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)

G-proteins are transducing proteins that couple a large number of membrane-bound receptors to a variety of intracellular effector systems. Pertussis toxin ADP-ribosylates certain G-proteins causing inhibition of their function. In porcine coronary arteries, pertussis toxin inhibited the endothelium-dependent relaxations evoked by alpha-2-adrenergic or serotonergic receptor stimulation, and by aggregating platelets or thrombin. Relaxations to nitric oxide and endothelium-dependent relaxations to bradykinin, adenosine diphosphate or A23187 were unaffected by the toxin. Therefore, certain endothelium-dependent relaxations are mediated by activation of a pertussis toxin-sensitive G-protein in the endothelial cells, most likely Gi-protein. In porcine coronary arteries with regenerated endothelium (following in vivo denudation), the endothelium-dependent relaxations caused by the pertussis toxin-sensitive stimuli were reduced and were not further affected by pertussis toxin. Relaxations to the other stimuli were not altered by the regeneration process and were still not affected by the toxin. In regenerating endothelial cells there may be a selective impairment of the G-protein-dependent mechanism for releasing EDRF, which may predispose the blood vessel to vasospasm or the initiation of vascular disease.
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PMID:G-proteins and endothelial responses. 212 22

The activation of endothelial cells by endothelium-dependent vasodilators has been investigated using bioassay, patch clamp and 45Ca flux methods. Cultured pulmonary artery endothelial cells have been demonstrated to release EDRF in response to thrombin, bradykinin, ATP and the calcium ionophore A23187. The resting membrane potential of the endothelial cells was -56 mV and the cells were depolarized by increasing extracellular K+ or by the addition of (0.1-1.0 mM)Ba2+ to the bathing solution. The electrophysiological properties of the cultured endothelial cells suggest that the membrane potential is maintained by an inward rectifying K+ channel with a mean single channel conductance of 35.6 pS. The absence of a depolarization-activated inward current and the reduction of 45Ca influx with high K+ solution suggests that there are no functional voltage-dependent calcium or sodium channels. Thrombin and bradykinin were shown to evoke not only an inward current (carried by Na+ and Ca2+) but also an increase in 45Ca influx suggesting that the increase in intracellular calcium necessary for EDRF release is mediated by an opening of a receptor operated channel. High doses of thrombin and bradykinin induced intracellular calcium release, however, at low doses of thrombin no intracellular calcium release was observed. We propose that the increased cytosolic calcium concentration in endothelial cells induced by endothelium dependent vasodilators is due to the influx of Ca2+ through a receptor operated ion channel and to a lesser degree to intracellular release of calcium from a yet undefined intracellular store.
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PMID:Calcium entry through receptor-operated channels in bovine pulmonary artery endothelial cells. 244 44

Changes in viscous drag acting upon the endothelial lining and a number of circulating agonists (ATP, ADP, serotonin, thrombin) stimulate the release of EDRF from intact endothelial cells. EDRF is probably identical with nitric oxide (NO), the vasoactive compound which is also formed in the metabolism of nitrovasodilators in the vasculature (some of them directly release NO without the essential foregoing bioconversion step). Albuminally released NO stimulates soluble guanylate cyclase (sGC) in the vasculature initiating vasodilation; luminally released NO stimulates, sGC in platelets and increases cyclic GMP inhibiting platelet activation and aggregation. Endothelial impairment brings about loss of dilator and antiaggregant capacity.
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PMID:[Inhibition of thrombocyte aggregation and adhesion by endothelium-derived relaxant factor (EDRF) and their pathophysiologic significance]. 251 72

We studied the effects and the mechanism of action of the cyclic GMP-lowering substance 6-anilino-5,8-quinolinedione (LY 83583) on cyclic GMP-mediated inhibition of platelet function. The activation of washed human platelets by thrombin was counteracted by 8-bromo-cyclic GMP and the direct activators of soluble guanylate cyclase, sodium nitroprusside and endothelium-derived relaxant factor (EDRF = nitric oxide). LY 83583 significantly antagonized the inhibitory effect of sodium nitroprusside and EDRF, but not that of 8-bromo-cyclic GMP, on thrombin-induced aggregation, ATP-release, adhesion to native endothelial cells and increase in concentration of free intracellular calcium ions. In accordance, increases in intracellular cyclic GMP by sodium nitroprusside and EDRF were attenuated by LY 83583. The inhibition of cyclic GMP-mediated effects on platelets by LY 83583 could be related to inhibition of platelet soluble guanylate cyclase, as the activation of the purified enzyme from platelets by sodium nitroprusside was directly inhibited by LY 83583. This effect of LY 83583 was attenuated in the presence of superoxide dismutase. Our findings support the hypothesis that sodium nitroprusside and EDRF inhibit platelet activation by stimulation of soluble guanylate cyclase via nitric oxide. Consequently, inhibition of nitric oxide-induced cyclic GMP formation by LY 83583, which may act by intracellular generation of superoxide anions, facilitates platelet activation.
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PMID:LY 83583 (6-anilino-5,8-quinolinedione) blocks nitrovasodilator-induced cyclic GMP increases and inhibition of platelet activation. 255 29

