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

---

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

Flunarizine, a calcium (Ca2+)-entry blocker, selective for vascular tissues, inhibits in a concn-dependent way the contraction of isolated rat caudal artery preparations induced by mediators derived from thrombin-stimulated rat platelets. This inhibition is slow in onset and is of prolonged duration. Specific measurements and pharmacological analysis show 5-hydroxytryptamine (5HT) and thromboxane A2 (TXA2) to be the main mediators involved. Comparison with exogenously added agonists shows amplification between 5HT and TXA2 at the level of the vascular smooth muscle cells. Combined treatment with ketanserin, a selective 5HT2 receptor antagonist, and suprofen, a fatty acid cyclo-oxygenase inhibitor, shows that flunarizine inhibits the 5HT-induced as well as the prostaglandin-induced components of the contraction. The compound does not affect the release of 5HT from the platelet and does not interfere with the biosynthesis of TXA2 from endogenous platelet arachidonic acid; it reduces the amounts of TXB2 and HHT and increases the production of HETE from exogenous [14C]arachidonic acid by washed rat platelets.
...
PMID:Platelet-mediated vascular contractions. Inhibition by flunarizine, a calcium-entry blocker. 640 80

Palmitaldehyde acetal phosphatidic acid ( PGAP ) caused dose-dependent aggregation of human platelets resuspended in modified Tyrode medium, with a threshold concentration of 0.5-1 microM and an EC50 of 4 microM. Concentrations of PGAP which elicited biphasic irreversible aggregation concomitantly induced formation of 1.02 +/- 0.029 nmol (mean +/- s.e. mean) of malondialdehyde (MDA) per 10(9) platelets and caused release of 58 +/- 2.8% of platelet [14C]-5-hydroxytryptamine ([14C]-5-HT) from prelabelled platelets; no MDA formation or [14C]-5-HT release occurred at lower doses of PGAP which elicited only monophasic reversible aggregation. Adenosine 5'-pyrophosphate (ADP)-induced platelet activation resulted in formation of 0.344 +/- 0.004 nmol of MDA per 10(9) platelets in association with irreversible aggregation and 49.1 +/- 1% release of [14C]-5-HT. Mepacrine, a phospholipase A2 inhibitor, at 2.5 microM reduced PGAP -induced MDA formation and [14C]-5-HT release by the resuspended platelets without affecting irreversible aggregation; higher concentrations of mepacrine abolished all three responses. Chlorpromazine, a calmodulin antagonist, similarly inhibited PGAP -induced MDA formation and irreversible aggregation, and at 100 microM abolished monophasic aggregation. The cyclo-oxygenase inhibitor indomethacin caused a concentration-dependent reduction of PGAP -induced MDA formation by resuspended human platelets without significantly inhibiting [14C]-5-HT release or irreversible aggregation; concentrations (greater than or equal to 1.75 microM) which inhibited MDA formation by more than 94% abolished [14C]-5-HT release, and converted second phase irreversible aggregation to an extensive reversible response. 2-Methylthioadenosine 5'-phosphate (2 methylthio-AMP), an ADP antagonist, inhibited PGAP -induced MDA formation, [14C]-5-HT release and second phase aggregation in the human platelet suspensions in a parallel, concentration-dependent manner; at 9.4 microM 2-methylthio-AMP, both MDA formation and [14C]-5-HT release were abolished and monophasic, reversible aggregation remained. Albumin was required for aggregation of washed human platelets to PGAP . Irreversible PGAP -induced aggregation of washed [14C]-arachidonate-labelled platelets was accompanied by a low net loss of 14C from platelet phospholipids, an equivalent increase in 14C in free fatty acids, and the appearance of 14C in thromboxane (Tx)B2; mepacrine reduced the loss in 14C from phospholipids and inhibited aggregation and formation of [14C]-TxA2. Thrombin-induced aggregation was accompanied by substantial loss of 14C from phospholipids and equivalent gains of 14C in free fatty acids and TxB2; mepacrine pretreatment caused partial inhibition of thrombin-induced aggregation, halved the net 14C loss from phospholipids, but had little effect on the appearance of 14C in TxB2. 6 It is concluded that in human platelets PGAP-induced dense granule release and irreversible aggregation are dependent on the liberation of arachidonate and its metabolism via prostaglandin endoperoxides to thromboxane, that PGAP and thrombin elicit mobilization of arachidonate from different pools of membrane phospholipids, and that the mechanism of PGAP-activation of human platelets differs from those of thrombin- and ADP-activation.
...
PMID:Arachidonate metabolism, 5-hydroxytryptamine release and aggregation in human platelets activated by palmitaldehyde acetal phosphatidic acid. 642

