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

---

Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adverse effects of protamine sulfate, used to neutralize the anticoagulant action of heparin, include systemic hypotension, pulmonary artery hypertension, thrombocytopenia and leukopenia. For further evaluation of protamine's mechanism of action, a three-part investigation was performed. In part I platelet-rich plasma (PRP) was prepared from canine blood samples (n = 6) taken before and 2 minutes after injection of protamine. In part II human PRP (n = 5) was preincubated with protamine or distilled water. Adenosine diphosphate-induced aggregation of protamine-treated platelets was unchanged, but thrombin-induced aggregation was inhibited in both canine and human preparations (p less than 0.05). In part III thrombocytopenia was produced in splenectomized dogs (n = 5), using microporous filters, to 4.5-8.4% of the initial platelet count. Protamine reversal of the heparinization caused hypotension (maximally -29 mmHg 90 s after protamine), but not pulmonary arterial hypertension. Leukopenia developed before additional thrombocytopenia appeared. Protamine-platelet interaction inhibits thrombin-induced platelet aggregation. Platelets may play an important role in the pulmonary pressure rise during protamine reversal, but do not mediate the systemic hypotension.
...
PMID:The effect of protamine sulfate on platelet function. 338 50

Experiments were designed to study endothelium-dependent relaxations in human renal arteries (N = 13) and peripheral arteries (N = 8) suspended in organ chambers for isometric tension recording. In contracted arterial rings, acetylcholine caused endothelium-dependent relaxations that were not inhibited by indomethacin in either artery but were significantly augmented in the renal artery. Adenosine diphosphate and thrombin caused endothelium-dependent relaxations in renal but not in peripheral arteries. This finding suggests a heterogeneity of endothelium-dependent relaxations in human arteries and indicates that the relaxations are mediated by the release of an endothelium-derived relaxing factor (or factors) rather than the release of prostacyclin.
...
PMID:Endothelium-dependent relaxations in human arteries. 347 72

1. Adenosine diphosphate (ADP) and adrenaline caused the aggregation of human platelets suspended in plasma containing citrate anticoagulant and stirred at 37 degrees C. The aggregation occurred in two phases and the second phase was associated with the appearance in the plasma of up to 30% of the ATP and 55% of the ADP present in the platelets. The concentration of ADP appearing in the plasma was up to 7 times the concentration added.2. Radioactivity was released by ADP and by adrenaline from platelets labelled with radioactive 5-hydroxytryptamine; this release was closely correlated with the second phase of aggregation and with the release of nucleotides.3. Acid phosphatase, beta-glucuronidase and adenylate kinase were released to a small extent during second phase aggregation by ADP or adrenaline; thrombin and collagen particles caused significantly greater release of beta-glucuronidase than of either acid phosphatase or of adenylate kinase.4. Morphological changes indicating degranulation of the platelets were observed during the second phase of aggregation produced by adrenaline and by ADP.5. The second phase of aggregation, degranulation of platelets, and the release of nucleotides, of labelled 5-hydroxytryptamine and of enzymes, were all inhibited by concentrations of amitriptyline which did not inhibit aggregation.
...
PMID:The release of nucleotides, 5-hydroxytryptamine and enzymes from human blood platelets during aggregation. 564 42

