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)

The effects of S35b (4-methyl-3-phenyl sulfonylfuroxan), a new phenyl sulfonylfuroxan compound, were investigated on human platelets activated by different agonists. Platelet aggregation evoked by arachidonic acid (AA), collagen, ADP and thrombin was inhibited by the drug in a dose-dependent manner. S35b inhibited the AA-induced increase of cytosolic free Ca2+ ([Ca2+]i) and production of malondialdehyde. A primary action of the compound on cyclooxygenase is unlikely since: (1) U-46619 (15s-hydroxy-11,9-[epoxymethano]-prosta-5Z,13E-dienoic acid, a stable epoxymethano analog of prostaglandin H2) could not reverse the inhibitory effect of S35b on AA-induced aggregation and [Ca2+]i increase; (2) U-46619-induced aggregation and [Ca2+]i rise were inhibited by S35b; and (3) at high collagen concentrations platelet aggregation (which is unresponsive to aspirin under such conditions) was blocked by S35b as well. Thus the drug action is likely to be exerted at an early step of the platelet activation pathway. The elevation in the platelet cGMP level evoked by S35b in a time- and concentration-dependent manner can account for the inhibitory effect: increased cGMP levels could interfere, for instance, with G protein-phospholipase C coupling and subsequent phosphoinositide hydrolysis.
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PMID:Characterization of a new compound, S35b, as a guanylate cyclase activator in human platelets. 134 17

Thrombin, a peptide with native protease activity, caused a rapid (less than 1 min) increase in glycogenolysis of about 30%, assessed from rates of production of glucose+lactate+pyruvate, and in oxygen uptake in perfused rat liver. These increases were followed by a rapid return to basal values within 5 min. The effect of thrombin on glycogenolysis was dose-dependent and was maximal at perfusate concentrations around 1 U/ml. Interestingly, the effect of thrombin on glycogenolysis could be elicited only once in any given liver. The activation of glycogenolysis by thrombin was diminished nearly 50% by prior infusion of the protease inhibitor, diisopropyl fluorophosphate (10 microM), and over 90% when thrombin was treated with diisopropyl fluorophosphate prior to infusion. The stimulation of glycogenolysis by thrombin could be detected in isolated hepatocytes or in livers stored for 24 h in cold Euro-Collins solution, a treatment which destroys endothelial cells. Further, thrombin stimulated production of prostaglandin D2 from arachidonic acid in cultured hepatic endothelial but not Kupffer cells. The effect of thrombin on carbohydrate output was also blocked by a phospholipase A2 inhibitor (quinacrine, 50 microM) and by an inhibitor of the cyclooxygenase (indomethacin, 20 microM), suggesting the involvement of cyclooxygenase in the mechanism of action of thrombin. In support of this idea, the transient kinetics of stimulation of glycogenolysis by thrombin and arachidonic acid was nearly identical to release of thromboxane B2 (80-420 pg/ml) and prostaglandin D2 (300-900 pg/ml) from the perfused liver. Further, a second addition of thrombin failed to increase thromboxane and prostaglandin D2 release as well as carbohydrate production, supporting a causal link between these phenomena. Taken together, these data support the hypothesis that thrombin interacts with receptors in the liver, possibly on endothelial cells, leading to activation of phospholipase A2 and subsequent transient production of prostaglandins and thromboxanes. These mediators subsequently interact with receptors on parenchymal cells, leading to a transient stimulation of glycogenolysis.
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PMID:Transient activation of hepatic glycogenolysis by thrombin in perfused rat livers. 139 79

The effect of thrombin on mesangial cell function was investigated. Thrombin caused a dose-dependent increase in [3H] thymidine incorporation (EC50 = 0.36 +/- 0.09 U/ml), intracellular calcium [(Ca++)i] mobilization (EC50 = 1.9 +/- 0.5 U/ml) and prostaglandin E2 (PGE2) production (EC50 = 0.25 +/- 0.02 U/ml) in rat glomerular mesangial cells. These effects were blocked by the thrombin inhibitor, hirudin (KB = 10.4 +/- 0.2 nM). The role of (Ca++)i mobilization and arachidonate metabolism in thrombin-stimulated proliferation was tested by the addition of the calcium channel blocker, nifedipine, and the cyclooxygenase inhibitor, indomethacin, to mesangial cell cultures. Indomethacin, at doses that completely inhibited the thrombin-mediated production of PGE2, had no significant effect on proliferation. The Ca++ channel blocker, nifedipine, inhibited both PGE2 production and [3H] thymidine incorporation in a dose-dependent fashion, but only at concentrations considered nonspecific. In addition to its effects on PGE2, thymidine incorporation and Ca++ mobilization, thrombin caused mesangial cell contraction as determined by a substrate distortion technique. This effect was not inhibited by indomethacin. These results indicate that thrombin can alter mesangial cell function in vitro.
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PMID:Effect of thrombin on proliferation, contraction and prostaglandin production of rat glomerular mesangial cells in culture. 140 2