Changes in isometric tension due to intra- or extraluminal addition of vasoactive agents were determined in isolated perfused segments of canine left circumflex coronary artery. Segments denuded of endothelium were more sensitive to the contractile action of 5-hydroxytryptamine and potassium during intraluminal addition. In segments with intact endothelium, the sensitivity to intraluminal, but not extraluminal, 5-hydroxytryptamine was decreased in comparison to denuded segments; that to potassium was unchanged. In segments with intact endothelium contracted with prostaglandin F2 alpha, intraluminal, but not extraluminal, acetylcholine, adenosine diphosphate, or thrombin caused relaxation. Intraluminal 5-hydroxytryptamine and aggregating platelets caused relaxation or attenuated contractions in a majority of vessels studied; extraluminal addition caused only contractions. Thus the endothelium is responsible for opposite smooth muscle responses to intra- versus extraluminal vasoactive substances released from aggregating platelets. During intraluminal thrombosis the endothelium may inhibit smooth muscle contraction by responding to 5-hydroxytryptamine and adenosine diphosphate released from platelets and to thrombin; where the endothelium is damaged, the luminal aspect of the blood vessel wall, which is more sensitive to 5-hydroxytryptamine, may become the site of coronary spasm.
...
PMID:Endothelium and asymmetrical responses of the coronary arterial wall. 647 35

Using scanning electron microscopy and light scattering we have investigated the shape change of bovine platelets. The extents of shape change obtained by ADP and 5-hydroxytryptamine(5HT) increased in dose-dependent manner, and the maximum obtained by these agonists were additive. The agonist-specific desensitization in shape change was observed with ADP, 5HT and thrombin. The extent of desensitization by pre-exposure to ADP was dependent upon the concentration of ADP. It was strongly indicated that receptors or their subsequent stimuli-transmission apparatus became unable to respond to further stimulation after the exposure to the initial stimulation.
...
PMID:Agonist-specific desensitization of shape change of platelets. 650 24

The specificity of refractory state of bovine platelets developed by various agonists was examined. When bovine unwashed platelets were preincubated with 5-hydroxytryptamine (5HT) (or ADP), they became non responding to that agonist (refractory) but they responded quite normally to collagen, thrombin and ADP (or 5HT). When platelets became refractory to 5HT, the synergistic aggregation normally obtained with this agonist plus ADP was lost, but that with ADP plus thrombin was not changed. Platelets made refractory to ADP (or 5HT) after the aggregation and disaggregation cycle by the agonist responded normally to 5HT (or ADP). These results strongly indicate that platelets become refractory to one agonist without impairing the sensitivity to any other agonists.
...
PMID:Agonist-specific refractory states of bovine platelets-disappearance of synergism in aggregation. 664 2

Human platelets appear to accumulate quinacrine both in a thrombin-releasable compartment (dense bodies or amine storage vesicles) and in another compartment from which it is released by agents known to collapse pH gradients (possibly lysosomes with an acidic interior). Approximately 61% of the total amount of quinacrine present in human platelets resides in dense bodies and 14+ in lysosomes, with the remainder probably present in the cytoplasm. Other basic amines are accumulated in the three compartments to widely varying extents, suggesting that several factors besides the existence of pH gradients act to determine the distribution of these substances within the cell. The fluorescence emission of quinacrine excited with 420 nm light is completely quenched for quinacrine inside both dense bodies and lysosomes, and the absorption of 440 nm light is decreased by approximately 25%. Quinacrine added to dense bodies at 37 degrees C induces the efflux of 5-hydroxytryptamine (5HT) from the bodies. There is, however, no 5HT loss following quinacrine entry at 0 degree C, and the relationship between the two types of amine movement varies according to incubation time at 0 degree C and 37 degrees C. This action of quinacrine therefore does not appear to be associated with stoichiometric exchange of 5HT and quinacrine, but rather to modulation of the passive permeability of the dense body membrane for 5HT.
...
PMID:Quinacrine and basic amines in human platelets: subcellular compartmentation and effects on serotonin. 670 2

5-hydroxytryptamine (5-ht) secretion and thromboxane B2 (TxB2) production by platelet-rich plasma in response to the Ionophore A23187 or the sulphydryl group reagent N-ethyl maleimide (NEM) were potentiated in the presence of EDTA. No such potentiation by EDTA was observed using aspirin-treated platelets. The addition of Ca2+ and also Mg2+ to suspensions of washed human platelets reduced the rate and extent of TxB2 formation in response to thrombin, A23187, collagen or NEM. In contrast, Sr2+ resulted in spontaneous TxB2 production and 5-HT secretion.
...
PMID:Studies on the role of calcium in the control of thromboxane B2 production. 678 15

