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)

Sensitized rabbit lung fragments release a platelet-activating factor (PAFL) after challenge with specific antigen or monospecific antibody to rabbit IgE. This release requires calcium and is less evident in lungs from rabbits producing IgG as well as IgE antibody. The PAFL released from lung stimulates the secretion of serotonin from washed rabbit platelets. PAFL is distinguishable from ADP or thrombin and has properties similar to PAF derived from basophils (PAFB). It is not, however, identical to PAFB since rabbit platelets specifically desenitized to PAF still respond by releasing serotonin if stimulated with PAFL.
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PMID:IgE-induced release of a platelet-activating factor from rabbit lung. 5 74

We have studied the effects of the antithrombitic agent PCA 4230 on the entry of Mn2+, used here as a Ca2+ surrogate for Ca2+ channels, and on the release of Ca2+ from the intracellular stores in stimulated human platelets loaded with fura-2. PCA 4230 prevented receptor-operated calcium entry activated by thrombin, ADP and collagen with no modification of the Ca2+ release from the intracellular stores. PCA 4230 also inhibited cytochrome P-450-mediated O-dealkylase activity with the same concentration-dependence as the thrombin-induced Mn2+ entry. These results suggest that the inhibitory effects of PCA 4230 on Ca2+ influx may be due to its interaction with cytochrome P-450, which has been proposed recently to be involved in the activation of receptor-operated Ca2+ channels. In addition, PCA 4230 inhibited both PAF-induced Ca2+ entry and Ca2+ release, behaving as a PAF-antagonist. All these effects contribute to explain the antithrombitic action of PCA 4230.
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PMID:Effects of the antithrombitic agent PCA 4230 on agonist-induced Ca2+ entry and Ca2+ release in human platelets. 131 57

The change in intracellular Ca2+ concentration ([Ca2+]i) following platelet stimulation results from mobilization, influx and restoration of Ca2+. To determine whether inositol 1,4,5 trisphosphate (IP3) is involved in Ca2+ influx, the relationship between IP3 formation (IP3) and Ca2+ influx ( delta [Ca2+]i) was investigated in platelets stimulated wtih various agonists (thrombin, ADP, PAF, STA2, etc). The ratio of IP3 to delta [Ca2+]i varied among the agonists, although delta [Ca2+]i was increased, depending on the amount of agonist. Furthermore, in spite of the similar delta [Ca2+]i, IP3 was smaller at 20 degrees C compared with that at 37 degrees C in thrombin-stimulated platelets. These results indicate that Ca2+ influx in platelets might be regulated by receptor-operated Ca2+ channel rather than by an IP3 mediated mechanism. As for Ca2+ restoration, calpain was demonstrated to play a role through Ca(2+)-ATPase activation by limited proteolysis.
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PMID:[The regulatory mechanism of free Ca2+ concentration in activated platelets]. 131 11

Aglafoline, isolated from Aglaia elliptifolia Merr, inhibited in a selective and concentration-dependent manner the aggregation and ATP release reaction induced in washed rabbit platelets by PAF (platelet-activating factor). The IC50 values of aglafoline, BN52021 and kadsurenone on PAF (3.6 nM)-induced platelet aggregation were about 50, 12 and 18 microM, respectively. Aglafoline also inhibited [3H]PAF (3.6 nM) binding to washed rabbit platelets with an IC50 value of 17.8 +/- 2.6 microM. The concentration-response curve of PAF-induced platelet aggregation was shifted to the right by aglafoline with pA2 and pA10 values of 5.97 and 5.04, respectively. Although thromboxane B2 formation caused by collagen and thrombin was partially suppressed by aglafoline, thromboxane B2 formation caused by ionophore A23187 and arachidonic acid was not affected. Aglafoline inhibited the [3H]inositol monophosphate formation caused by PAF but not that caused by collagen or thrombin in the presence of indomethacin (20 microM). The cAMP content of washed rabbit platelets was not affected by aglafoline. Rat femoral intravenous administration of aglafoline (10 mg/kg) did not affect blood pressure. However, aglafoline (10 mg/kg) both prophylactically and therapeutically antagonized PAF (2.5 micrograms/kg)-induced hypotensive shock in rats. Intravenous PAF (30 ng/kg) caused severe bronchoconstriction in guinea pigs. This effect was completely blocked by aglafoline. This implies aglafoline is an effective PAF antagonist not only in vitro, but also in vivo.
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PMID:PAF antagonism in vitro and in vivo by aglafoline from Aglaia elliptifolia Merr. 132 22

