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

Blood of 16 patients with essential thrombocythemia (ET), 9 patients with reactive thrombocytosis (RT) and 13 healthy persons was used for platelet aggregation studies. When the aggregation was induced with adenosine diphosphate (0.01 microM), collagen (0.1 micrograms/ml) or platelet activating factor (PAF 0.5 microM) the plasma of the patients with ET showed significantly decreased aggregation (35%-44% of the value for the control groups). Independent of inhibitors of platelet aggregation, thrombin (0.05 U/ml) caused similar aggregation in healthy controls and patients with ET; patients with RT showed an increase aggregation. Adrenalin-induced aggregation discriminated best between patients with ET and controls. Adrenalin in concentrations ranging from 0.01 micrograms/ml to 100 micrograms/ml caused comparable dose-related amounts of aggregation in healthy controls and patients with RT. Over the whole concentration range, patients with ET showed significantly decreased aggregation (28%-34% of the value for the control groups). This difference proved to be independent of the influence of inhibitors of platelet aggregation. Though concentrations of alpha1-acid glycoprotein never reached inhibitory levels in the plasma of patients with ET (n = 12) they were significantly higher compared with those in normal plasma (n = 12). Fibrinogen concentrations in plasma of ET-patients (n = 12) were in the normal range. Cellular adenosine 3'-5'-cyclic monophosphate concentrations in ET (n = 10) are comparable with normal values (n = 5). The significance of the results for diagnosis and better pathophysiological understanding of ET is discussed.
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PMID:[Thrombocyte function in essential thrombocythemia and reactive thrombocytosis]. 283 4

We have studied synergism between adrenaline (epinephrine) and low concentrations of thrombin in gel-filtered human platelets prelabelled with [32P]Pi. Suspensions of platelets, which did not contain added fibrinogen, were incubated at 37 degrees C to measure changes in the levels of 32P-labelled phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol 4-phosphate (PIP) and phosphatidate (PA), aggregation and dense-granule secretion after stimulation. Adrenaline alone (3.5-4.0 microM) did not cause a change in any parameter (phosphoinositide metabolism, aggregation and dense-granule secretion), but markedly enhanced the thrombin-induced responses over a narrow range of thrombin concentrations (0.03-0.08 units/ml). The thrombin-induced hydrolysis of inositol phospholipids by phospholipase C, which was measured as the formation of [32P]PA, was potentiated by adrenaline, as was the increase in the levels of [32P]PIP2 and [32P]PIP. The presence of adrenaline caused a shift to the left for the thrombin-induced changes in the phosphoinositide metabolism, without affecting the maximal levels of 32P-labelled compounds obtained. A similar shift by adrenaline in the dose-response relationship was previously demonstrated for thrombin-induced aggregation and dense-granule secretion. Also, the narrow range of concentrations of thrombin over which adrenaline potentiates thrombin-induced platelet responses is the same for changes in phosphoinositide metabolism and physiological responses (aggregation and dense-granule secretion). Our observations clearly indicate that adrenaline directly or indirectly influences thrombin-induced changes in phosphoinositide metabolism.
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PMID:Synergism between thrombin and adrenaline (epinephrine) in human platelets. Marked potentiation of inositol phospholipid metabolism. 284 24

The aim of this study was to elucidate the role of platelet aggregation as a risk factor for ischemic heart disease (IHD) and the relationship between fatty acids and platelet function. Platelet aggregation upon adenosine diphosphate (ADP), adrenaline and thrombin were measured in middle aged men in east and west, two regions of Finland with a nearly twofold difference in IHD mortality. Platelet aggregation results were correlated with the fatty acid compositions of plasma lipid fractions, adipose tissue triglycerides and platelet phospholipids. There was no significant east-west difference in platelet reactivity to ADP, adrenaline and thrombin. ADP-induced platelet aggregation showed significant negative correlations with all the platelet C20-C22 n-3 polyunsaturated fatty acids (PUFA), but significant positive correlations with the percentage of 18:2n-6 in adipose tissue and plasma cholesterol esters (CE) and triglycerides (TG). Adrenaline-induced aggregation correlated negatively with the percentage of 20:5n-3 in plasma CE and TG, and positively with the total percentage of saturated fatty acids in platelets. Aggregation upon thrombin had a negative correlation with the 20:3n-6/20: 4n-6 ratio in plasma CE and a positive correlation with 18:2n-6 in adipose tissue. The percentages of the major PUFA in platelets correlated significantly with the same fatty acids in plasma CE and phospholipids PL. Platelet 20: 5n-3 had a highly significant negative correlation with the percentage of 18: 2n-6 in plasma and adipose tissue lipids. Platelet 20: 4n-6 was unrelated to its precursors in plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Dietary fats and platelet function among Finnish men. 292 2

