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 inhibition of platelet adhesion by nitric oxide (NO) and prostacyclin and their mechanism of action was studied. Platelet adhesion to collagen fibrils and endothelial cell matrix was inhibited completely by NO but only partially by prostacyclin. Adhesion of platelets to endothelial cell monolayers was inhibited by bradykinin. This effect of bradykinin was unaffected by aspirin, and was accounted for by the amounts of NO released by the endothelial cells. Inhibition of platelet adhesion by NO and prostacyclin was potentiated by selective inhibitors of cGMP phosphodiesterase, but not of cAMP phosphodiesterase, indicating that elevation of cGMP regulates platelet adhesion.
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PMID:The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. 282 88

The pharmacological properties of saterinone [+/-)-1,2-dihydro-5-[4-[2-hydroxy-3-[4-(2-methoxyphenyl)-1-piperazinyl] propoxy]phenyl]-6-methyl-2-oxo-3-pyridine-carbonitrile, BDF 8634) were investigated in isolated organs of the guinea pig and in human platelets. Saterinone was found to be a potent antagonist at vascular alpha 1-adrenoceptors with a pA2-value of 8.46 +/- 0.12. Besides its affinity for alpha 1-adrenoceptors saterinone exerted a positive inotropic effect in the isolated papillary muscle at an EC50-value of 3.2 X 10(-6)mol/l indicating 10-fold greater potency than milrinone. Comparable EC50-values were also found for the inotropic, chronotropic and bronchodilatory actions of the drug, indicating a common mechanism for these effects. The inotropic effects were not mediated by beta-adrenergic or H2-histaminergic receptors, but were shown to involve an elevation of myocardial cyclic adenosine monophosphate (cAMP) content. Saterinone also inhibited crude cAMP phosphodiesterase (PDE) activity in homogenates obtained from guinea pig right ventricles. The IC50-value for PDE-inhibition was 2.3 X 10(-5) mol/l and thus at a higher concentration than the inotropic effect. Saterinone was a potent inhibitor of human platelet aggregation induced by adenosine diphosphate, collagen and arachidonate. Against the latter agonist, saterinone was about 40-fold more effective than acetylsalicylic acid. In conclusion, saterinone exhibited a dual mechanism of action--direct inotropic effects in the myocardium and alpha 1-receptor blockade in the guinea pig vasculature.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pharmacological properties of the positive inotropic and alpha 1-adrenoceptor blocking agent saterinone. 290 45

Prostacyclin (PGI2) inactivates platelets by stimulation of adenylate cyclase, and its effect can be potentiated in vitro by simultaneous inhibition of cyclic AMP phosphodiesterase. The interaction of synthetic PGI2 and the potent phosphodiesterase inhibitor HL 725 was studied in a model of systemic platelet activation by intravenous injection of collagen. Platelet aggregate formation was evaluated by continuous on-line measurement of the circulating platelet count. Collagen injection in rabbits receiving vehicle caused a 30 +/- 3% decrease in the circulating platelet count. Infusion of PGI2 (0.05, 0.1 and 0.75 micrograms kg-1 min-1) dose-dependently inhibited this decrease. HL 725 (0.5, 1 and 3 micrograms kg-1 min-1) caused a slight but significant effect. Combinations of PGI2 and HL 725, respectively, at 0.25 + 1.0 and 0.1 + 0.5 micrograms kg-1 min-1 inhibited platelet aggregate formation to a greater extent than when either substance was used alone and produced a comparable inhibition to PGI2 at 0.75 micrograms kg-1 min-1. Collagen induced an acute fall in the mean arterial blood pressure (MABP) which also was inhibited by PGI2, HL 725 and their combinations. The infusion of a combination of PGI2 and HL 725 before collagen produced a decrease in the MABP which was greater than when either compound was used on its own. Thus, PGI2 and the phosphodiesterase inhibitor HL 725 interact in vivo to inhibit platelet aggregation and lower MABP.
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PMID:In vivo interaction of prostacyclin with an inhibitor of cyclic nucleotide phosphodiesterase, HL 725. 298 63

