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)

Anagrelide (BL-4162A, 6,7-dichloro-1,5-dihydroimidazo[2, 1-6] quinazolin-2[3H]one monohydrochloride hydrate) is a potent and broad spectrum inhibitor of platelet aggregation. Prior studies showed that anagrelide inhibited platelet cyclic AMP (cAMP) phosphodiesterase activity but did not appreciably elevate platelet cAMP levels. We examined the effects of anagrelide on washed human platelets and found that anagrelide caused significant elevation of cAMP levels. Anagrelide treatment also resulted in activation of the platelet cAMP-dependent protein kinase at anagrelide concentrations of 0.1 to 1 microgram/ml, which inhibited platelet aggregation but caused only small increases in platelet cAMP content. When whole platelets were incubated with radiolabeled phosphate, anagrelide increased phosphorylation of platelet proteins with relative molecular weights of 22, 26, 50 and 80 kilodaltons. The pattern of protein phosphorylation stimulated by anagrelide treatment was similar to that observed when the platelets were treated with forskolin. Anagrelide also inhibited the rise in intracellular Ca++ caused by thrombin, as measured using Fura-2-loaded platelets. The inhibition of increased intracellular Ca++ resulted from block of thrombin-induced mobilization of intracellular Ca++, as well as prevention of Ca++ influx through the plasma membrane. Anagrelide itself had no influence on inositol 1,4,5-trisphosphate-induced Caz5++ release from isolated platelet membrane vesicles. These studies suggest that anagrelide inhibits platelet phosphodiesterase activity in intact platelets resulting in an elevation in cAMP levels sufficient to activate the cAMP-dependent protein kinase and inhibit agonist-activated Ca++ fluxes.
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PMID:Effects of anagrelide on platelet cAMP levels, cAMP-dependent protein kinase and thrombin-induced Ca++ fluxes. 282 59

Pentoxifylline has been claimed to work a beneficial effect in arterial insufficiency by improving erythrocyte deformability and thus improving blood flow. A number of observations, including the drug concentrations required to work the red cell effect, suggested that this was not likely to be a complete explanation. We therefore examined the effect of pentoxifylline on several granulocyte and platelet functions. Pentoxifylline inhibited platelet aggregation in response to 4 mumol/L adenosine diphosphate; although statistically significant inhibition was seen at 1 mumol/L pentoxifylline, over 200 mumol/L was required for 50% inhibition. The adherence of unstimulated platelets to cultured endothelial cells was not strongly inhibited by pentoxifylline; however, the additional increment in adherence seen in the presence of thrombin was strongly inhibited (50% attenuative dose [AD50] = 18 mumol/L). Granulocyte aggregation in response to C5a was modestly inhibited (AD30 approximately equal to 8 mumol/L; AD50 greater than 1 mmol/L), and the adherence of unstimulated polymorphonuclear neutrophils (PMNs) to endothelium was uninhibited. The C5a-mediated augmentation of PMN adherence to endothelium was mildly inhibited (AD50 = 240 mumol/L). Inhibition of PMN chemotaxis to N-Formyl-methionyl-leucyl-phenylalanine (FMLP) or C5a (AD50 = 12 mumol/L) and inhibition of superoxide production in response to FMLP-cytochalasin B (AD50 = 24 mumol/L) were seen at more clinically credible concentrations. Perhaps most important, pentoxifylline blocked the ability of platelet activation factor to prime neutrophils for enhanced response to subsequent stimuli (AD50 approximately equal to 8 mumol/L; AD60 = 10 mumol/L when production was the indicator system); in vivo, this could broaden the drug's effect to include functions that it does not inhibit potently in a primary fashion. Although pentoxifylline is known to be a phosphodiesterase inhibitor, and we found it to elevate intracellular cyclic adenosine monophosphate in stimulated PMNs, we found it to be only marginally more potent than theophylline in this regard; therefore, the failure of theophylline to inhibit PMN priming suggests that this enzyme inhibition is not a complete explanation of the pharmacologic action of pentoxifylline. We suggest that the effects of pentoxifylline on platelet and granulocyte function are likely to contribute to the drug's clinical efficacy.
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PMID:Pentoxifylline inhibits granulocyte and platelet function, including granulocyte priming by platelet activating factor. 284 Apr 77