Palmitaldehyde acetal phosphatidic acid ( PGAP ) caused dose-dependent aggregation of human platelets resuspended in modified Tyrode medium, with a threshold concentration of 0.5-1 microM and an EC50 of 4 microM. Concentrations of PGAP which elicited biphasic irreversible aggregation concomitantly induced formation of 1.02 +/- 0.029 nmol (mean +/- s.e. mean) of malondialdehyde (MDA) per 10(9) platelets and caused release of 58 +/- 2.8% of platelet [14C]-5-hydroxytryptamine ([14C]-5-HT) from prelabelled platelets; no MDA formation or [14C]-5-HT release occurred at lower doses of PGAP which elicited only monophasic reversible aggregation. Adenosine 5'-pyrophosphate (ADP)-induced platelet activation resulted in formation of 0.344 +/- 0.004 nmol of MDA per 10(9) platelets in association with irreversible aggregation and 49.1 +/- 1% release of [14C]-5-HT. Mepacrine, a phospholipase A2 inhibitor, at 2.5 microM reduced PGAP -induced MDA formation and [14C]-5-HT release by the resuspended platelets without affecting irreversible aggregation; higher concentrations of mepacrine abolished all three responses. Chlorpromazine, a calmodulin antagonist, similarly inhibited PGAP -induced MDA formation and irreversible aggregation, and at 100 microM abolished monophasic aggregation. The cyclo-oxygenase inhibitor indomethacin caused a concentration-dependent reduction of PGAP -induced MDA formation by resuspended human platelets without significantly inhibiting [14C]-5-HT release or irreversible aggregation; concentrations (greater than or equal to 1.75 microM) which inhibited MDA formation by more than 94% abolished [14C]-5-HT release, and converted second phase irreversible aggregation to an extensive reversible response. 2-Methylthioadenosine 5'-phosphate (2 methylthio-AMP), an ADP antagonist, inhibited PGAP -induced MDA formation, [14C]-5-HT release and second phase aggregation in the human platelet suspensions in a parallel, concentration-dependent manner; at 9.4 microM 2-methylthio-AMP, both MDA formation and [14C]-5-HT release were abolished and monophasic, reversible aggregation remained. Albumin was required for aggregation of washed human platelets to PGAP . Irreversible PGAP -induced aggregation of washed [14C]-arachidonate-labelled platelets was accompanied by a low net loss of 14C from platelet phospholipids, an equivalent increase in 14C in free fatty acids, and the appearance of 14C in thromboxane (Tx)B2; mepacrine reduced the loss in 14C from phospholipids and inhibited aggregation and formation of [14C]-TxA2. Thrombin-induced aggregation was accompanied by substantial loss of 14C from phospholipids and equivalent gains of 14C in free fatty acids and TxB2; mepacrine pretreatment caused partial inhibition of thrombin-induced aggregation, halved the net 14C loss from phospholipids, but had little effect on the appearance of 14C in TxB2. 6 It is concluded that in human platelets PGAP-induced dense granule release and irreversible aggregation are dependent on the liberation of arachidonate and its metabolism via prostaglandin endoperoxides to thromboxane, that PGAP and thrombin elicit mobilization of arachidonate from different pools of membrane phospholipids, and that the mechanism of PGAP-activation of human platelets differs from those of thrombin- and ADP-activation.
...
PMID:Arachidonate metabolism, 5-hydroxytryptamine release and aggregation in human platelets activated by palmitaldehyde acetal phosphatidic acid. 642

1 5'-N-ethylcarboxamidoadenosine (NECA) is an adenosine analogue which is 22,900 times more potent than adenosine as a vasodilator. Adenosine and some of its analogues are also inhibitors of human platelet aggregation. NECA was tested for its effects on human platelets. 2 NECA (1 microM) inhibited human platelet aggregation induced by adenosine 5'-diphosphate (ADP), adrenaline, 5-hydroxytryptamine (5-HT) and thrombin more powerfully than adenosine. NECA was 5 to 10 times more potent than adenosine at inhibiting ADP- and adrenaline-induced aggregation. 3 NECA, like adenosine, caused dose-dependent increases in levels of platelet adenosine 3',5'-cyclic monophosphate (cyclic AMP), which were competitively inhibited by theophylline, an adenosine antagonist. 4 These effects of NECA, like those of adenosine, were completely stereospecific as the L-enantiomer of NECA was inactive. 5 NECA did not interfere with the inhibition by ADP of prostaglandin E1 (PGE1)-stimulated adenylate cyclase. 6 NECA is the most potent analogue of adenosine tested so far on human platelets, and is the first example of a 5' modification to retain affinity for the platelet adenosine receptor.
...
PMID:5'-N-ethylcarboxamidoadenosine: a potent inhibitor of human platelet aggregation. 726 Apr 85

