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)

Casein-elicited rat peritoneal polymorphonuclear leukocytes (PMNL) and rabbit platelets were prelabelled with [1-14C]arachidonic acid, and the effect of timegadine, a new anti-inflammatory agent, on the release and metabolism of arachidonic acid induced by A23187 (PMNL) and thrombin (platelets) was studied and compared with the effect of other compounds reported to affect these enzymatic mechanisms. Timegadine inhibited arachidonic acid release from both cells (IC50 = 2.7 X 10(-5) M), the lipoxygenase activity in PMNL (IC50 = 4.1 X 10(-5) M) and the cyclooxygenase activity in platelets (IC50 = 3.1 X 10(-8) M). By these mechanisms, PMNL leukotriene B4 formation was inhibited by 50% at 2.0 X 10(-5) M, platelet thromboxane B2 at 3.2 X 10(-8) M, and platelet 12-HETE at 4.9 X 10(-5) M. These effects might add to the understanding of the anti-inflammatory properties of timegadine.
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PMID:Multiple effects of a new anti-inflammatory agent, timegadine, on arachidonic acid release and metabolism in neutrophils and platelets. 629 40

Thrombin, the central regulatory enzyme in coagulation, when incubated in nanomolar concentrations with murine neuroblastoma cells produced a rapid and marked increase in tritiated guanosine 3',5'-monophosphate (cyclic GMP) formation that was blocked by hirudin and competitively antagonized by dansylarginine N-(3-ethyl-1,5-pentanediyl)amide. Diisopropylphosphofluoridate-inactivated thrombin as well as the serine protease trypsin were markedly less potent and less effective than alpha-thrombin in producing this effect. Thrombin-stimulated cyclic GMP formation was inhibited by mepacrine and nordihydroguaiaretic acid but unaffected by indomethacin, suggesting that lipoxygenase metabolites of arachidonic acid are involved in the response. These results suggest that a thrombin-like protease in the brain may be involved with the function of neurons or that thrombin interactions with nerve cells, such as those following cerebral hemorrhage or other trauma of the central nervous system, may be important in the subsequent neuropathology.
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PMID:Thrombin stimulation of guanosine 3',5'-monophosphate formation in murine neuroblastoma cells (clone N1E-115). 630 70

The endothelial cells can enzymatically activate (e.g. angiotensin II) or destroy (e.g. bradykinin, norepinephrine, 5-hydroxytryptamine) vasoactive substances present in the blood (fig. 1). They also generate prostacyclin, which in several vascular areas has potent vasodilator properties (fig. 1). In addition, endothelial cells play an obligatory role in the relaxation induced by acetylcholine in isolated arteries (fig. 2). This is also the case for the inhibitory effect of adenosine triphosphate (fig. 3), arachidonic acid, bradykinin, histamine and thrombin. The inhibitory responses generated by the endothelial cells are not all mediated by identical cellular events. Thus, the endothelium-mediated relaxations induced by arachidonic acid are due mainly to the production of prostacyclin, while those induced by acetylcholine, bradykinin and histamine involve a product of lipoxygenase; the mechanism underlying endothelium-mediated responses to adenosine triphosphate and thrombin are unknown (fig. 4). In isolated veins contracted with norepinephrine, thrombin and arachidonic acid cause increases in tension which are abolished by endothelium removal. In several arteries and veins, the absence of endothelium prevents or reduces the occurrence of further contractions caused by anoxia. Thus, the cells of the intima recognize the presence of certain substances in the blood and in turn generate signals which alter the contractile behavior of the smooth muscle cells of the media.
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PMID:[Role of the endothelium in the function of vascular fibers]. 636