Gel-filtered human platelets that had been pre-labelled with [32P]Pi were stimulated with thrombin, ionomycin or the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA). The effect of the hexacationic aminoglycoside antibiotic, neomycin, on platelet physiological responses, such as aggregation and secretion, as well as changes in phosphoinositide metabolism was studied. Neomycin strongly inhibited thrombin-induced aggregation and secretion whereas the antibiotic had no effect on ionomycin- or TPA-induced platelet functions. The thrombin-induced enhancement of inositol phospholipid metabolism was strongly inhibited by the presence of neomycin whereas the TPA- or ionomycin-induced increase in inositol [32P]polyphospholipids remained unaffected. The inhibitory effect of some other aminoglycoside antibiotics was compared to that of neomycin and the data demonstrate that the inhibition of platelet secretion and phosphatidic acid production was dependent on the cationic charge of the antibiotic. It is suggested that neomycin inhibits signal transduction in platelets at a level prior to the inositol-phospholipid-specific phosphodiesterase.
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PMID:Neomycin inhibits platelet functions and inositol phospholipid metabolism upon stimulation with thrombin, but not with ionomycin or 12-O-tetradecanoyl-phorbol 13-acetate. 284 97

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

Continuous intravenous infusion of prostacyclin (prostaglandin I2, PGI2) in rabbits induced refractoriness to PGI2-induced inhibition of platelet function. Although inhibited during earlier stages, platelet response to adenosine diphosphate and thrombin became normal within 24 hours of PGI2 infusion. Cross-mixing experiments with platelets and plasma from infused and control animals suggested that the altered response to PGI2 was caused by a defect intrinsic in the platelets. PGI2-stimulated cyclic adenosine monophosphate (cAMP) production was reduced in platelets from infused rabbits as compared with those from controls. Platelets refractory to PGI2 were refractory to PGE1 and PGD2, as well. Because PGE1 but not PGD2 shares the same platelet receptor as PGI2, the phenomenon could not be ascribed to receptor-specific downregulation, which was also shown by refractoriness of platelets from infused rabbits to the nonprostanoid inhibitor of platelet function adenosine. Either increased concentrations of ineffective inhibitors or their combination with phosphodiesterase inhibitors overcame refractoriness of resistant platelets, which also responded to inhibition by dibutyryl cAMP, indicating residual activity of adenylate cyclase. That at least the catalytic subunit of the enzyme was still working in refractory platelets was shown by inhibition of aggregation induced by forskolin, a non-receptor-mediated activator of adenylate cyclase. Impairment of the adenylate cyclase regulatory subunit, possibly accompanied by multireceptor downregulation, may explain the paradoxical refractoriness of platelets to prolonged infusion of PGI2. Such an effect may limit the benefit of PGI2 in treatment of thromboembolic disease.
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PMID:Refractoriness of platelets to prostaglandins after infusion in rabbits. 299 53

