Inhibitory effect of glyburide on thrombin-induced platelet aggregation and phosphoinositide metabolism in normal human platelets

Platelets ◽  
1999 ◽  
Vol 10 (1) ◽  
pp. 45-51
Author(s):  
H. Wada
Keyword(s):  
Platelet Aggregation ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Phosphoinositide Metabolism ◽  
Normal Human

Ticlopidine Facilitates the Deaggregation of Human Platelets Aggregated by Thrombin

1994 ◽  
Vol 71 (01) ◽  
pp. 091-094 ◽  
Author(s):  
M Cattaneo ◽  
B Akkawat ◽  
R L Kinlough-Rathbone ◽  
M A Packham ◽  
C Cimminiello ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Platelet Aggregation ◽  
Prostaglandin E1 ◽  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Before And After ◽  
Normal Human ◽  
Platelet Aggregates ◽  
Induced Aggregation

SummaryNormal human platelets aggregated by thrombin undergo the release reaction and are not readily deaggregated by the combination of inhibitors hirudin, prostaglandin E1 (PGE1) and chymotrypsin. Released adenosine diphosphate (ADP) plays an important role in the stabilization of thrombin-induced human platelet aggregates. Since ticlopidine inhibits the platelet responses to ADP, we studied thrombin-induced aggregation and deaggregation of 14C-serotonin-labeled platelets from 12 patients with cardiovascular disease before and 7 days after the oral administration of ticlopidine, 250 mg b.i.d. Before and after ticlopidine, platelets stimulated with 1 U/ml thrombin aggregated, released about 80–90% 14C-serotinin and did not deaggregate spontaneously within 5 min from stimulation. Before ticlopidine, hirudin (5× the activity of thrombin) and PGE1 (10 μmol/1) plus chymotrypsin (10 U/ml) or plasmin (0.06 U/ml), added at the peak of platelet aggregation, caused slight or no platelet deaggregation. After ticlopidine, the extent of platelet deaggregation caused by the same inhibitors was significantly greater than before ticlopidine. The addition of ADP (10 μmol/1) to platelet suspensions 5 s after thrombin did not prevent the deaggregation of ticlopidine-treated platelets. Thus, ticlopidine facilitates the deaggregation of thrombin-induced human platelet aggregates, most probably because it inhibits the effects of ADP on platelets.

Opposite Effect of Lysine on Platelet Aggregation Induced by Arachidonate and by Other Aggregants

1982 ◽  
Vol 48 (01) ◽  
pp. 078-083 ◽  
Author(s):  
C Ts'ao ◽  
S J Hart ◽  
D V Krajewski ◽  
P G Sorensen
Keyword(s):  
Platelet Aggregation ◽  
Secondary Phase ◽  
Aminocaproic Acid ◽  
Adenosine Diphosphate ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Primary Phase ◽  
High Doses ◽  
The Many ◽  
Induced Aggregation

SummaryEarlier, we found that ε-aminocaproic acid (EACA) inhibited human platelet aggregation induced by adenosine diphosphate (ADP) and collagen, but not aggregation by arachidonic acid (AA). Since EACA is structurally similar to lysine, yet these two agents exhibit vast difference in their antifibrinolytic activities, we chose to study the effect of lysine on platelet aggregation. We used L-lysine-HCl in these studies because of its high solubility in aqueous solutions while causing no change in pH when added to human plasma. With lysine, we repeatedly found inhibition of ADP-, collagen- and ristocetin-induced aggregation, but potentiation of AA-induced aggregation. Both the inhibitory and potentiation effects were dose-dependent. Low doses of lysine inhibited the secondary phase of aggregation; high doses of it also inhibited the primary phase of aggregation. Potentiation of AA-induced aggregation was accompanied by increased release of serotonin and formation of malondialdehyde. These effects were not confined to human platelets; rat platelets were similarly affected. Platelets, exposed to lysine and then washed and resuspended in an artificial medium not containing lysine, remained hypersensitive to AA, but no longer showed decreased aggregation by collagen. Comparing the effects of lysine with equimolar concentrations of sucrose, EACA, and α-amino-n-butyric acid, we attribute the potent inhibitory effect of lysine to either the excess positive charge or H+ and C1− ions. The -NH2 group on the α-carbon on lysine appears to be the determining factor for the potentiation effect; the effect seems to be exerted on the cyclooxygenase level of AA metabolism. Lysine and other chemicals with platelet-affecting properties similar to lysine may be used as a tool for the study of the many aspects of a platelet aggregation reaction.

