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)

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

This study examined the platelet-aggregating and procoagulant activities of two hematogenously disseminating tumors, a mouse lymphoblastic leukemia (L5178Y) and a mouse renal adenocarcinoma (RAG). Tumor-induced human platelet aggregation was inhibited by addition of the following agents to platelet-rich plasma (PRP): a calcium channel blocker (verapamil), a chelator of divalent cations (EDTA), stimulators of adenylate cyclase (2-fluoroadenosine and forskolin), and inhibitors of cAMP phosphodiesterase (oxagrelate and papaverine). The platelet-aggregating activities of both cell lines were completely blocked by treatment of the cells with heat, sonication, phospholipase A2, and Triton X-100. These data suggest that L5178Y and RAG cell-induced human platelet aggregation are dependent on a heat-labile phospholipid component of the tumor cell membrane. L5178Y cells had greater platelet-aggregating activity in human plasma than in rat or mouse plasma, whereas RAG cells had greater procoagulant activity in rat or mouse plasma than in human plasma. The procoagulant activity of RAG cells in rat and mouse plasma was demonstrated by three lines of evidence: RAG cells induced heparinized PRP to clot; the thrombin inhibitor DAPA lengthened of the clotting time and the lag time before aggregation; and RAG cells shortened of the recalcification time of the plasma. The above data indicate that RAG cell-induced murine platelet aggregation and coagulation is dependent on thrombin generation.
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PMID:Murine tumor-induced platelet aggregation and coagulation: mechanisms, inhibitors, and species differences. 359 Jan 14

The enzyme contents of four venom samples of Calloselasma rhodostoma were analyzed. The venoms contained phosphodiesterase, alkaline phosphomonoesterase, 5'-nucleotidase, protease, phospholipase A, L-amino acid oxidase, hyaluronidase, arginine ester hydrolase, arginine amidase, fibrinogenase and coagulant enzyme activities. There is significant variation in the contents of coagulant enzyme, arginine ester hydrolase, hyaluronidase, protease, phosphodiesterase, alkaline phosphomonoesterase and L-amino acid oxidase. DEAE-Sephacel ion exchange chromatography of the venom resolved it into eight major protein fractions. The eight fractions were heterogeneous and exhibited more than one type of enzymatic activity. The 5'-nucleotidase, alkaline phosphomonoesterase, protease, coagulant enzyme, arginine ester hydrolase, arginine amidase and fibrinogenase exist in multiple forms.
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PMID:Enzymatic activities of Calloselasma rhodostoma (Malayan pit viper) venom. 375 Mar 51

The present data disagree with earlier suggestions that thrombin's effect on platelets is to cause a decrease in intracellular cyclic 3',5'-adenosine monophosphate. Washed human platelets or platelet-rich plasma were incubated at 37 degrees C with human thrombin. After centrifugation, the supernates were assayed for nucleotides and calcium released. The platelet pellets, and in some experiments the supernates as well, were assayed by radioimmunoassay for intracellular cyclic AMP. In the washed platelet system, increasing doses of thrombin to 0.5 U/cc induced increasing release of nucleotides and calcium. This was accompanied by an average twofold increase in intracellular cyclic AMP levels. Prostaglandin E(1), which inhibited 30-50% of release, induced a four- to fivefold increase in cyclic AMP levels that was additive to the cyclic AMP-stimulatory effect of thrombin. Theophylline, which inhibited only 20-40% of nucleotide release, was synergistic with thrombin in the intracellular accumulation of cyclic AMP. The time-course of cyclic AMP accumulation in response to thrombin was slower than thrombin-induced nucleotide release. Similar findings were made in the platelet-rich plasma system where thrombin stimulation of nucleotide release also resulted in a marked accumulation of intracellular cyclic AMP. Thrombin did not appear to stimulate the release of intracellular cyclic AMP. The mechanism underlying these observations was not apparent. The thrombin had no measurable inhibitory effect on platelet phosphodiesterase activity in either intact washed cells or the platelet homogenate supernates. Furthermore, thrombin inhibited, rather than stimulated, platelet adenyl cyclase activity in both intact washed cells and washed platelet particulate fractions. Of note, however, was the finding that thrombin did not completely inhibit the adenyl cyclase activity of prostaglandin-stimulated cells. Further work is needed to clarify the significance of this observation.Nonetheless, the accumulation of intracellular cyclic AMP in response to thrombin observed in the present study suggests that the antagonistic actions of various agents on the platelet release reaction, thought to underlie platelet function, may depend upon a mechanism more intricate than a straightforward mediation through directly opposite effects on platelet cyclic AMP.
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PMID:Thrombin-induced increase in intracellular cyclic 3',5'-adenosine monophosphate in human platelets. 434 94