Elevation in intracellular cyclic GMP levels is the proposed proximal mechanism for the vasodilatory and platelet inhibitory action of nitrovasodilators and of nitric oxide, the putative endothelium-derived relaxing factor. In this study, the stable cyclic GMP analogs, 8-bromo-cGMP and N2, 2'-O-dibutyryl-cGMP were found to inhibit the release of [3H]-arachidonic acid from gamma thrombin-stimulated human platelets in a time- and dose-dependent manner. Inhibition of the formation of arachidonic acid metabolites, 12-HETE and thromboxane B2, paralleled that of arachidonic acid release and was accompanied by a dose-dependent inhibition of platelet aggregation. The formation of phosphatidic acid, a metabolite of phospholipase C, however, was relatively preserved. At a concentration of 8-bromo-cGMP (2 mM) that produced near-total inhibition of arachidonic acid release, phosphatidic acid formation remained at 60% of control levels. Thus, cGMP analogs have a preferential inhibitory effect on the release and subsequent metabolism of arachidonic acid. The phospholipase A2/arachidonic acid pathway appears to be an important target for the physiologic action of cGMP, and EDRF, and for the pharmacologic action of nitrovasodilators.
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PMID:Cyclic GMP analogs inhibit gamma thrombin-induced arachidonic acid release in human platelets. 255 18

Significant advances have been made in our understanding of the role of the vascular endothelium in preventing thrombosis and in decreasing vascular spasm. The endothelium provides a surface receptor, thrombomodulin, that binds thrombin. In this form, thrombin loses its ability to clot fibrinogen or to aggregate platelets, but is able to activate protein C. In its activated state, protein C is able to act as an inhibitor of coagulation by virtue of its proteolytic destruction of Factors Va and VIIIa. Congenital deficiency of protein C is associated with early and recurrent thrombosis. The discovery that the endothelium is responsible for the production of a short-acting inhibitor of smooth-muscle contraction (EDRF) was a remarkable advance. One of the EDRF substances has been demonstrated to be NO, which has inhibitory effects on both smooth muscle and blood platelets. Activity of EDRF appears to be diminished or lost as a consequence of atherosclerosis, and stimuli that cause vasodilation via the EDRF pathway in normal vessels cause vasoconstriction in atherosclerotic arteries. Regression of atherosclerosis in experimental animals appears to be associated with restoration of EDRF activity.
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PMID:The endothelium, platelets, and coronary vasospasm. 264 64

We investigated the hypothesis that thrombin-induced attachment of platelets to endothelial cells is modulated by EDRF. Thrombin significantly increased binding of radiolabelled platelets to cultured endothelium and to an intact pulmonary vasculature under flow conditions. These increases in binding were potentiated with hemoglobin (HB) and inhibited by superoxide dismutase (SOD) in both systems. We suggest that thrombin, in addition to enhancing platelet adhesion, elicits EDRF release from endothelial cells and that EDRF serves an antithrombotic function in the down regulation of platelet adhesion.
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PMID:Thrombin induced platelet adhesion to endothelium is modified by endothelial derived relaxing factor (EDRF). 278 17