Inhibition of fibrin-platelet interactions by fibrinogen-degradation fragment D

1977 ◽  
Vol 233 (2) ◽  
pp. H305-H311
Author(s):  
K. G. Orloff ◽  
D. Michaeli
Keyword(s):  
Platelet Aggregation ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Human Fibrinogen ◽  
Platelet Serotonin ◽  
Saturable Binding ◽  
Cover Up

Homogenized fibrin induced platelet aggregation and the release of serotonin from human platelets. Fragment D, purified from a plasmin digest of human fibrinogen, inhibited these platelet-fibrin interactions. Using a radiolabeled fragment D, it was possible to demonstrate saturable binding of fragment D to fibrin. Nonlabeled fragment D competed with the radiolabeled fragment D for binding to fibrin. Furthermore, the binding of fragment D to fibrin paralleled its ability to inhibit the fibrin-induced release of platelet serotonin. It is postulated that the inhibitory effect of fragment D on fibrin activation of platelets is due to the binding of fragment D to fibrin. The bound fragment D may cover up or block sites on fibrin that are involved in fibrin-platelet interactions. This would then result in inhibition of the fibrin-induced platelet aggregation and release of platelet serotonin.

scholarly journals Cigarette Smoke Extract Inhibits Platelet Aggregation by Suppressing Cyclooxygenase Activity

TH Open ◽  
2017 ◽  
Vol 01 (02) ◽  
pp. e122-e129
Author(s):  
Hitoshi Kashiwagi ◽  
Koh-ichi Yuhki ◽  
Yoshitaka Imamichi ◽  
Fumiaki Kojima ◽  
Shima Kumei ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Cigarette Smoke ◽  
Platelet Function ◽  
Inhibitory Effect ◽  
Cigarette Smoke Extract ◽  
Human Platelets ◽  
Receptor Subtypes ◽  
Ic50 Value ◽  
Induced Aggregation ◽  
Cox 1

AbstractThe results of studies that were performed to determine whether cigarette smoking affects platelet function have been controversial, and the effects of nicotine- and tar-free cigarette smoke extract (CSE) on platelet function remain to be determined. The aim of this study was to determine the effect of CSE on platelet aggregation and to clarify the mechanism by which CSE affects platelet function. CSE inhibited murine platelet aggregation induced by 9,11-dideoxy-9α,11α-methanoepoxy-prosta-5Z,13E-dien-1-oic acid (U-46619), a thromboxane (TX) A2 receptor agonist, and that induced by collagen with respective IC50 values of 1.05 ± 0.14% and 1.34 ± 0.19%. A similar inhibitory action of CSE was also observed in human platelets. CSE inhibited arachidonic acid–induced TXA2 production in murine platelets with an IC50 value of 7.32 ± 2.00%. Accordingly, the inhibitory effect of CSE on collagen-induced aggregation was significantly blunted in platelets lacking the TXA2 receptor compared with the inhibitory effect in control platelets. In contrast, the antiplatelet effects of CSE in platelets lacking each inhibitory prostanoid receptor, prostaglandin (PG) I2 receptor and PGE2 receptor subtypes EP2 and EP4, were not significantly different from the effects in respective control platelets. Among the enzymes responsible for TXA2 production in platelets, the activity of cyclooxygenase (COX)-1 was inhibited by CSE with an IC50 value of 1.07 ± 0.15% in an uncompetitive manner. In contrast, the activity of TX synthase was enhanced by CSE. The results indicate that CSE inhibits COX-1 activity and thereby decreases TXA2 production in platelets, leading to inhibition of platelet aggregation.

Role of phosphoinositide 3-kinase β in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways

2010 ◽  
Vol 429 (2) ◽  
pp. 369-377 ◽  
Author(s):  
Analia Garcia ◽  
Soochong Kim ◽  
Kamala Bhavaraju ◽  
Simone M. Schoenwaelder ◽  
Satya P. Kunapuli
Keyword(s):  
Platelet Aggregation ◽  
Critical Role ◽  
Thromboxane A2 ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
P2y12 Receptor ◽  
Functional Responses ◽  
Induce Platelet Aggregation ◽  
Erk Phosphorylation