Evidence which bears on the hypothesis that agents that increase platelet cyclic adenosine 3',5' monophosphate (cAMP) tend to inhibit platelet aggregation, whereas agents whose action is to induce or augment platelet aggregation are associated with a decrease in platelet content of this cyclic nucleotide is reviewed. Using radiolabeled cAMP in incubation with various agents, it was found that caffeine, colagen, thrombin, prostaglandins E1 and E2, and phosphodiesterase inhibitors are all agents that increase platelet cAMP and inhibit platelet aggregation.
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PMID:Cyclic 3',5'-adenosine monophosphate in human blood platelets. IV. Regulatory role of cyclic amp in platelet function. 434 63

The effects of 9 beta-methyl carbacyclin, a chemically stable analogue of epoprostenol (prostacyclin, PGI2) were studied, in comparison with epoprostenol, both in vitro and in vivo in man. In vitro 9 beta-methyl carbacyclin and epoprostenol inhibited platelet aggregation induced by ADP, collagen, the endoperoxide analogue U46619 and arachidonic acid. The potency of 9 beta-methyl carbacyclin relative to epoprostenol was comparable in ADP and collagen-aggregated platelet rich plasma (PRP), 9 beta-methyl carbacyclin being 0.01 times as active as epoprostenol. The anti-aggregatory potencies of the two compounds were comparable in PRP and whole blood. The phosphodiesterase inhibitor isobutyl methyl xanthine enhanced the anti-aggregatory activity of both compounds in vitro. 9 beta-methyl carbacyclin and epoprostenol elevated platelet cyclic AMP, 9 beta-methyl carbacyclin being 0.04 times as active as epoprostenol. In a placebo controlled trial both drugs produces significant headache and facial flushing when compared with placebo. Nasal stuffiness, abdominal discomfort and nausea were reported on all three treatments. Both drugs caused significant and comparable increase in heart rate and decrease in pre-ejection (PEP) and PEP/left ventricular ejection time (LVET) ratio compared with placebo. Systolic and diastolic blood pressure, LVET and QS2 index were unchanged. Platelet aggregation responses to ADP were significantly inhibited by all three doses of both drugs compared with placebo. Bleeding time was significantly longer during epoprostenol infusion than either placebo or 9 beta-methyl carbacyclin infusion. Neither drug had significant effect, compared with placebo, on kaolin activated clotting time in PPP, PRP or in PRP in the presence of heparin, prothrombin time, partial thromboplastin time, thrombin clotting time, fibrinogen, fibrinogen degradation products or euglobulin clot lysis time. The pharmacodynamic effects and duration of action of 9 beta-methyl carbacyclin and of epoprostenol are similar; 9 beta-methyl carbacyclin is approximately 100 times less potent than epoprostenol in man.
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PMID:A chemically stable analogue, 9 beta-methyl carbacyclin, with similar effects to epoprostenol (prostacyclin, PGI2) in man. 608 4