Human neutrophils in suspension undergo a metabolic burst and generate reactive O2- metabolites upon exposure to many soluble and particulate stimuli. They can also be stimulated to produce O2- when in contact with surfaces. We found that when neutrophils were allowed to settle into protein-coated surfaces the amount of O2- they generated varied with the nature of the protein: IgG greater than bovine serum albumin greater than plastic greater than gelatin greater than serum greater than collagen. However, when polymorphonuclear leukocytes were permitted to settle onto a surface and then were stimulated with either phorbol myristate acetate or N-formyl-methionyl-leucyl-phenylalanine the O2- response was greatly diminished compared to control cells that were exposed to the stimulus in suspension. In contrast, superoxide production in response to the particulate stimulus opsonized zymosan was similar in both suspended and settled neutrophils. The degree of inhibition was not related to the degree of adherence since the diminished response occurred with all of the surfaces tested and in the presence of cytochalasin B. Onset of inhibition was very rapid as was recovery when cells were resuspended. Whereas production of O2- was greatly inhibited by surface contact, release of lysosomal enzymes was only slightly affected. The effect of surface contact did not appear to be mediated via activation of adenylate cyclase since the combination of a phosphodiesterase inhibitor and exogenous dibuteryl cyclic adenosine monophosphate did not inhibit phorbal myristate acetate O2- production, but surface contact did. These data indicate that surface contact such as would occur during diapedesis and chemotaxis profoundly alters neutrophil behavior by an unknown mechanism and imply that observations made on polymorphonuclear leukocytes in suspension cannot be generalized to polymorphonuclear leukocytes in tissue.
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PMID:Surface contact inhibits neutrophil superoxide generation induced by soluble stimuli. 298 69

Certain esters of dihydropyranocoumarin and dihydrofuranocoumarin alcohols have previously been shown to inhibit the cAMP-phosphodiesterase from bovine heart. We now report that these naturally occurring coumarins inhibit the high affinity (Km = 1.1 microM) cAMP-phosphodiesterase from human platelets with activities that closely correlate with those obtained using phosphodiesterase from bovine heart tissue. Additionally the coumarins inhibit the aggregation of human platelets induced with ADP, adrenaline and collagen with activities comparable to those of dipyridamole. A lack of significant correlation between these metabolic and functional activities indicates that there exist, besides cAMP-phosphodiesterase inhibition, additional mechanisms of action for the platelet aggregation inhibitory effect of dihydropyrano- and dihydrofuranocoumarins.
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PMID:Inhibition of human platelet aggregation by dihydropyrano- and dihydrofuranocoumarins, a new class of cAMP-phosphodiesterase inhibitors. 298 67

This study with the new analog Ro 15-2041 (7-bromo-1,5-dihydro-3,6-dimethylimidazo[2,1-b]quinazolin-2(3H)-on e) confirms and substantially extends the activity spectrum of imidazoquinazolinones as potent platelet function inhibitors. Ro 15-2041 inhibited platelet aggregation induced by all common platelet agonists in platelet-rich plasma obtained from various species including man (IC50 = 1-3 microM). The compound potentiated platelet inhibition by prostacyclin, the prostacyclin-induced increase of intraplatelet cyclic (c) AMP levels and inhibited the collagen-induced release of serotonin and beta-thromboglobulin. Ro 15-2041 reduced the increase and accelerated the normalization of cytosolic free Ca++ in thrombin-stimulated human platelets. Ro 15-2041 is a potent (IC50 = 70 nM) and selective inhibitor of platelet cAMP-phosphodiesterase activity. Whereas Ro 15-2041 caused complete inhibition of cAMP-phosphodiesterase activity in human platelet supernatants, breakdown of cAMP in cardiac homogenates was depressed to maximally 50%. In human brain and rabbit uterus Ro 15-2041 was at least 1000 times less potent. By comparison, papaverine fully inhibited phosphodiesterase activity in all four tissues with similar IC50 values of about 5 microM. Furthermore, Ro 15-2041 selectively inhibited cAMP-phosphodiesterase activity of a bovine calmodulin-independent but not of a calmodulin-dependent enzyme preparation. The compound exhibited significant p.o. activity in various ex vivo and in vivo platelet function tests.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:7-Bromo-1,5-dihydro-3,6-dimethylimidazo[2,1-b]quinazolin-2(3H)- one (Ro 15-2041), a potent antithrombotic agent that selectively inhibits platelet cyclic AMP-phosphodiesterase. 299 47