In vitro stimulation of washed rat platelets (2.5 X 10(10)/1) with thrombin (0.002 U/1) as well as their activation on de-endothelialized vascular preparations, produced a strong contraction of isolated rat caudal arteries. Pharmacodissection and specific measurements of various mediators (5-hydroxytryptamine, thromboxane B2, ATP) showed the platelet-mediated contraction to be mainly mediated by 5-hydroxytryptamine, either by its direct effect or through amplification of prostaglandin-effects at the level of the vessel or the platelets. Platelet-mediated vasospastic episodes were effectively reduced by ketanserin, a selective 5-HT2 receptor antagonist.
...
PMID:Platelet-mediated vascular contractions: inhibition of the serotonergic component by ketanserin. 681 52

A 16-year-old boy with a bleeding disorder since infancy has a long bleeding time, normal platelet count and morphology and normal plasma factor-VIII activities. His platelets undergo normal shape change and primary aggregation in response to ADP but show defective 5-hydroxytryptamine (5-HT) secretion and aggregation in response to adrenaline, sodium arachidonate, U44069, PAF-acether, A23187 and low concentrations of collagen. Thrombin and higher concentrations of collagen produce a normal response. Secretion of beta-thromboglobulin and platelet factor 4 parallels that of 5-HT. Thromboxane B2 is produced normally in response to exogenous arachidonate and to stimulation by thrombin, collagen and A23187 in all concentrations tested. The patient's endoperoxides and thromboxane A2 aggregate aspirin-treated platelets, though his platelets are themselves unresponsive. Cyclic AMP is present at normal concentration in the patient's unstimulated platelet-rich plasma, and PGI2 inhibits platelet aggregation by ADP and thrombin in a normal dose-related plasma, and PGI2 inhibits platelet aggregation by ADP and thrombin in a normal dose-related manner. Platelet ultrastructure, 5-HT uptake and content of adenine nucleotides, platelet factor 4 and beta-thromboglobulin are all within normal limits. When the patient's platelets were loaded with the fluorescent dye quin 2, which serves as an indicator of cytoplasmic free calcium ions, their responses to thrombin, whether in the presence or virtual absence of extracellular Ca2+, were entirely normal in respect of free calcium ions, secretion, shape-change and aggregation. In response to ionomycin, however, a normal increase in free calcium ions was accompanied by normal shape-change but virtually no aggregation or 5-HT secretion. The platelet calmodulin content was normal. These findings show that the defect in this patient's platelets is of utilization of cytoplasmic Ca2+ for secretion and aggregation, rather than of Ca2+ uptake or mobilization of Ca2+ from intracellular storage sites. It is suggested that the most likely site of the defect is the phosphorylation of one of the proteins concerned in the secretory mechanism.
...
PMID:A new congenital defect of platelet secretion: impaired responsiveness of the platelets to cytoplasmic free calcium. 683 Jul

Spontaneous and drug-induced liberation of 14C-5-hydroxytryptamine (14C-5HT), 3H-dopamine (3H-DA) and 3H-noradrenaline (3H-NA) from normal and reserpinized human blood-platelets has been determined from measurements of the amine contents before and after incubation in tris-buffer. In normal platelets the spontaneous liberation of 3H-catecholamines was more marked than that of 14C-5HT, but was less in percent for all these labelled amines than in reserpinized platelets. Thrombin lowered amine contents more in normal than in reserpinized platelets. The initial thrombin-induced decrease of 14C-5HT, in contrast to that of 3H-catecholamines, showed a partial recovery after 30 min which was abolished by imipramine. The benzoquinolizine Ro 4-1284 diminished all the amines in normal, but not in reserpinized platelets. In normal platelets tryamine affected 14C-5HT and 3H-DA about equally, whereas 3H-NA much less. Octopamine showed a similar pattern as tryamine, but was less potent. P-chlormethamphetamine (PCMA) and amphetamine decreased 3H-DA less markedly than 14C-5HT and 3H-NA not at all. In reserpinized platelets these arylalkylamines induced a decrease of 14C-5HT but not of 3H-catecholamines. It is concluded that (a) 3H-catecholamines like 14C-5HT are mainly localized in the granular pool of normal human platelets, (b) the pattern of action of a drug on intra- and extragranular amines depends not only on the nature of the drug and the amine to be liberated, but in comparison with previous results also on the species, (c) platelets are not completely satisfactory models for monoaminergic neurons, especially catecholaminergic ones regarding drug-induced amine liberation.
...
PMID:Liberation of catecholamines and 5-hydroxytryptamine from human blood-platelets. 691 85


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---