Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitrate derivatives have in vivo and in vitro platelet anti-aggregant properties in addition to their vasodilatory effects. The mode of action is related to increased intracytoplasmic cyclic GMP concentrations. It has been shown that isosorbide dinitrate (ISDN) has this type of platelet anti-aggregant activity but the reported results about the active concentrations and the inhibited pathways of activation are contradictory. This study was designed to determine whether ISDN has in vitro platelet anti-aggregant activity at low doses and to verify if this effect is selective by aggregation induced by ADP. Finally, a possible potentialisation of the inhibitors due to ISDN was looked for with cyclic nucleotide phosphodiesterase inhibitors and with agents simulating the effect of adenylate cyclase. The results showed that: 1) ISDN had platelet anti-aggregant activity in vitro at concentrations of about 10-7 M, 2) that this effect was not limited to the aggregation induced by ADP as the aggregation induced by PAF-acether was also inhibited by low dose ISDN, 3) of the cyclic nucleotide modulators tested, only quercetine (flavonoide) potentialised the effects of ISDN.
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PMID:[Isosorbide dinitrate inhibits in vitro platelet aggregation at submicromolar concentrations]. 132 33

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

In the platelet-rich plasma of rabbits, 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-5-methyl-3(2H)-pyridazinone (CI-930) inhibited platelet aggregation triggered by AA, U-46619, ADP, collagen and PAF, with the IC50 values of 0.91, 0.73, 2.12, 2.35 and 7.15 mumols/L, respectively. The inhibitory effect of CI-930 on AA-induced aggregation was potentiated by PGE1, an adenylate cyclase activator, and antagonized by SQ-22536, an adenylate cyclase inhibitor. The contents of cAMP in washed rabbit platelets were increased by CI-930 5-50 mumols/L. In the concentration range of 0.5-500 mumols/L, CI-930 reduced the synthesis of TXB2 by either washed rat or rabbit platelets or rat pleural neutrophils. At the same time, CI-930 induced a dose-dependent increase of PGE2, PGF2a, and PGD2 biosynthesis by rat platelets and had no significant influence on the formation of 6-keto-PGF1a by the neutrophils. It is showed that CI-930 is an anti-platelet agent with a wide-spectrum activity and its anti-aggregating action may be exerted by dual mechanisms, both increasing cAMP contents and selectively inhibiting TXA2 synthesis in platelets.
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PMID:Effects of CI-930, a novel phosphodiesterase III inhibitor, on platelet aggregation and arachidonic acid metabolism. 196 75

We investigated the regulation of the adhesiveness of the human promonocytic cell line U-937, differentiated along the monocytic pathway either by 1,25-(OH)2-cholecalciferol or a combination of retinoic acid and dibutyryl cAMP. Adhesion to untreated polystyrene plastic was induced by inflammatory agents like PAF, fMLP or LTB4. The response to PAF first appeared after 48hr of differentiation and was inhibited by PAF antagonists and protein kinase C inhibitors indicating involvement of the phosphatidyl-inositol pathway in the stimulating effect. On the other hand, all the c-AMP raising agents tested inhibited PAF-induced cell adhesion, whatever their target membrane receptors, the Gs transducing protein, the catalytic unit of adenylate cyclase or cAMP phosphodiesterase. Direct stimulation of protein kinase A by Br8-cAMP had a similar effect. Moreover, PAF was able to increase cAMP levels. This suggests the existence of a cAMP based negative control mechanism limiting the action of PAF.
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PMID:The adhesiveness of monocytic U937 cells is stimulated by pro-inflammatory agents and inhibited by adenosine 3':5'-cyclic monophosphate. 215 91