PI3Ks (phosphoinositide 3-kinases) play a critical role in platelet functional responses. PI3Ks are activated upon P2Y12 receptor stimulation and generate pro-aggregatory signals. P2Y12 receptor has been shown to play a key role in the platelet aggregation and thromboxane A2 generation caused by co-stimulation with Gq or Gz, or super-stimulation of Gi pathways. In the present study, we evaluated the role of specific PI3K isoforms α, β, γ and δ in platelet aggregation, thromboxane A2 generation and ERK (extracellular-signal-regulated kinase) activation. Our results show that loss of the PI3K signal impaired the ability of ADP to induce platelet aggregation, ERK phosphorylation and thromboxane A2 generation. We also show that Gq plus Gi- or Gi plus Gz-mediated platelet aggregation, ERK phosphorylation and thromboxane A2 generation in human platelets was inhibited by TGX-221, a PI3Kβ-selective inhibitor, but not by PIK75 (a PI3Kα inhibitor), AS252424 (a PI3Kγ inhibitor) or IC87114 (a PI3Kδ inhibitor). TGX-221 also showed a similar inhibitory effect on the Gi plus Gz-mediated platelet responses in platelets from P2Y1−/− mice. Finally, 2MeSADP (2-methyl-thio-ADP)-induced Akt phosphorylation was significantly inhibited in the presence of TGX-221, suggesting a critical role for PI3Kβ in Gi-mediated signalling. Taken together, our results demonstrate that PI3Kβ plays an important role in ADP-induced platelet aggregation. Moreover, PI3Kβ mediates ADP-induced thromboxane A2 generation by regulating ERK phosphorylation.

scholarly journals Acquired IgG antibody occurring in a thrombasthenic patient: its effect on human platelet function

Blood ◽  
1978 ◽  
Vol 51 (6) ◽  
pp. 1065-1071 ◽  
Author(s):  
S Levy-Toledano ◽  
G Tobelem ◽  
C Legrand ◽  
R Bredoux ◽  
L Degos ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Human Platelet ◽  
Shape Change ◽  
Antigenic Site ◽  
Human Platelets ◽  
Clot Retraction ◽  
Igg Antibody ◽  
Normal Human ◽  
Induced Aggregation ◽  
Bovine Factor

Abstract In subagglutinating amounts, an IgG antibody isolated from the plasma of a polytransfused thrombasthenic patient (L) inhibited ADP-, epinephrine-, collagen-, and thrombin-induced aggregation of normal human platelets. The inhibition of ADP-induced aggregation was strongly diminished following the prior incubation of the antibody with control human platelet stroma but not with the stroma prepared from the platelets of two different thrombasthenic patients. The IgG(L) did not affect the binding of 14C-ADP to control human platelet membranes and did not inhibit the ADP-induced shape change. Bovine factor VIIIVWF- induced agglutination and ristocetin-induced aggregation of control human platelets were not inhibited in the presence of the antibody. The IgG(L) strongly inhibited ADP-induced retraction of reptilase clot and thrombin-induced clot retraction. This antibody therefore induced a thrombasthenialike state in normal human platelets, suggesting that the antigenic site recognized by the antibody plays a central role in the later stages of the mechanism of platelet aggregation induced by physiologic aggregation-inducing agents.

scholarly journals Xanthohumol, a Prenylated Flavonoid from Hops (Humulus lupulus), Prevents Platelet Activation in Human Platelets

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Ye-Ming Lee ◽  
Kuo-Hsien Hsieh ◽  
Wan-Jung Lu ◽  
Hsiu-Chu Chou ◽  
Duen-Suey Chou ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Protein Kinase ◽  
Platelet Activation ◽  
Therapeutic Potential ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Humulus Lupulus ◽  
Mitogen Activated Protein Kinase ◽  
Akt Phosphorylation ◽  
Mitogen Activated Protein

Xanthohumol is the principal prenylated flavonoid in the hop plant (Humulus lupulusL.). Xanthohumol was found to be a very potent cancer chemopreventive agent through regulation of diverse mechanisms. However, no data are available concerning the effects of xanthohumol on platelet activation. The aim of this paper was to examine the antiplatelet effect of xanthohumol in washed human platelets. In the present paper, xanthohumol exhibited more-potent activity in inhibiting platelet aggregation stimulated by collagen. Xanthohumol inhibited platelet activation accompanied by relative [Ca2+]imobilization, thromboxane A2formation, hydroxyl radical (OH●) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and Akt phosphorylation. Neither SQ22536, an inhibitor of adenylate cyclase, nor ODQ, an inhibitor of guanylate cyclase, reversed the xanthohumol-mediated inhibitory effect on platelet aggregation. Furthermore, xanthohumol did not significantly increase nitrate formation in platelets. This study demonstrates for the first time that xanthohumol possesses potent antiplatelet activity which may initially inhibit the PI3-kinase/Akt, p38 MAPK, and PLCγ2-PKC cascades, followed by inhibition of the thromboxane A2formation, thereby leading to inhibition of [Ca2+]iand finally inhibition of platelet aggregation. Therefore, this novel role of xanthohumol may represent a high therapeutic potential for treatment or prevention of cardiovascular diseases.

scholarly journals Endothelium-derived relaxing factor inhibits thrombin-induced platelet aggregation by inhibiting platelet phospholipase C