R 59 022 (6-[2-[4-[(4-fluorophenyl) phenylmethylene)-1-piperidinyl]ethyl]-7-methyl-5H-thiazolo[3,2-alpha] pyrimidin-5-one) was found to inhibit diacylglycerol kinase in human red blood cell membranes at concentrations where polyphosphoinositide phosphodiesterase, phosphatidylinositol kinase, and phosphatidylinositol 4-phosphate kinase activity remained unaffected. The concentration needed for half-maximal inhibition (IC50) was 2.8 +/- 1.5 X 10(-6) M for the kinase acting on endogenous diacylglycerol and 3.3 +/- 0.4 X 10(-6) M when 1-oleoyl-2-acetylglycerol (OAG) was added exogenously as substrate. In intact platelets, R 59 022 inhibits the phosphorylation of OAG to 1-oleoyl-2-acetylglyceryl-3-phosphoric acid (OAPA) (IC50: 3.8 +/- 1.2 X 10(-6) M); concomitantly the stimulation of protein kinase C activity by OAG was amplified. When in platelets inositol lipid turnover is accelerated by thrombin, further addition of R 59 022 results in a marked elevation of diacylglycerol levels, a decreased formation of phosphatidic acid and an increased protein kinase C activity as compared with the controls. It is concluded that in studies on the signal-transducing system coupled to inositol lipid metabolism R 59 022 might occupy a role comparable to cyclic AMP phosphodiesterase inhibitors, since it potentiates the effect of the putative second messenger diacylglycerol by preventing its rapid metabolism.
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PMID:R 59 022, a diacylglycerol kinase inhibitor. Its effect on diacylglycerol and thrombin-induced C kinase activation in the intact platelet. 299 35

Thrombin inhibits adenylate cyclase and stimulates GTP hydrolysis by high-affinity GTPase(s) in membranes of human platelets at almost identical concentrations. Both of these thrombin actions are similar to those observed with agonist-activated alpha 2-adrenoceptors coupling to the inhibitory guanine nucleotide-binding protein N1. However, stimulation of GTP hydrolysis caused by adrenaline (alpha 2-adrenoceptor agonist) and by thrombin at maximally effective concentrations was partially additive, whereas with regard to adenylate cyclase inhibition no additive response was observed. Furthermore, treatment of platelet membranes with pertussis toxin, which inactivates Ni and largely abolishes thrombin- and adrenaline-induced adenylate cyclase inhibition and adrenaline-induced GTPase stimulation, decreased the thrombin-induced stimulation of GTP hydrolysis by only about 30%. Additionally, the thiol reagent N-ethylmalemide (NEM) at rather low concentrations abolished thrombin- and adrenaline-induced stimulation of GTP hydrolysis was decreased by only 30-40% by treatment of platelet membranes with even high concentrations of NEM. Treatment with cholera toxin, which inhibits GTPase activity of the Ns (stimulatory guanine nucleotide-binding) protein, has no effect on thrombin-stimulated GTP hydrolysis. The data suggest that thrombin interaction with its receptor sites in platelet membranes leads to stimulation of two GTP-hydrolysing enzymes. One of these enzymes is apparently Ni and is also activated by agonist-activated alpha 2-adrenoceptors and is inactivated by pertussis toxin and NEM treatment. The other GTP-hydrolysing enzyme activated by thrombin may represent a guanine nucleotide-binding protein apparently involved in the coupling of thrombin receptors to the phosphoinositide phosphodiesterase.
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PMID:Evidence for two GTPases activated by thrombin in membranes of human platelets. 302 30

Two different methods were used to study directly alpha-thrombin modulation of polyphosphoinositide breakdown in membranes prepared from Chinese hamster lung (CHL) fibroblasts. In the first one we labelled the lipid pool by incubating the intact cells with myo-[3H]inositol prior to membrane isolation; in the other we used exogenous [3H]PIP2 with phosphatidylethanolamine (1:10) added as liposomes to freshly isolated membranes. A Ca2+-dependent PIP2 and PIP phospholipase C activity was characterized by measuring the rate of formation of inositol tris- and bisphosphate. Basal phospholipase C activity was stimulated up to 3-fold by GTP or GTP-gamma-S. Of the two mitogens, alpha-thrombin and EGF, known to stimulate DNA synthesis in Chinese hamster fibroblasts, only alpha-thrombin is a potent activator of PIP2 breakdown in intact cells. Consistent with this observation, alpha-thrombin but not EGF potentiated GTP-gamma-S-dependent phospholipase C activity in membrane preparations. These results strongly support the hypothesis that a GTP-binding protein couples alpha-thrombin receptor to PIP2 hydrolysis. Because both methods used to assay phospholipase C gave identical results, we conclude that the coupling is at the level of PIP2-phosphodiesterase activity.
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PMID:Evidence for a GTP-binding protein coupling thrombin receptor to PIP2-phospholipase C in membranes of hamster fibroblasts. 302 38