The effects of adenosine and its analogues on the polymerization of actin in pig platelets and the possible mechanism were investigated. The results show that: Thrombin (0.5 U/ml) and ADP (50 mumol/L) stimulate actin polymerization in pig platelets: Adenosine, 5'-chloro-5'-deoxyadenosine, 2'-deoxyadenosine strongly inhibit thrombin- and/or ADP-induced actin polymerization. Adenosine and 5'-chloro-5'-deoxyadenosine strongly inhibit the phosphorylation of phosphatidylinositol in dose-dependent manner, and adenosine reverses the formation of thrombin-stimulated inositol bisphosphate, which has proved to promote the polymerization of actin in saponin-permeated platelets. These suggest that the inhibition of adenosine and its analogues on phosphatidylinositol turnover might involve in their inhibition on actin polymerization in platelets, and phosphatidylinositol turnover might play an important role in actin polymerization during cell activation.
...
PMID:[Inhibition effects of adenosine and its analogues on actin polymerization in pig platelets and the possible mechanism]. 791 89

Human erythroleukemia (HEL) cells express megakaryocyte/platelet membrane markers and thus have been used as a model for studying platelet membrane receptors and their coupling to cell signaling pathways. Our previous studies, however, indicated that platelets and HEL cells possess different subtypes of adenosine A2 receptors. Furthermore, we now report that, whereas adenosine inhibits intracellular Ca2+ increases in platelets, it potentiates the rise in intracellular Ca2+ produced by thrombin, prostaglandin E1, thapsigargin, and the calcium ionophore A23187 in HEL cells. Stable adenosine analogs potentiated intracellular Ca2+ increases with a rank order of potencies of 5'-N-ethylcarboxamidoadenosine (NECA) > (R)-(-)-N6-(2-phenylisopropyl)adenosine (R-PIA) >> CGS 21680, suggesting that this effect is mediated by A2b receptors. EC50 values for NECA and R-PIA were 0.8 and 42 microM, respectively. NECA (100 microM) potentiated by 2-3-fold the increase in intracellular Ca2+ produced by 0.3 unit/ml thrombin. This effect was mimicked by cholera toxin and was shared by other Gs-coupled receptors, such as those activated by the prostacyclin analog iloprost and prostaglandin E1, indicating the involvement of Gs proteins. Adenosine analogs also increased intracellular cAMP with the same rank order of potencies. The membrane-permeable analog 8-bromo-cAMP, however, had no effect on intracellular Ca2+ levels, indicating that the potentiation of intracellular Ca2+ increases and the activation of adenylate cyclase are parallel but independent events. The increase in intracellular Ca2+ produced by adenosine is due not to an increase in phosphoinositide hydrolysis but, rather, to an increase in calcium influx, and it is lost if cells are studied in the absence of extracellular Ca2+. We conclude, therefore, that adenosine A2b receptors in HEL cells are coupled to Gs proteins and their activation leads to stimulation of adenylate cyclase and, independently, to potentiation of the rise in intracellular Ca2+. We speculate that A2b receptors in HEL cells activate a calcium channel through a cholera toxin-sensitive mechanism that requires an initial increase in intracellular Ca2+.
...
PMID:Positive modulation of intracellular Ca2+ levels by adenosine A2b receptors, prostacyclin, and prostaglandin E1 via a cholera toxin-sensitive mechanism in human erythroleukemia cells. 802 9

Pre-incubation of equine platelets in platelet-rich plasma with adenosine 5'-diphosphate (ADP) induced a reduction in aggregation responsiveness to subsequent additions of ADP. The desensitisation was shown to be homologous since the responsiveness to platelet-activating factor, thrombin, collagen, 5-hydroxytryptamine or ionomycin remained unchanged. Adenosine 5'-(beta-thio)-diphosphate (ADP beta S), a non-hydrolysable analogue of ADP, was shown to act as an agonist inducing aggregation by interaction with the ADP receptor. ADP beta S was then used in the desensitisation studies in which residual ADP was degraded by the addition of apyrase. The desensitisation to ADP beta S fully recovered by one hour after pre-treatment with ADP and was not induced by an extracellular mediator. The mechanism of desensitisation is therefore likely to involve the ADP receptor or proximal intermediates in the signal transduction pathway for ADP.
...
PMID:ADP induces desensitisation of equine platelet aggregation responses: studies using ADP beta S, a stable analogue of ADP. 846 Feb 66