Amentoflavone hexaacetate (AmAc) was synthesized from natural amentoflavone (Am), a biflavonoid extracted from Viburnum lantana L. Am does not inhibit aggregation of intact platelets up to a concentration of 100 microM but inhibits human platelet cAMP phosphodiesterase (IC50 = 22.0 microM). AmAc is a potent inhibitor of the aggregation of washed human platelets induced by ADP (IC50 = 2.3 microM) or collagen (IC50 = 4.7 microM). AmAc inhibits crude (IC50 = 8.6 microM) or partially purified (IC50 = 42.2 microM) human platelet cAMP phosphodiesterase. In the presence of prostaglandin E1, AmAc (10 microM) induces a 3.7-fold increase in total platelet cAMP. The characteristics of this action suggest a role for cAMP in the mechanism of action of AmAc. The incubation of AmAc with intact platelets for 5 min is necessary for its activity.
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PMID:Inhibition of human platelet cyclic AMP phosphodiesterase and of platelet aggregation by a hemisynthetic flavonoid, amentoflavone hexaacetate. 300 88

The term 'stimulus-secretion coupling' has, since first enunciated, been held to involve the mobilization of cytosol Ca2+, which in turn is sufficient to trigger exocytotic secretory processes in metabolically competent cells. However, recent studies on a wide range of secretory cell types indicate that a role for Ca2+ can be obviated: examples are stimulation with phorbol ester (phorbol myristate acetate, PMA) which causes the activation of protein kinase C or the stimulation of platelets with collagen. Ca2+-independent exocytosis also occurs when analogues of GTP are injected through the lumen of patch pipettes directly into the cytosol of mass cells. The results presented here suggest that GTP analogues can activate secretory processes by actions at two distinct locations: one may be at the level of the receptor involving the activation of polyphosphoinositide (PPI) phosphodiesterase with consequent liberation of diacylglycerol (DG); the other involves direct activation of the exocytotic mechanism. These conclusions are based on measurements of exocytotic secretion from permeabilized neutrophils into which we have been able to introduce, individually and in combination, Ca2+ chelators (EGTA and BAPTA), Ca2+ (buffered at micromolar concentrations with EGTA), analogues of GTP and GDP and the direct activator of protein kinase C, PMA.
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PMID:Two roles for guanine nucleotides in the stimulus-secretion sequence of neutrophils. 300 81

Trapidil effect on platelet aggregation in vitro and in vivo as well as on phosphodiesterase (PDE) activity was studied. Both ADP- and collagen-induced aggregation of human and rabbit platelets was inhibited by trapidil at concentrations of 60 mumol/l. The PDE activity of human platelet lysates was blocked at concentrations that were necessary to inhibit aggregation. Papaverine exerted 5 times higher inhibitory effects on aggregation and PDE activity as compared to trapidil. Infusion of trapidil to rabbits caused aggregation inhibition in vivo. Papaverine at equimolar doses was more effective than trapidil. At therapeutic doses trapidil is unlikely to produce adequate plasma levels for inhibition of platelet aggregation.
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PMID:[Effect of trapidil and papaverine on thrombocyte aggregation and phosphodiesterase activity]. 302 60

Among all the purified components from A. acutus venom, including ADPase, 5'-nucleotidase, phospholipase A2 and fibrinogenases, only the venom ADPase (50-100 micrograms/ml) shows marked inhibitory action on ADP (10 microM)-, collagen (10 micrograms/ml)- and sodium arachidonate (100 microM)-induced platelet aggregations of rabbit platelet-rich plasma. The venom 5'-nucleotidase (100 micrograms/ml) inhibited ADP-induced platelet aggregation by 31 +/- 4% (n = 4, P less than 0.05). Fibrinogenolytic enzymes (fractions I and IX, 100 micrograms/ml) did not significantly inhibit platelet aggregation induced by ADP (10 microM), collagen (10 micrograms/ml) or sodium arachidonate (100 microM). However, when the fibrinogenase (fraction IX, 100 micrograms/ml) was preincubated with platelet-rich plasma for 30 min it inhibited collagen (20 micrograms/ml)- and ADP (10 microM)-induced platelet aggregations by 34 +/- 9% (n = 4, P less than 0.05) and 35 +/- 6% (n = 4, P less than 0.05), respectively. The phospholipase A2 (100 micrograms/ml) did not affect platelet aggregation. The venom ADPase is a single chain polypeptide with a molecular weight of 94,000. The specific ADPase activity is estimated to be 4.3 mu moles Pi/min/mg of protein. It also possesses phosphodiesterase and weak 5'-nucleotidase activities.
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PMID:Platelet aggregation inhibitors from Agkistrodon acutus snake venom. 303 52


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