The effect of prostaglandin E1 (PGE1) and compound BW245C, adenyl-cyclase activators, theophylline, papaverine and dipyridamole, phosphodiesterase (PDE) inhibitors and pyridoxal-5-phosphate (PALP) on inhibition of platelet aggregation (PA) and platelet c-AMP accumulation was determined in human platelet-rich plasma (PRP) and washed platelets. PGE1 at 280 nM and BW245C at 7.7 nM induced a significant PA inhibition in PRP and washed platelets (though less pronounced by PGE1) concomitant to a very large increase (8-13-fold) in platelet c-AMP level both in PRP and washed platelets. At comparable PA inhibition, c-AMP level was not significantly changed by PALP and only moderately (but significantly) increased (2-4.6-fold) by PDE inhibitors. PALP or theophylline potentiated both PGE1-induced platelet c-AMP accumulation and PA inhibition. Yet PALP potentiated theophylline-induced PA inhibition without affecting platelet c-AMP level. Our results indicate that 2 c-AMP pools are presumably present in the platelets, since at comparable c-AMP accumulation PDE inhibitors or BW245C were more effective than PGE1 in PA inhibition in PRP. Moreover, this pattern was more pronounced in washed platelets and was also found in the presence of thrombin and adenosine diphosphate which induced a decrease in platelet c-AMP level. The effect of PALP on PA inhibition is presumably mediated by 2 mechanisms: a) a direct effect on the platelet membrane independent from the c-AMP system. b) In the presence of PGE1 the increment in PA inhibition, is through further indirect activation of the adenyl-cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of adenyl-cyclase activators, phosphodiesterase inhibitors and pyridoxal-5-phosphate on platelet aggregation and adenosine-3'-5'-cyclic monophosphate accumulation. 609 48

Calcium ionophore A23187 (10 microM) as well as thrombin (10 U/ml) stimulated the biosynthesis of prostacyclin in cultured rabbit mesothelial cells; in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine (Mix, 1 mM) the cyclic AMP (cAMP) content was also elevated. Both effects were inhibited by indomethacin (28 microM). Exogenous prostacyclin elicited by itself a clear enhancement of intracellular cAMP. An increased cAMP content was also obtained with isoproterenol (10 microM), whose activity was antagonized by propranolol (10 microM). These two products however, had no effect on the prostacyclin release. In all these experiments, inhibition of phosphodiesterase with Mix, was necessary to obtain detectable cAMP levels. In the presence of Mix, the stimulation of prostacyclin production by A23187 and thrombin was significantly lower as compared to the stimulation in the absence of Mix. Our results suggest that increased prostacyclin biosynthesis results in adenylate cyclase stimulation. This rise in intracellular cAMP in the presence of Mix, is accompanied by a downward regulation of further prostacyclin production.
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PMID:Relationship between prostacyclin biosynthesis and cyclic AMP in cultured rabbit mesothelial cells. 619 Dec 26

Incubation of primary monolayer cultures of human umbilical vein endothelial cells with buffer, thrombin (0.5 unit/ml), ionophore A23187 (10 microM), arachidonic acid (20 microM), prostaglandin H2 (PGH2) (4 microM) resulted in prostacyclin (PGI2) production in nanomolar quantities to the extent of 36 +/- 2, 276 +/- 13, 485 +/- 32, 533 +/- 22, and 532 +/- 22, respectively, as measured by radioimmunoassay of 6-keto-PGF alpha. Preincubation of the endothelium with 1 mM 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate, an antagonist of cytoplasmic Ca2+, or with 4 mM 1-methyl-3-isobutylxanthine (MIX), an inhibitor of cyclic nucleotide phosphodiesterase activity, blocked PGI2 release induced by thrombin or A23187, decreased arachidonic acid-induced release by approximately 50%, but had no effect on PGH2-induced release. Radioimmunoassay of cAMP in the endothelium showed that the basal level (1.85 +/- 0.14 pmol of cAMP per 4.5 x 10(5) cells) was increased by an average of 3.9-fold with 4 mM MIX. PGI2 (0.4 microM) had no significant effect on cAMP levels in the absence of MIX, but caused a 2-fold increase with 4 mM MIX. The findings suggest that: (i) the stimulation of PGI2 biosynthesis is mediated by Ca2+, (ii) increased cAMP inhibits PGI2 production, and (iii) cAMP phosphodiesterase activity modulates PGI2-induced increases in the intracellular concentration of cAMP.
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PMID:Role of Ca2+ and cyclic AMP in the regulation of the production of prostacyclin by the vascular endothelium. 628 72


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