Despite their physicochemical and mechanistic differences platelet activating factor (or acetylglycerylether phosphorylcholine; AGEPC) and thrombin, both platelet stimulatory agents, induce phosphoinositide turnover in platelets. We therefore investigated the stimulation of the phosphoinositide phosphodiesterase by these agents and questioned whether they evoked hydrolysis of the same or different pools of phosphoinositides. [3H]Inositol-labelled rabbit platelets were challenged with thrombin and/or AGEPC under a variety of protocols, and the phospholipase C mediated production of radioactive inositol monophosphate (IP); inositol bisphosphate (IP2) and inositol trisphosphate (IP3) was used as the parameter. AGEPC (1 X 10(-9) M) caused a transient maximum (5 to 6-fold) increase in [3H]IP3 at 5 s followed by a decrease. Thrombin (2 U/ml) elicited an increase in [3H]IP3 at a much slower rate than AGEPC; 2 fold at 5 s, 5 fold at 30 s and a maximum 6 to 8-fold at 2-5 min. Compared to AGEPC, thrombin stimulated generation of [3H]IP2 and [3H]IP were severalfold higher. When thrombin and AGEPC were added together to platelets there was no evidence for an additive increase in inositol polyphosphate levels except at earlier time points where increases were submaximal. When AGEPC was added at various time intervals after thrombin pretreatment, no additional increases in [3H]IP3 were observed over that maximally seen with thrombin or AGEPC alone. In another set of experiments, submaximal increases (about 1/4 and 1/2 of maximum) in [3H]IP3 were achieved by using selected concentrations of thrombin (0.1 U and 0.3 U, respectively) and then AGEPC (1 X 10(-9) M) was added for 5 s. Once again the increase in [3H]IP3 was close to the maximal level seen with thrombin or AGEPC individually. It is concluded that thrombin and AGEPC differentially activated phosphoinositide phosphodiesterase (phospholipase C) in rabbit platelets and that the stimulation of the phospholipase C by these two stimuli causes IP3 production via hydrolysis of a common pool of phosphatidylinositol 4,5-bisphosphate.
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PMID:Activation of phospholipase C in platelets by platelet activating factor and thrombin causes hydrolysis of a common pool of phosphatidylinositol 4,5-bisphosphate. 303 49

This study was designed to determine the in vivo effects of a phosphodiesterase inhibitor (HL 725) in combination with a thromboxane synthase inhibitor (CGS 13080) or prostacyclin (PGI2) as inhibitors of thrombin-induced changes in platelet function and prevention of sudden death. In anesthetized rabbits, the i.v. administration of thrombin reduced the circulating number of platelets from 256,000 +/- 32,000/microliter to 8 +/- 2% of the initial value, and produced a right ventricular thrombus of 285 +/- 52 mg. All animals died within 5 min. PGI2 (0.3 microgram/kg/min) or HL 725 (2 micrograms/kg/min) did not prevent the thrombin-induced fall in the number of circulating platelets, the formation of a right ventricular thrombus or death. Administration of 2 mg/kg of CGS 13080 reduced significantly the mass of the right ventricular thrombus, but did not prevent completely the reduction in the circulating platelet count or death. After the administration of the combination of CGS 13080 with HL 725, the thrombocytopenia was transient, the right ventricular thrombus was reduced (P less than .05), and survival increased to 75% (P less than .05). The combination of PGI2 with HL 725 was similar in benefit to the combination of CGS 13080 and HL 725. Survival for the group of the combination of CGS 13080 with 725 was significantly greater than survival in the CGS 13080 or HL 725 groups, indicating a synergistic effect for the combination. The decrease in blood pressure response to HL 725 was greater with PGI2, but not with CGS 13080.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of the effects of a thromboxane synthase inhibitor or prostacyclin in combination with a phosphodiesterase inhibitor for prevention of experimental thrombosis and sudden death in rabbits. 329 21


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