Intact human platelets were stimulated with alpha or gamma thrombin in the presence and absence of epinephrine and the ability of these agonists to stimulate aggregation, arachidonic acid release and protein phosphorylation was measured. Epinephrine alone had no effect on any of these events. Both alpha and gamma thrombin induced platelet aggregation which was potentiated in each case by epinephrine. Similarly, both thrombin species were able to induce the phosphorylation of platelet 20 KDa and 47KDa proteins. The gamma thrombin-induced phosphorylation was slightly enhanced by epinephrine. In contrast, only alpha thrombin was capable of inducing significant arachidonic acid release and the small release induced by gamma thrombin was reduced by epinephrine. These results show that the agonist-induced phosphorylation of the 47KDa protein by protein kinase C does not impart the ability to activate phospholipase A2 in human platelets, and questions the suggestion that the 47KDa protein is lipocortin.
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PMID:Phosphorylation of the 47 KDa protein in gamma-thrombin-stimulated human platelets does not activate phospholipase A2: evidence against lipocortin. 294 6

Stimulation of washed rat platelets with thrombin resulted in an increased turnover of phosphoinositides. Adrenaline and isoproterenol both inhibited thrombin-induced phosphatidic acid formation in a dose-dependent manner. Inhibitory responses of both compounds were blocked by a beta-adrenoceptor antagonist. However, isoproterenol was a more potent inhibitor than adrenaline. Addition of a selective alpha2-adrenoceptor antagonist potentiated the inhibitory effect of adrenaline up to the level observed with isoproterenol. Prestimulation of beta-adrenoceptors with isoproterenol, followed by addition of adrenaline (or noradrenaline) markedly diminished the inhibitory effect induced by the full beta-adrenoceptor agonist. Our results indicate that, in rat platelets, catecholamines are able to counteract, via alpha2-receptors, the beta-adrenoceptor-mediated inhibition of thrombin-induced phosphatidic acid formation. This suggests that catecholamines, by controlling cAMP level, may modulate phospholipase C activity and thereby platelet reactivity.
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PMID:Influence of adrenoceptors on thrombin-induced phosphoinositide metabolism in rat platelets. 300 Mar 62

Epinephrine at concentrations varying between 3.3 and 12.5 nM had no effect on blood platelets when added alone, but augmented the in vitro platelet response to collagen and thrombin. Both aggregation and secretion responses were enhanced. Norepinephrine produced similar effects but was 50-60% less active than epinephrine. The minimum concentration of epinephrine or norepinephrine to achieve potentiation of platelet responses was even lower in the presence of 5-hydroxy- tryptamine. In contrast to the effects observed with higher concentrations of catecholamines, the synergistic interaction of these low concentrations of catecholamines with other agonists was not transient. The augmented response to catecholamines was mediated by platelet alpha 2-adrenoceptors. The response was inhibited by aspirin indicating that metabolism of arachidonic acid contributes to the synergy between low concentrations of catecholamines and other agonists. These studies show that the levels of the hormones epinephrine and norepinephrine obtained in circulating blood in humans, can be sufficient to enhance platelet responses. The action of catecholamines on platelets may be important in hemostasis and could provide an explanation for the association between certain risk factors and cardiovascular disease.
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PMID:Effect on human platelets of catecholamines at levels achieved in the circulation. 300 19

Adrenaline (1 to 10 microM) can induce the aggregation of human platelets suspended in citrated plasma but does not induce the aggregation of washed human platelets at doses as high as 1 mM, although these platelets respond normally to ADP, PAF-acether, collagen, arachidonic acid, thrombin, the endoperoxide analog U-46619 and the Ca2+ ionophore A23187. Adrenaline (0.5 microM) potentiates the aggregation and secretion induced by all the previous agonists in citrated platelet-rich plasma (cPRP) or in washed platelets. The activation by adrenaline of human platelets is mediated by alpha 2-adrenergic receptors, as demonstrated by inhibition with a series of adrenergic antagonists. The alpha-adrenergic antagonist nicergoline inhibits the activation of human platelets by adrenaline in the following situations: nicergoline inhibits the aggregation and secretion caused by adrenaline in cPRP (IC50 0.22 microM and 0.28 microM respectively); nicergoline inhibits the aggregation and secretion induced by the combination of adrenaline and each aggregating agent listed above in cPRP (IC50 ranging from 0.1 to 2.5 microM) or in washed platelets (IC50 ranging from 0.1 to 0.8 microM); nicergoline inhibits the binding of 3H-yohimbine to washed human platelets (IC50 0.26 microM); the intravenous administration of nicergoline (0.5 mg/kg per day) to patients inhibits significantly the ex vivo response of their platelets to adrenaline in cPRP. High concentrations of nicergoline also inhibit the aggregation and secretion induced by the aggregating agents listed above in cPRP (IC50 range 108 to 670 microM) and in washed platelets (IC50 range 27 to 140 microM) and the adhesion of platelets to collagen-coated surfaces. This latter effect is not mediated through blockade of alpha-adrenoceptors. A possible role of adrenaline in platelet activation in vivo could justify the use of nicergoline (Sermion), an alpha-adrenergic antagonist in combination therapy to prevent arterial thrombosis.
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PMID:Potentiation by adrenaline of human platelet activation and the inhibition by the alpha-adrenergic antagonist nicergoline of platelet adhesion, secretion and aggregation. 302 Sep 42