Certain bioflavonoids and phenolic compounds have long been known to enhance catecholamine responses, in vivo and in vitro. In the present studies the flavone, baicalein, potentiated nerve-stimulated contractions in vitro in rat tail and femoral artery isometric ring preparations. Inhibition of catecholamine reuptake with cocaine or catecholamine metabolism with tropolone and parglyine (monoamine oxidase and catecholamine-O-methyl transferase inhibitors, respectively) did not alter baicalein's ability to potentiate contractile responses to nerve stimulation. Baicalein (10(-5) M), the prototype flavone, also increased sensitivity to exogenous norepinephrine, serotonin, arginine vasopressin and to the noncatecholamine alpha-1 and alpha-2 adrenergic agonists, cirazoline and tramazoline. Structure-function studies indicated that flavone potentiation required three contiguous A or B ring hydroxylations. Several nonflavone phenol derivatives with three contiguous hydroxyls also potentiated nerve stimulation responses. As baicalein is a potent lipoxygenase inhibitor, comparisons were made between potentiating ability and lipoxygenase inhibitory activity in a series of flavonoids. There was no direct correlation between inhibition of 12-hydroxy-5,8,10,14-eicosatetraenoic acid levels in thrombin stimulated human platelets and potentiation of contractile responses in the femoral artery. Additionally, the specific substrate analog lipoxygenase inhibitor, 5,8,11-eicosatriynoic acid, and the cyclooxygenase inhibitor, ibuprofen, were nonpotentiating. Ibuprofen pretreatment did not alter the potentiating action of baicalein. It is concluded that flavonoids with three contiguous hydroxyls on either the A or B ring increase in vitro vascular responsiveness via a post-synaptic process, independent of cyclooxygenase, lipoxygenase, monoamine oxidase or catecholamine-O-methyl transferase activity.
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PMID:Flavonoid potentiation of contractile responses in rat blood vessels. 140 5

A dose-dependent effect of magnesium on the inhibition of platelet aggregation and release of ATP from dense granules was observed in human platelets (in whole blood, platelet-rich plasma, or washed platelets) against various aggregation agents (ADP, U46619, collagen, or thrombin). The synthesis and release of the proaggregatory cyclooxygenase (CO) and lipoxygenase (LO) products, thromboxane A2 (TXA2) and 12-hydroxyeicosatetraenoic acid (12-HETE), respectively, in platelets were also inhibited by Mg in a dose-dependent manner (IC50 4 to 6 mmol/L). These Mg-mediated activities were further enhanced when platelets were preincubated with insulin (100 microU/mL). The effect of extracellular Mg on the change of intracellular calcium concentration ([Ca2+]i) was assessed using Fura-2/AM loaded cells in the presence or absence of extracellular Ca. Thrombin-stimulated influx of Ca ions decreased from 194 +/- 30 nmol/L to 156 +/- 21 nmol/L in the presence of 5 mmol/L Mg and to 111 +/- 16 nmol/L in 10 mmol/L Mg. However, the intracellular Ca release (as determined in the presence of 5 mmol/L EGTA) was not affected by Mg. The intracellular Ca-dependent protein kinase C and myosin light chain kinase activities on the phosphorylation of endogenous p47 and p20 proteins studied after 2 min of thrombin addition decreased only 10 to 25% in the presence of 5 to 10 mmol/L Mg. Similar results were obtained when EGTA was added prior to the initiation of protein phosphorylation. We conclude that Mg can dose dependently inhibit a wide variety of agonists on platelet aggregation. Furthermore, insulin can potentiate the inhibitory effects of Mg on platelet activation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of extracellular magnesium on platelet activation and intracellular calcium mobilization. 141 32

In the present study performed on rats, we investigated the influence of an in vivo acute iron load on several platelet parameters and their modification after vitamin E supplementation. Iron load was achieved by injecting iron dextran corresponding to 0.1 mg Fe3+ per kg in the gluteus muscles. Control rats were injected with an equal amount of a dextran solution. Analyses were performed 18 h after injection. By comparison with controls, in iron-injected animals, we found significant increases of: (1) serum total iron (by 110%); (2) aggregation of isolated platelets induced by low concentration of thrombin and ADP (by 350% and 120%, respectively); (3) thrombin-induced endogenous serotonin secretion (by 94%). We also studied the mobilization of radiolabeled arachidonate preincorporated into platelet phospholipids. The results indicated that the thrombin-stimulated release of arachidonate and formation of cyclooxygenase and lipoxygenase products (particularly thromboxane B2), were significantly increased. We also found in plasma an increase (by 67%) of malondialdehyde (MDA) as well as a decrease of vitamin E (by 60%). When vitamin E was injected the day before iron injection, platelet hyperactivity and thromboxane biosynthesis were reduced as well as the plasma MDA concentration. Consequently, given the key role of calcium flux in the activation processes in platelets, we also investigated the thrombin-induced Ca2+ uptake by means of radiocalcium. We found that in platelets from iron-treated rats the Ca2+ uptake amounted to 3670 +/- 201 pmol/10(9) platelets (plt) and was significantly different from controls (1680 +/- 192 pmol/10(9) plt, P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of vitamin E on acute iron load-potentiated aggregation, secretion, calcium uptake and thromboxane biosynthesis in rat platelets. 146 49