Kinins are potent mediators of rheumatoid inflammation. The components of the kinin-forming system are hyperactive in RA. Excessive release of kinins in the synovial fluid can produce oedema, pain and loss of functions due to activation of B1 and B2 receptors. These receptors could be stimulated via injury, trauma, coagulation pathways (Hageman factor and thrombin) and immune complexes. The activated B1 and B2 receptors might cause release of other powerful non-cytokines and cytokines mediators of inflammation, for example, PGE2, PGI2, LTs, histamine, PAF, IL-1 and TNF derived mainly from polymorphonuclear leukocytes, macrophages, endothelial cells and synovial tissue. These mediators are capable of inducing bone and cartilage damage, hypertrophic synovitis, vessels proliferation, inflammatory cells migration, and possibly angiogenesis in pannus formation. These pathological changes, however, are not yet defined in human model of chronic inflammation (RA). Hence, the role of kinin and its interacting inflammatory mediators would soon start to clarify the detailed questions they revealed in clinical and experimental models of chronic inflammatory joint diseases. Several B1 and B2 receptor antagonists are being synthesized in an attempt to study the molecular functions of kinins in inflammatory processes (RA, periodontitis and osteomyelitis), and they represent and important area for continued research in rheumatology. Future development of specific, potent and stable B1 and B2 receptor antagonists or combined B1 and B2 antagonists with y-IFN might serve as pharmacological basis of more effective rationally-based therapies for RA. This may lead to significant advances in our knowledge of the mechanisms and therapeutics of rheumatic diseases.
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PMID:Involvement of the kinin-forming system in the physiopathology of rheumatoid inflammation. 133 58

The binding of PAF in vitro to its receptors on platelets gradually becomes irreversible. This property has been applied to the measurement of PAF in circulating blood, the concept being that in vivo contact with endogenous PAF diminishes subsequent in vitro binding of 3H-labeled PAF. Here we show that, when platelets are stimulated with thrombin, the subsequent binding of [3H]PAF is greatly reduced, probably due to proteolytic damage of the PAF receptors. In addition, [3H]PAF binding is decreased, when the cell's energy status is low, which is seen during thrombin-induced secretion. Thus, the detection of PAF in circulating blood based on the binding to PAF receptors on platelets is severely hampered when platelets make contact with thrombin.
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PMID:Effect of platelet agonists on the binding of platelet-activating factor to human platelets. 133 23

HA-29, 2-[(3-methoxyphenyl)methyl]-pyrano[2,3-c]pyrazol-6(1H)-one, was investigated for its inhibitory mechanism of action in washed rabbit platelets. This compound inhibited the aggregation and ATP release of rabbit platelets induced by arachidonic acid and collagen in a concentration-dependent manner, without affecting those induced by ADP, PAF and thrombin. Prolongation of the incubation time of HA-29 with platelets did not cause further inhibition and the aggregability of the agent-treated platelets could be restored after washing of platelets. The concentration-response curve of U-46619-induced platelet aggregation was shifted to the right by HA-29 in a concentration-dependent manner, but the maximal aggregation was suppressed by HA-29. The pA2 and pA10 values of HA-29 on U-46619-induced platelet aggregation were 4.26 and 3.58, respectively, with a slope value of -1.4. The U-46619-induced aggregation was markedly disaggregated by HA-29 even it was added 5 min after U-46619. HA-29 inhibited the secondary aggregation and ATP release, but not the primary aggregation of human platelet-rich plasma induced by ADP and epinephrine. Thromboxane B2 formation caused by arachidonic acid, collagen and thrombin was markedly suppressed by HA-29. HA-29 also inhibited the formation of prostaglandin D2 caused by arachidonic acid. HA-29 inhibited almost completely the formation of inositol monophosphate caused by U-46619, but not that by collagen or thrombin. HA-29 did not affect U-46619-induced contraction of rat aorta. It is concluded that the antiplatelet effect of HA-29 is due to the inhibition of thromboxane A2 formation and blockade of thromboxane A2/prostaglandin endoperoxide receptor.
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PMID:HA-29: an inhibitor of thromboxane A2 formation with antagonism of thromboxane A2/prostaglandin endoperoxide receptor in rabbit platelets. 141 84