Platelet-activating factor (PAF or 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is the most potent lipid mediator yet discovered. It is known to stimulate a wide span of biological responses ranging from aggregation and degranulation of platelets and neutrophils to a variety of cellular effects involving the stimulation of chemotaxis; chemokinesis; superoxide formation; protein phosphorylation; activation of protein kinase C, arachidonic acid, and phosphoinositide metabolites; glycogenolysis; and tumor necrosis factor production. Obviously, with such a diversity of biological activities, it is not surprising that PAF has been considered to be a key component in numerous diseases related to hypersensitivity and inflammatory responses. Evidence has also been presented for the role of PAF in physiological processes, particularly those involving reproduction and fetal development. Furthermore, because of its potent hypotensive action, PAF has been implicated as a contributing factor in blood pressure regulation. PAF is produced by two independent enzymatic pathways. The remodeling route involves the structural modification of a membrane lipid (1-alkyl-2-acyl-sn-glycero-3-phosphocholine) by replacement of the acyl moiety with an acetate group. An alternate route is the de novo synthesis of PAF from an O-alkyl analogue of a lysophosphatidic acid that requires a reaction sequence of acetylation, dephosphorylation, and phosphocholine addition steps. Hypersensitivity and other pathophysiological reactions are thought to be caused by activation of the remodeling pathway, whereas the de novo route is believed to be the source of endogenous levels of PAF required for physiological functions. Inactivation of PAF occurs when the acetate group is hydrolyzed by an acetylhydrolase that is present in both extra- and intracellular compartments, although the catalytic activity of the two forms of acetylhydrolase are identical, some of their properties differ. The control of PAF metabolism is very complex, but acetylhydrolase, Ca2+, phosphorylation/dephosphorylation of enzymes, and fatty acids (especially polyunsaturates) appear to be important regulatory factors. Specific PAF receptors have clearly been demonstrated on several different types of cells, and although the mechanism of PAF actions is poorly understood, it appears that the PAF/receptor-induced responses are closely associated with the signal transduction process; both G proteins and adenyl cyclase appear to be involved. Because significant quantities of PAF are often retained within certain cells, the possibility of PAF serving as an intracellular mediator has also been proposed.
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PMID:Platelet-activating factor and related acetylated lipids as potent biologically active cellular mediators. 224 Jan 90

In experiments on human platelets, inhibition of Na+/H+ exchange was caused either by equimolar substitution of external Na+ with choline or N-methyl-D-glucamine, by decreasing the pHo to 6.8, or by an inhibitor of the antiport 5-(N-ethyl-N-isopropyl)amiloride (EIPA). In all these cases a considerable inhibition of PAF-induced platelet aggregation and as a rule a more or less marked decrease in the cytoplasmic Ca2+ signal (quin-2-loaded platelets) occurred. Stimulation by 10(-7) M PAF caused biphasic pHi changes in human platelets loaded with the pH-sensitive fluorescent probe BCECF: a small transient decrease, followed by a sustained increase of 0.02 +/- 0.006 pH units, resulted from stimulation of the Na+/H+ exchange. Thrombin (0.1 U/ml) also caused biphasic pHi changes, but the alkalinization step was more pronounced (0.15 +/- 0.03 U). Every means of Na+/H+ exchange inhibition prevented a rise in pHi in stimulated platelets. Activation of the adenylate cyclase system by carbacyclin suppressed the agonist-induced pHi increase. The inhibition of neither cyclooxygenase by 10(-5) M indomethacin nor calmodulin-dependent enzymes by 10(-5) M calmidazolium affected the agonist-induced pHi signals. A decrease in temperature from 37 to 24 degrees C caused a considerable increase in the lag phase of the pHi signal induced by tetradecanoyl phorbol acetate (TPA), but did not affect the kinetics of the pHi signal induced by PAF. An inhibitor of protein kinase C (PKC), compound H-7 (60 microM), completely abolished the TPA-induced increase in pHi but caused only a partial inhibition of the pHi signal in about 50% of the experiments with PAF. On the basis of these results the conclusion is drawn that the activation of PKC is not the only pathway for the PAF-induced stimulation of Na+/H+ exchange. The PAF-induced pHi rise depended both on the presence of extracellular Ca2+ and on the [Ca2+]i increase. On the other hand, inhibition of Na+/H+ exchange decreased the magnitude of the Ca2+i signal in PAF-induced platelets loaded with quin-2, but did not influence the Ca2+ mobilization from intracellular stores as measured by quin-2 or chlortetracycline in experiments with thrombin-stimulated platelets. We conclude that in PAF-activated platelets some initial increase of [Ca2+]i is essential for Na+/H+ exchange activation while activated antiport potentiates a full-scale Ca2+ influx into the cells.
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PMID:Na+/H+ exchange in PAF-stimulated platelets. 256 35

In experiments with human platelets it has been shown, that stimulation of adenylate cyclase by carbacycline (CC)--a stable analog of prostacyclin, does not affect the initial pHi decrease caused by thrombin and PAF, but it abolishes the second phase of pHi changes, a pHi increase resulted from Na+/H+ exchange activation. CC also abolishes pHi increase induced by ionophore A23187 and the activator of protein kinase C, phorbol ester (TPA). The results obtained suggest that cAMP exerts inhibitory action on the agonist induced activation of Na+/H+ exchange but does not affect its pHi-sensitivity in the resting cell.
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PMID:[Effect of adenylate cyclase system activation on Na+/H+-exchange in human platelets]. 284 21