The present study was designed to determine whether interference with the metabolism of arachidonic acid or the entry of extracellular calcium affects the responses of the canine saphenous vein to acetylcholine, potassium or norepinephrine. Rings of canine saphenous vein, with or without endothelium, were suspended in organ chambers filled with physiological salt solution and set at their optimal length for isometric tension recording. Removal of the endothelium, confirmed by the absence of the characteristic relaxation induced by thrombin in intact rings, did not affect concentration-response curves to acetylcholine or norepinephrine. The cyclooxygenase inhibitor, indomethacin, augmented the response to acetylcholine. This effect was comparable in rings with and without endothelium and in rings pretreated with phentolamine. Indomethacin did not alter the response to norepinephrine but augmented that to potassium. Similar results were obtained with the cyclooxygenase inhibitors, acetylsalicylic acid and meclofenamate. The antioxidant and lipoxygenase inhibitor nordihydroguaiaretic acid and the cyclooxygenase/lipoxygenase inhibitor phenidone blocked the ability of indomethacin to augment acetylcholine- and potassium-induced contractions. Arachidonic acid-induced contractions were not blocked by indomethacin but were inhibited by nordihydroguaiaretic acid, phenidone and the calcium entry blockers diltiazem and nimodipine. Diltiazem and nimodipine inhibited responses to potassium and acetylcholine without affecting those to norepinephrine. The augmentation by indomethacin of potassium- and acetylcholine-evoked contractions was inhibited by diltiazem and nimodipine. In rings of femoral artery denuded of endothelium, indomethacin had no effect on the responses to acetylcholine, norepinephrine or potassium. These results suggest that, in the canine saphenous vein but not in the femoral artery, activation of the lipoxygenase pathway for the metabolism of arachidonic acid augments preferentially contractions which depend upon the entry of extracellular calcium.
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PMID:Effects of inhibitors of arachidonic acid metabolism and calcium entry on responses to acetylcholine, potassium and norepinephrine in the isolated canine saphenous vein. 640 42

5,8,11-Eicosatrienoic acid (20:3 omega 9), a fatty acid increased in the platelet phospholipids of man and animals fed saturated fats, was either added to human platelets simultaneously with the aggregating agents, or incorporated into the platelet phospholipids by preincubation. 20:3 omega 9 markedly increased the response of platelets to all aggregating agents tested when added simultaneously with the agent, but solely to thrombin and ionophore, after incorporation into the platelet phospholipids. The potentiating effects of 20:3 omega 9 on thrombin aggregation do not appear to be related to prostaglandin formation, but rather to the production of a monohydroxy derivative through the lipoxygenase pathway.
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PMID:Potentiating effect of 5,8,11-eicosatrienoic acid on human platelet aggregation. 640 33

Mouse platelets were aggregated by arachidonate, thrombin, collagen and ADP. In general they were, like rat platelets, more aggregative in heparinized PRP than in citrated (3.8%) PRP. Mouse platelets underwent the release reaction when aggregated by arachidonate, collagen and thrombin, but not when stimulated by ADP. The aggregation of the platelets to arachidonate was inhibited by cyclooxygenase inhibitors and by prostacyclin. Studies with tritiated arachidonate showed that mouse platelets possess the lipoxygenase and cyclooxygenase pathways found in other mammalian platelets and produce thromboxane and 12-HETE. The mouse provides a convenient model for the study of many conditions known to affect platelet aggregation. The similarity of mouse platelets to the platelets of other mammals together with the ability to study large numbers of animals at low cost, should encourage further use of mouse platelets.
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PMID:Some properties of mouse platelets. 641 87

We examined the roles of the cyclooxygenase and lipoxygenase pathways in the alterations in lung fluid and protein exchange after pulmonary microembolism. Infusion of alpha-thrombin (T) (55 +/- 13 U/kg) immediately increased mean pulmonary arterial pressure (Ppa) and mean pulmonary vascular resistance (PVR), but both Ppa and PVR waned with time after T. Cyclooxygenase inhibition with either indomethacin or ketoprofen produced sustained increases in Ppa and PVR. The initial increases in Ppa in the cyclooxygenase-inhibited groups (CI) were matched to the control group by administering greater amounts of T. In the control group, T rapidly increased pulmonary lymph flow (Qlym) by two- to threefold, and this was associated with a steady increase in lymph-to-plasma protein concentration ratio (L/P). In contrast, in cyclooxygenase-inhibited (CI) groups, Qlym increased gradually to greater levels than in the control group, and L/P did not change. The effect on lung vascular permeability was determined by inflating a left atrial balloon catheter to raise pulmonary capillary pressure (Pc). An increase in Pc after T in the control group further increased Qlym and did not change L/P, whereas the increase in Pc after T in CI groups further increased Qlym and decreased L/P, indicating that cyclooxygenase inhibition prevented the increase in permeability. We determined whether lipoxygenase activation contributed to the increase in Qlym in CI groups by examining the effects of BW755C, an inhibitor of both cyclooxygenase and lipoxygenase pathways. BW755C resulted in the same increase in Qlym after T as in the control group, but the increase in Qlym was associated with a decrease in L/P. Therefore, inhibition of both pathways prevented the permeability increase and the greater increase in Qlym. The results indicate that cyclooxygenase and lipoxygenase pathways contribute to the increases in pulmonary transvascular fluid and protein fluxes after thrombin.
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PMID:Effects of cyclooxygenase and lipoxygenase inhibition on lung fluid balance after thrombin. 641 64