We have previously shown that acutely administered ethanol, resulting in blood alcohol concentrations of 40-90 mM, inhibits experimentally induced arterial thrombosis in rabbits. This inhibition by ethanol in vivo is more pronounced than that observed on stimulated platelets in vitro, when a similar concentration of ethanol is added before an aggregating agent. It may be, then, that ethanol has combined effects in vivo with other inhibitors of platelet function. Adenosine has been found to be an important mediator of some of the in vivo effects of ethanol, and we investigated whether ethanol has combined inhibitory effects with adenosine on thrombin-stimulated platelet responses in vitro. Aggregation and secretion of [14C]serotonin from washed, prelabeled rabbit platelets, pretreated with aspirin, were studied. Maximal aggregation induced by 0.15 units thrombin/ml was slightly inhibited by 87 mM ethanol; secretion of serotonin was reduced from 24% to 12%. However, when thrombin-induced aggregation was significantly reduced by 1 microM adenosine, ethanol, at 44 and 87 mM, further inhibited aggregation. Secretion of [14C]serotonin was reduced to < 3%, with the combination of adenosine and the higher concentration of ethanol. Ethanol did not increase platelet cyclic AMP (cAMP) above basal levels, nor did it affect the increase in cAMP caused by adenosine. The adenosine receptor antagonist, 8-phenyltheophylline, at 1 microM, blocked the inhibitory effects of adenosine on platelet responses and prevented the adenosine-induced increase in cAMP. Unexpectedly, however, 8-phenyltheophylline (1-2 microM) did not completely block the combined inhibitory effects of ethanol and adenosine; this incomplete reversal was not associated with increases in cAMP over basal levels.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Combined inhibitory effects of ethanol and adenosine on the responses of rabbit platelets to thrombin. 856 2

1. The influence of the novel nitric oxide-donor GEA 3175 on thrombin- and ionomycin-stimulated human platelets was investigated. The effect of GEA 3175 was compared with that of adenosine, an activator of platelet adenylyl cyclase. 2. GEA 3175 inhibited thrombin-induced secretion of ATP but did not affect aggregation; similar results were obtained with adenosine. 3. Thrombin-stimulated rises in the cytosolic free Ca2+ concentration, [Ca2+]i, were dose-dependently inhibited by GEA 3175 and adenosine. GEA 3175 and adenosine maximally reduced the initial rise in [Ca2+]i by 41% and 35%, respectively. 4. Simultaneous exposure to GEA 3175 and adenosine nearly abolished both the functional responses (i.e. aggregation and degranulation) and the rises in [Ca2+]i in thrombin-stimulated platelets. 5. Aggregation and increases in [Ca2+]i triggered in platelets by the Ca(2+)-ionophore ionomycin were only marginally affected by a combination of GEA 3175 and adenosine. 6. GEA 3175 potently increased the guanosine 3':5'-cyclic monophosphate (cyclic GMP) content in platelets but did not affect adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels. Adenosine did not increase either the cyclic AMP or the cyclic GMP levels in platelets. However, adenosine and GEA 3175 combined significantly elevated the platelet cyclic AMP content. 7. The results show that simultaneous exposure to GEA 3175 and adenosine promotes potent anti-aggregatory properties in platelets in vitro. The findings suggest that blockage of the cytosolic Ca(2+)-signal, which is probably mediated by an amplified cyclic nucleotide response, is an important event during the synergistic inhibition of thrombin-induced aggregation.
...
PMID:Synergistic inhibition of thrombin-induced platelet aggregation by the novel nitric oxide-donor GEA 3175 and adenosine. 886 53


<< Previous 1 2 3 4 5 Next >>

---