It has been demonstrated by other investigators that endothelium-dependent vasodilators are more effective on arterial tissue than on venous tissue. The purpose of this study was to determine if this was due to a difference in the sensitivity of arterial and venous smooth muscle to the endothelial dilator (EDRF) or to a difference in the ability of arterial and venous endothelia to release EDRF. To differentiate between these two possibilities, an in vitro "sandwich" preparation was used in which the mechanical response to endothelium-dependent dilators of a de-endothelialized vessel was determined when "sandwiched" with an endothelialized vessel. Using dog femoral artery and saphenous vein, it was determined that acetylcholine (ACh), the ionophore A23187, and thrombin were endothelium-dependent dilators of the femoral artery, but their dilatory ability was significantly less in the saphenous vein. However, if the de-endothelialized saphenous vein was "sandwiched" with an endothelialized femoral artery, both ACh and A23187 significantly relaxed the vein. No relaxation of the de-endothelialized femoral artery occurred when it was "sandwiched" with an intact saphenous vein. Sodium nitroprusside, thought to act by a mechanism similar to EDRF, relaxed equally the saphenous vein and femoral artery. These observations suggest that the difference in responsiveness between femoral arteries and saphenous veins to endothelium-dependent dilators is due more to differences in the ability of their endothelia to release EDRF than to an inability of their smooth muscle to respond to EDRF.
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PMID:Venous and arterial endothelia: different dilator abilities in dog vessels. 310 60

Endothelial cells can produce at least 3 substances which cause relaxation of vascular smooth muscle: (1) endothelium-derived nitric oxide (NO, which is secreted not only toward the underlying vascular smooth muscle but also into the blood vessel lumen). NO also has a physiological role at the interface between the endothelial cells and the blood content; in particular, NO inhibits the adhesion of platelets and leukocytes to the endothelium. (2) Endothelium-derived hyperpolarizing factor, presumably a labile metabolite of arachidonic acid formed through the P-450 pathway, which appears to act on smooth muscle by being one of the few physiologic openers of the potassium channels. (3) Prostacyclin, which can be considered as an endothelium-derived relaxing substance, given its vasodilator activity and its primarily endothelial origin. One of the main factors modulating the release of these EDRFs is the shear stress of blood on the arterial wall, which explains why flow-induced vasodilation is endothelium-dependent in the intact organism. The peptide bradykinin is a potent stimulus for EDRF release. The normal lifespan of an adult human endothelial cell is some 30 years, after which aging takes its toll and the cells must be replaced. The regenerated cells lose some of their ability to release EDRF, in particular in response to platelet aggregation and thrombin. Finally, in hypertension and atherosclerosis, a decrease in endothelium-dependent relaxation is obvious in response to a variety of stimuli. All converting enzyme inhibitors tested so far share a potentiating effect on endothelium-dependent relaxation to bradykinin, and augmented local production of bradykinin may help to explain the acute vasodilator properties of these compounds.
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PMID:Endothelium-derived relaxing factors and converting enzyme inhibition. 748 85

We previously reported that thrombin produces endothelium-dependent relaxation and endothelium-independent constrictions in canine coronary arteries. To determine whether these opposing vascular effects of thrombin are mediated by the same receptor mechanism, but at different cell types, we investigated the effects of thrombin receptor agonist peptide (TRAP) on isolated canine coronary arteries with and without intact endothelium. In coronary arteries with intact endothelium, addition of 0.01-3.0 microM TRAP, a 14-amino acid residue peptide (SFLLRNPNDKYEPF) homologous to the newly exposed N-terminus after cleavage of the cloned human thrombin receptor, produced rapid, dose-dependent relaxation (Emax = -89.6 +/- 2.3%, n = 26). Threshold concentration was 0.03 microM, and IC50 value was 0.3 microM. Mechanical disruption of the endothelium completely abolished the TRAP-induced relaxation; instead a dose-dependent contraction was observed. Expressed as a percentage of the maximum 70 mM KCl-induced contraction, the maximum contraction observed with 3 microM TRAP was 62.0 +/- 4.1% (n = 32). Pretreatment of endothelium-intact coronary arteries with either 3 microM hemoglobin or 0.25 mM NG-monomethyl-L-arginine (L-NMMA), specific inhibitors of endothelium-derived relaxing factor or nitric oxide (EDRF/NO), also inhibited the relaxation and unmasked the constrictor effect. The pharmacokinetic characteristics of the opposing coronary vascular effects of TRAP are similar to those observed with thrombin, but specific thrombin inhibitors, such as hirudin and D-phenylalanyl-prolyl-L-arginine chloromethyl ketone (PPACK), which inhibit both thrombin relaxant and constrictor effects, had no effect on TRAP-induced responses.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Receptor mechanism of thrombin-induced endothelium-dependent and endothelium-independent coronary vascular effects in dogs. 750 64


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