We studied the effect of the methanol extract of garlic bulbs (EOG) and of three pure components isolated from it (F1, F2, F3), on human platelet aggregation induced by ADP, epinephrine, collagen, thrombin, arachidonate, PAF, and the ionophore A-23187. Incubation of PRP with EOG, either in methanol or in homologous PPP, inhibits platelet aggregation induced by all of the above mentioned agonists. F1, F2, and F3 also inhibit platelet aggregation, however, F3 was about four times more potent. Addition of EOG or F3 to platelets that have already been irreversibly aggregated by 10 microM ADP, induces rapid deaggregation. Inhibition of aggregation was still present after three hours. The inhibitory effect persisted even after the treated platelets were Gel-Filtered (GFP) or separated from plasma through a metrizamide gradient and resuspended in new homologous PPP. Thrombin-induced release of ATP from GFP was inhibited by 75-80% after EOG or F3 treatment. Incorporation of [3-H]-arachidonate by intact platelets was decreased by 50-60% in treated platelets. However, platelets incubated with the inhibitors after incorporation of radiolabeled arachidonate, although did not aggregate, produced, after thrombin activation similar amounts of radiolabeled TXB2 and lipoxygenase products as the controls. Electron microscopy of inhibited platelets, in the presence of thrombin, showed no degranulation but an increase of spherical forms. Our results suggest that the effects described might be mediate by a perturbation of the physicochemical properties of the plasma membrane rather than by affecting arachidonate or calcium metabolism in the cells. Chemical structures of F1, F2 and F3 have been provisionally assigned: F1 is diallytrisulfide, F2 is 2-vinyl-1,3-dithiene, and F3 is most probably allyl 1,5-hexadienyltrisulfide.
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PMID:Effects of garlic extract and of three pure components isolated from it on human platelet aggregation, arachidonate metabolism, release reaction and platelet ultrastructure. 641 74

The significant numbers of platelet contaminants bound to the surface of freshly isolated human monocytes can be removed during incubations in fresh human serum. We used cells purified by these means to examine the cyclooxygenase and lipoxygenase metabolites of arachidonic acid synthesized in response to various stimuli. Thromboxane is the single major product synthesized by human monocytes in response to inflammatory particles (opsonized zymosan or immunoglobulin G complex-coated beads). The molar amounts produced were equivalent to those by platelets stimulated with thrombin. In contrast, exposure to calcium ionophore A23187 led to greatly enhanced lipoxygenase metabolite synthesis. Under these conditions, levels of leukotriene B4 (30 to 70 pmol/10(6) cells) and leukotriene C4 (up to 20 pmol/10(6) cells) production were five- to tenfold higher than those observed with particulate stimuli. The circulating human monocyte is a source of a variety of vasoactive mediators derived from arachidonic acid.
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PMID:The cyclooxygenase and lipoxygenase activities of platelet-depleted human monocytes. 643 75

It has been reported that the addition of nonaggregating concentrations of collagen, epinephrine, thrombin or arachidonic acid to platelets potentiate their responses to subsequent subthreshold concentrations of aggregating agents. We have previously reported that low concentrations of methylmercury will potentiate human platelet ATP secretion and that this effect is blocked by aspirin. Using rat platelets we have examined the effect of low concentrations of methylmercury on the metabolism of arachidonic acid. Low concentrations of methylmercury (20-100 microM) inhibit washed platelet lipoxygenase activity. In experiments using platelet rich plasma a higher concentration of methylmercury was required to produce a comparable inhibition of arachidonic acid metabolism. At these concentrations no inhibition of platelet thromboxane synthetase was seen. These findings suggest that methylmercury potentiates platelet aggregation and secretion by reducing the inhibitory effect of 12 HPETE on thromboxane biosynthesis.
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PMID:The effect of methylmercuric chloride on arachidonic acid metabolism by platelet lipoxygenase. 643 30


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