G619, a 4-OH-isophthalic acid derivative, was studied for its capacity to inhibit platelet aggregation. G619 dose-dependently inhibited U46619, collagen, ADP, PAF, thrombin and epinephrine-induced platelet aggregation in vitro. The IC50 values for inhibition of U46619-induced human and rabbit platelet aggregation were 39 and 43 microM, respectively. G619, at 100 microM, inhibited high concentration collagen (10 micrograms/ml)-induced aggregation of rabbit platelets pretreated with indomethacin and increased the level of cAMP in washed rabbit platelets by 30% (p less than 0.01 vs basal). However, G619, did not inhibit fibrinogen binding to GPIIb/IIIa receptor, phosphodiesterase, U46619-induced contractile responses on canine saphenous vein or rabbit aorta, calcium-induced vasoconstriction and thrombin or PAF-induced elevation of [Ca++]i in platelets in vitro. In vivo, the U46619-induced maximal thrombocytopenia in rats was reduced from 40% (vehicle) to 22% and 18% by 10 and 30 mg/kg of G619 i.v., respectively. G619 (30 mg/kg) had no effect on the U46619-induced vasopressor response or sudden death in rats, and had no effect on TxB2 formation. Our results indicate that G619 is a broad-spectrum platelet aggregation inhibitor and may have its effect on a common mechanism for platelet aggregation besides an effect on the thromboxane A2 receptor.
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PMID:Pharmacological profile of G619, a new platelet aggregation inhibitor. 141

Using decreasing concentrations of PAF-acether or thrombin, it was possible to observe on human platelets, first, aggregation, classically associated to activation, then , below a threshold, cytotoxicity towards Schistosoma mansoni larvae, proposed here as stimulation. These two activities appeared as distinct and antithetic. However, their induction might be the consequence of triggering of the same receptors with different intensity, since PAF-induced, but not thrombin-induced, cytotoxicity could be inhibited with specific PAF-antagonists BN 52021 and BN 52024 also known to inhibit PAF-induced aggregation. These results give credit to the hypothesis that haemostatic and cytotoxic properties of platelets are two distinct functions of these blood elements.
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PMID:Separate induction of human blood platelet aggregation or cytotoxicity by different concentrations of PAF-acether and thrombin. 141 87

Hypoxia alters endothelial cell function and metabolism. Since PAF is synthesized by endothelial cells and capable of modulating endothelial cell responses, we investigated the effect of hypoxia on synthesis and release of PAF from endothelial cells. We found: (1) Approx. 90% of the radylPAF derivative in stimulated endothelial cells is acylPAF. (2) Acute hypoxic (15 min-1 h) priming increased ionophore- and thrombin-induced radylPAF accumulation. (3) Long-term hypoxic exposure increased radylPAF accumulation at 24 and 48 h in the presence of ionophore. (4) Bioactive PAF was released into media and hypoxia and ionophore synergistically increased PAF release. (5) Hypoxia and ionophore stimulation increased phospholipase A2 activity and decreased acetylhydrolase activity in endothelial cells. We conclude that hypoxia and ionophore increase PAF synthesis and release from endothelial cells.
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PMID:Hypoxia increases stimulus-induced PAF production and release from human umbilical vein endothelial cells. 142 Feb 92


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