Epinephrine (E), isoproterenol (I), and dopamine (D) were compared with norepinephrine (N) for production of microthrombi during thrombin-induced disseminated intravascular coagulation (DIC) in rabbits. Only catecholamines acting on alpha-adrenoreceptors produced glomerular capillary thrombosis (GCT) typical of the generalized Shwartzman reaction (GSR). Epinephrine produced GCT three times (P less than 0.05) less severe than that produced by N, but beta-blockade with propranolol (P) rendered E equal to N in potency. I and D reduced fibrinogen consumption produced by thrombin. I (0.5-0.66 microgram/kg/min), as opposed to D, prevented the GSR produced by endotoxin in the pregnant rat and the cortisone-sensitized rabbit, and P increased the severity of the GSR in the pregnant rat. Alpha-adrenergic blockade with dibenzyline prevented the GSR produced by endotoxin in rats, whether pregnant, diabetic, or having a unilateral ureteral occlusion, and the classic reaction in rabbits, but not that produced in renal-hypertensive rats. Simultaneous alpha + beta stimulations by E triggered coronary and hepatic microthrombi, which were prevented by P. It is concluded that beta-adrenergic stimulation, as opposed to D-adrenergic stimulation, counterbalances alpha-adrenergic effects occurring in endotoxemia, which are required for production of the GSR in most models. These studies stress the risks and benefits of beta-blockade and provide additional evidence for the role of vasoactive agents and microcirculatory changes on selection of target organs for production of microthrombi during DIC.
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PMID:Vasoactive agents and production of thrombosis during intravascular coagulation. 3. Comparative effects of catecholamines. 303 Jan 18

The effects of low concentrations of epinephrine on the aggregation of macaque and human platelets by arachidonic acid (AA), collagen, and thrombin were studied. When epinephrine (0.05 to 1 microM) was added to macaque or human citrated or macaque heparinized platelets, either before or after the addition of near-threshold concentrations of AA, significant increases in aggregability were always seen. Epinephrine alone did not aggregate macaque platelets from citrated blood. When near-threshold concentrations of collagen or thrombin were present in the medium, low concentrations of epinephrine (0.05 to 0.50 microM) potentiated the aggregation of macaque and human citrated platelets and macaque heparinized platelets. The P values for the addition of epinephrine were less than 0.01 in all series. The ability of low epinephrine concentrations to potentiate aggregation of macaque platelets by other agonists is of particular significance because in humans the most important effect of epinephrine on platelets in vivo is probably the potentiation, by low concentrations, of aggregation induced by other aggregatory agents normally present in the blood in low concentrations.
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PMID:Potentiation with epinephrine of macaque platelet aggregation by other agonists: implications for studies on human atherosclerosis. 308 25

Epinephrine can in certain in vitro conditions induce the aggregation of human platelets and could play an important role in vivo in the appearance of thrombotic disorders when catecholamine levels are increased. This study examines some functional and biochemical responses to epinephrine. Epinephrine induces the aggregation and serotonin secretion of human platelets in citrated plasma. This is not due to a direct effect of citrate itself, such as the lowering of plasma free Ca2+ but more likely to the generation of traces of thrombin during blood collection, as suggested by abrogation of these platelet responses when hirudin was added before citrate. When washed human platelets suspended in Tyrode buffer containing 2 mM Ca2+, 0.35% albumin and apyrase, and 0.1-100 microM epinephrine were used, no shape change, aggregation, or secretion of serotonin was observed, nor was the platelet ultrastructure modified. Epinephrine does not modify platelet membrane fluidity, as studied with the lipophilic fluorescent probe trimethylammonium-diphenylhexatriene. It has no direct effect on fibrinogen binding to intact platelets, intracellular Ca2+ levels measured by quin2, or protein phosphorylation. Epinephrine potentiates the action of all types of aggregating agents on aggregation, secretion, intracellular Ca2+ levels, membrane fluidity, fibrinogen binding, or protein phosphorylation. These effects are mediated by alpha 2-adrenergic agonists and inhibited by alpha 2-adrenergic antagonists. This study shows that epinephrine alone does not induce modifications of morphology, metabolism, or function of intact and functional washed human platelets and that it cannot be considered per se as an aggregating agent. However, epinephrine interacts with alpha 2-adrenergic receptors on human platelets and potentiates biochemical and aggregatory responses induced by other platelet agonists.
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PMID:Epinephrine potentiates human platelet activation but is not an aggregating agent. 320 91


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