a model system. Both the cyclooxygenase inhibitors acetylsalicylic acid and indomethacin enhanced PAI-1 induction. The combined cyclooxygenase-lipoxygenase inhibitor, BW755C, dose-dependently inhibited induction. Since five other lipoxygenase inhibitors, a phospholipase inhibitor, an inhibitor of leukotriene formation and dexamethasone had no effect on the endotoxin-induced increase in PAI-1 synthesis, the effect of BW755C could not be ascribed to its known pharmacological properties. In addition, induction of PAI was enhanced by isobutyl-methylxanthine, a phosphodiesterase inhibitor, but not, however, by other phosphodiesterase inhibitors, or by forskolin or NG-nitro-L-arginine, suggesting an effect of isobutyl-methylxanthine other than through cyclic nucleotides. Heparin and hirudin had no effect either. Overall, the data showed that the induction of PAI-1 synthesis by endotoxin in vivo can be up- and down-regulated pharmacologically, but the mechanisms involved remain elusive.
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PMID:Pharmacological modulation of the endotoxin-induced increase in plasminogen activator inhibitor activity in rats. 128 Apr 69

5-Alkyl-2-aryl-4-pyridylimidazoles were synthesized and tested in rat ex vivo platelet aggregation studies. Among these compounds, 2-(2-fluorophenyl)-5-methyl-4-(3-pyridyl)imidazole (25) was most potent, and showed 98% inhibition at a dose of 10 mg/kg (p.o.). 25 had inhibitory activity on cyclooxygenase, thromboxane A2 (TXA2) synthetase, and phosphodiesterase, and also showed inhibited KCl-induced contraction of rat aorta. All compounds have little acute toxicity and appear to be free of adverse effects on the stomach.
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PMID:Studies on antiplatelet agents. I. Synthesis and platelet inhibitory activity of 5-alkyl-2-aryl-4-pyridylimidazoles. 129 22

The effect of azelastine on intracellular cyclic AMP concentration and on various indexes of cell activation was evaluated in guinea-pig alveolar macrophages and in human platelets. The effect of azelastine was further investigated on adenylate cyclase activity using membranes and homogenates from guinea-pig alveolar macrophages. Pretreatment of alveolar macrophages with azelastine prevented the activation induced by PAF-acether and by the chemotactic peptide fMLP as estimated by the reduced liberation of arachidonic acid metabolites formed by the cyclooxygenase and the lipoxygenase pathways. The effect of azelastine was concentration-dependent (50 to 500 microM) and reversible. Similarly, a short pretreatment with azelastine (100 microM) prevented arachidonic acid-induced platelet aggregation. This effect was also reversible after washing the platelets. In guinea-pig alveolar macrophages, azelastine induced a concentration-dependent (10 to 500 microM) increase in intracellular cyclic AMP and markedly potentiated the increase induced by PGE2. In human platelets, azelastine alone increased intracellular cyclic AMP concentration marginally only but, as in the case of macrophages, synergized with PGI2. Azelastine did not activate significantly adenylate cyclase unless a cytosolic factor was included within the membrane fraction. This effect of azelastine was not due to Ca2+ movements and was not modified by GTP. Our findings show that azelastine interferes with cell activation through a mechanism related to an increase in intracellular cyclic AMP concentration. The increase in cyclic AMP was induced by azelastine in intact cells and in homogenates but not in a crude membrane fraction. Those results indicate that azelastine modifies a cytosolic factor that may be phosphodiesterase. In addition, similarities between the effects of azelastine and those of reference phosphodiesterase inhibitors (theophylline, isobutyl-methyl-xanthine) are shown in this study, suggesting that azelastine might behave as a phosphodiesterase inhibitor.
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PMID:Azelastine potentiates the prostaglandin-induced increase of cyclic AMP content in human platelets and in guinea-pig alveolar macrophages. 137 22

Endotoxin is a major mediator of the life-threatening cardiovascular dysfunction that characterizes Gram-negative sepsis. In animal models of endotoxemia, pretreatment with ibuprofen or pentoxifylline attenuates some of these cardiovascular changes. To evaluate the effects of these agents on the human cardiovascular response to endotoxemia, hemodynamic variables were measured serially in 24 normal subjects who were given intravenous endotoxin. The subjects were randomized to receive oral ibuprofen (n = 9), pentoxifylline (n = 10), or no medication before endotoxin administration (n = 5). The subjects were volume loaded 3-5 h after endotoxin administration, and hemodynamic measurements were reassessed. Core temperature after endotoxin alone or endotoxin-pentoxifylline approached a maximum at 3 h (greater than or equal to 38.6 degrees C), while the endotoxin-ibuprofen group remained afebrile. At 3 and 5 h, all three groups had significant increases in heart rate, cardiac index, oxygen delivery, and oxygen consumption, while systemic vascular resistance index decreased significantly from baseline. The oxygen extraction ratio remained unchanged. After volume loading, the left ventricular ejection fraction and left ventricular end-diastolic and end-systolic volume indexes did not differ among the groups. The hyperdynamic cardiovascular response to endotoxin in humans occurs in the absence of fever and is not significantly ameliorated by oral cyclooxygenase or phosphodiesterase inhibition.
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PMID:Effects of ibuprofen and pentoxifylline on the cardiovascular response of normal humans to endotoxin. 140 57


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