The inhibition of human platelet aggregation produced by PGF2 alpha is not specific for thromboxane A2 mimetics. Aggregation waves induced by PAF and thrombin are also inhibited by PGF2 alpha (8 microM); ADP is unaffected. These effects are still seen in platelets from aspirin-treated donors and platelets desensitized to thromboxane-like agonists (e.g. 11,9-epoxymethano PGH2). In contrast the thromboxane receptor antagonist EP 045 (up to 20 microM) had no effect on primary aggregation induced by PAF, thrombin and ADP. We have previously shown that EP 045 (IC50 = 0.5 microM), but not PGF2 alpha (28 microM), displaces the specific binding of [3H] 9,11-epoxymethano PGH2 to washed human platelets. PGF2 alpha produces small increases in cAMP levels, and both this effect and the anti-aggregation are diminished by the adenyl cyclase inhibitor SQ 22536. The rise in cAMP induced by PGF2 alpha is inhibited to a greater extent by the presence of ADP than by thrombin, PAF or a thromboxane mimetic. The ability of aggregating agents to inhibit this increase correlates inversely with their sensitivity to inhibition by PGF2 alpha. We suggest that the very weak effect of PGF2 alpha on cyclic AMP production is sufficient to account for its inhibitory activity, and it is unlikely to be a competitive antagonist at the platelet thromboxane receptor as suggested by others.
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PMID:Mechanism of the inhibition of platelet aggregation produced by prostaglandin F2 alpha. 298 22

1-O-Alkyl-2-O-acetyl-sn-glyceryl-3-phosphocholine (platelet activating factor) inhibits human platelet adenylate cyclase via the GTP-dependent mechanism. Inhibition of adenylate cyclase correlates with the stimulation of high affinity hormone-sensitive GTPase. The half-maximal effects of PAF on both enzymes are observed at concentrations about 10(-8) M. Phentolamine, an alpha-adrenergic antagonist, does not abolish the PAF-induced inhibition of adenylate cyclase. The obtained data suggest that PAF receptors are coupled with the GTP-binding inhibitory protein.
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PMID:Stimulation of high-affinity hormone-sensitive GTPase of human platelets by 1-O-alkyl-2-O-acetyl-sn-glyceryl-3-phosphocholine (platelet activating factor). 299 53

Intravenous administration of PAF-acether to the guinea pig induces bronchoconstriction, hypotension, intravascular platelet aggregation, endothelial disruption, and platelet and neutrophil diapedesis. These effects are followed within 1 h by an eosinophilic infiltration into the bronchial walls, which was also noted after the administration of antigen to passively sensitized guinea pigs. Bronchoconstriction and eosinophil infiltration are 2 major features of asthma, and selective bronchial eosinophilia characterizes late asthmatic reactions. We compared the histologic effects of PAF-acether 6 and 24 h after its intravenous injection with those of experimental passive anaphylactic shock, which is used as a model for asthma. Six hours after PAF-acether or antigen (ovalbumin) administration, a marked lung eosinophil infiltration, particularly in the bronchial walls, was noted, together with mucous plugs containing eosinophils in the bronchial lumen. Epithelial desquamation was followed after 24 h by mucous metaplasia of the bronchial epithelium. These effects were not observed when the inactive metabolite lyso-PAF was used. Our results agree fully with the suggestion that the eosinophil mediates the pathophysiology of bronchial asthma and releases materials toxic for the respiratory epithelium. Two PAF-acether antagonists (BN 52021 and WEB 2086) prevented the eosinophil infiltration triggered by PAF-acether and by antigen. When PAF-acether or ovalbumin were injected into guinea pigs after antiplatelet serum or prostacyclin, the eosinophil infiltration was significantly reduced, suggesting that platelets or another adenylate cyclase-sensitive cell are important for the subsequent PAF-acether-induced eosinophil infiltration. Our results support an essential role for PAF-acether in an experimental model of allergic asthma.
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PMID:Eosinophil recruitment into guinea pig lungs after PAF-acether and allergen administration. Modulation by prostacyclin, platelet depletion, and selective antagonists. 328 30


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