As a source of several vasoactive factors, the endothelium takes part in the regulation of vascular tone. The most important endothelium-derived vasoactive substances are nitric oxide, prostacyclin, endothelin-1 and contracting factors requiring the activity of cyclooxygenase. The endothelium is an obvious target organ of cardiovascular risk factors. Accordingly, functional alterations do occur with aging, hypertension and hypercholesterolaemia. All three conditions are associated with a decreased basal and simulated release of endothelium-derived nitric oxide. On the other hand, the release of endothelin-1 appears to increase with age, while the sensitivity to the peptide markedly decreases under the same conditions. In the spontaneously hypertensive rat, acetylcholine and stretch evoke the release of a cyclooxygenase-dependent endothelium-derived contracting factor, most likely prostaglandin H2. The circulating levels of endothelin-1 on the other hand are not increased in experimental and human hypertension. In the porcine coronary circulation, oxidized low-density lipoproteins selectively reduced endothelium-dependent relaxations to aggregating platelets, serotonin and thrombin which are mediated by nitric oxide. The alterations of endothelial function occurring with aging, hypertension and hypercholesterolaemia may have important clinical implications for the pathogenesis of cardiovascular disease.
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PMID:Age, hypertension and hypercholesterolaemia alter endothelium-dependent vascular regulation. 150 46

The in vitro effects of three oral hypoglycaemic agents, gliclazide (1-(4-methylbenzensulfonyl)-3-[3-azabicylo(3,3,0)octyl]urea) , glibenclamide (1-[4-[2-(chloro-2-methoxybenzamide)-ethyl]-phenyl- sulfonyl]-3-cyclohexyl-urea) and glimepiride (1-[4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-carboxamide)- ethyl]-phenylsulphonyl]3-(4-methylcyclohexyl)-urea), on functions of human platelets were evaluated. None of these agents up to a concentration of 40 microM inhibited platelet aggregation induced by thrombin. Glibenclamide and glimepiride in the range of 20-40 microM suppressed Ca2+ release from internal Ca2+ stores induced by thrombin. Gliclazide showed no effect on arachidonic acid metabolism of human platelets. Glimepiride selectively inhibited the cyclooxygenase pathway, while the activities of 12-lipoxygenase and phospholipase A2 were unaffected. Glibenclamide inhibited both the cyclooxygenase and 12-lipoxygenase pathways. It also attenuated arachidonic acid release from phospholipase A2. Oral hypoglycaemic agents with inhibitory effects on arachidonic acid metabolism may prove useful for the treatment of diabetic patients with enhanced platelet functions.
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PMID:Effects of oral hypoglycaemic agents on platelet functions. 151 Jul 15

The effect of STA2, thrombin and NaF on PI metabolism and Ca mobilization was investigated in patients with three kinds of platelet dysfunction, one each with platelet cyclo-oxygenase deficiency (A), defective aggregation to A23187 (B) and defective aggregation to STA2 (C). These responses were normal in patient (A), suggesting cyclooxygenase activity did not affect PI metabolism and Ca mobilization. PI metabolism was also normal in (B), although Ca mobilization in response to A23187 was delayed and that in response to thrombin was defective in the presence of extracellular Ca2+. This suggests that the patient's platelets have a defective IP3-induced Ca mobilization pathway. STA2 selectively failed to induce IP3 formation and Ca mobilization in (C), although 3H-labelled thromboxane ligand (3H-U46619) bound to the patient's platelets normally. It was suggested that the patient's platelets have a defect in postreceptor signal transduction, especially thromboxane receptor-mediated PLC activation pathway.
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PMID:[PI metabolism and Ca mobilization in patients with platelet dysfunction]. 153 86

E5510 is an antiplatelet agent, recently synthesized in Japan. It inhibited human platelet aggregation ex-vivo induced by collagen, arachidonic acid, ADP, PAF, epinephrine and thrombin. In addition, it inhibited platelet adhesion and release reaction. In animal models of thrombosis, oral administration of a low dose of E5510 inhibited thrombus formation. Studies on its mode of action suggest that E5510 blocks multiple pathways of platelet activation: inhibition of arachidonic acid release, cyclooxygenase and PDE. Using healthy volunteers, inhibition of platelet aggregation was demonstrated with 1 hour after a single dose of E5510 and continued for more than 8 hours. No inhibition was observed 24 hours after administration. E5510 is currently under clinical evaluations in patients with various thrombotic diseases. This paper also describes the results of its clinical trials regarding the efficacy and safety using the patients with essential thrombocythemia.
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PMID:[Pharmacological aspects of a novel antiplatelet drug, E5510]. 161 92


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