Blood ◽  
1992 ◽  
Vol 79 (1) ◽  
pp. 110-116
Author(s):  
W Durante ◽  
MH Kroll ◽  
PM Vanhoutte ◽  
AI Schafer
Keyword(s):  
Platelet Aggregation ◽  
Phospholipase C ◽  
Calcium Concentration ◽  
Umbilical Vein ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Relaxing Factor ◽  
Kinase C ◽  
Endothelium Derived Relaxing Factor ◽  
Induced Aggregation

Endothelium-derived relaxing factor (EDRF) inhibits platelet function, but the mechanism underlying this inhibitory effect is not known. To examine this, cultured acetylsalicylic acid (ASA)-treated endothelial cells (EC) from bovine aorta (BAEC) or from human umbilical vein (HUVEC) were incubated with washed, ASA-treated human platelets. Incubation of platelets with either BAEC or HUVEC resulted in inhibition of thrombin-induced platelet aggregation that was dependent on the number of EC added. This effect was potentiated by superoxide dismutase and reversed by treating EC with NG-nitro-L-arginine or by treating platelets with methylene blue, indicating that the inhibition of platelet aggregation was due to the release of EDRF by EC. EC significantly blocked the thrombin stimulated breakdown of phosphatidylinositol-4,5-bisphosphate (PIP2) and the production of phosphatidic acid in [32P]orthophosphate-labeled platelets and of inositol trisphosphate in [3H]myoinositol-labeled platelets. In addition, the thrombin-mediated activation of protein kinase C (PKC) and phosphorylation of myosin light chain were inhibited in the presence of EC. Finally, thrombin stimulated an increase in cytosolic ionized calcium concentration ([Ca2+]i) in fura2-loaded platelets that was abolished by concentrations of EC which also blocked thrombin- induced aggregation. These data indicate that EDRF blocks thrombin- induced platelet aggregation by inhibiting the activation of PIP2- specific phospholipase C and thereby suppressing the consequent activation of PKC and the mobilization of [Ca2+]i.

The Inhibitory Effect of GR32191, a Thromboxane Receptor Blocking Drug, on Human Platelet Aggregation, Adhesion and Secretion

1989 ◽  
Vol 61 (03) ◽  
pp. 429-436 ◽  
Author(s):  
E J Hornby ◽  
M R Foster ◽  
P J McCabe ◽  
L E Stratton
Keyword(s):  
Platelet Aggregation ◽  
Thrombus Formation ◽  
Rabbit Aorta ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Camp Phosphodiesterase ◽  
Platelet Protein ◽  
Thromboxane Receptor ◽  
Serotonin Secretion

SummaryGR32191, a potent selective thromboxane receptor antagonist, has been shown to inhibit completely prostaglandin endoperoxide and thromboxane A2 (TxA2)-induced platelet aggregation, [14C]-serotonin secretion and β-thromboglobulin secretion. Deposition of human platelets onto damaged rabbit aorta in vitro is reduced in the presence of GR32191 which appears to inhibit aggregation of platelets but not direct adhesion of platelets to subendothelium. The effects of non-prostanoid platelet activating agents whose mode of action requires the biosynthesis of TxA2 are also inhibited by GR32191. Prostanoids which inhibit platelet function, such as prostacyclin or PGD2, retain their inhibitory properties in the presence of GR32191 which does not inhibit phospholipase A2, prostaglandin cyclooxygenase, thromboxane synthase, 12-lipoxygenase or cAMP phosphodiesterase activity. The inhibitory action of GR32191 on platelet aggregation, mural thrombus formation and platelet protein storage granule secretion suggests that it has potential in treatingthrombotic disease in man.

Potentiating Effect of Adenosine on Other Inhibitors of Platelet Aggregation

1972 ◽  
Vol 27 (02) ◽  
pp. 252-262 ◽  
Author(s):  
M. Murakami ◽  
K. Odake ◽  
M. Takase ◽  
K. Yoshino
Keyword(s):  
Platelet Aggregation ◽  
Inhibitory Action ◽  
Prostaglandin E1 ◽  
Adenine Nucleotide ◽  
Adenine Nucleotides ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
The Other ◽  
Other Hand ◽  
Adp Release

SummaryAdenosine was rapidly incorporated into human platelets, and the inhibitory effect of adenosine on platelet aggregation was correlated with the incorporation process. Adenosine potentiated the inhibitory action of other inhibitors, such as dipyridamole, prostaglandin E1 and Y-3642. The inhibition of aggregation was associated with the preservation of platelet adenine nucleotides and the prevention of ADP release. On the other hand, the radioactive adenine nucleotide pattern of platelets was not substantially affected by inhibitors. The relation of inhibition of aggregation with ADP release was discussed.

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