5'-N-Ethylcarboxamidoadenosine (NECA) Is A Potent, Stereospecific Inhibitor Of Human Platelet Aggregation

1981 ◽  
Author(s):  
N J Cusack ◽  
S M O Hourani
Keyword(s):  
Platelet Aggregation ◽  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Human Platelet ◽  
Human Platelets ◽  
Inhibit Platelet Aggregation ◽  
Inhibitory Potency ◽  
Adenosine Receptor Antagonist ◽  
Human Platelet Aggregation ◽  
Potent Vasodilator

Adenosine is a vasodilator, and also inhibits platelet aggregation apparently by acting at an external membrane receptor to increase levels of platelet cyclic AMP. Certain analogues of adenosine retain activity as vasodilators, and also inhibit platelet aggregation by raising levels of platelet cyclic AMP. NECA is an extraordinarily potent vasodilator, so its effects on human platelet function were tested.NECA (1 μM) inhibited human platelet aggregation induced by ADP, 5-HT, thrombin and adrenaline mere powerfully than adenosine (1 μM). NECA, even at micrcmolar concentrations, was 5 to 10 times more potent than adenosine as an inhibitor of aggregation induced by ADP (5μM or 200μM) or adrenaline (200μM). NECA (Ka = 0.95μM) caused increases in levels of platelet cyclic AMP, which could be competitively inhibited by theophylline (Ki = 8μM), an adenosine receptor antagonist. However, here NECA was only about 1.3 times more potent than adenosine (Ka = 1.2μM). The effects of NECA, like those of adenosine, were completely stereospecific, the L enantiomer of NECA being inactive. NECA (10μM) did not prevent inhibition of PGE1-stimulated adenylate cyclase by ADP (5 μM).NECA is the most potent analogue of adenosine yet tested on human platelets, and is the first example of a 5' modification to retain significant inhibitory potency.

Adenosine 5’-O-(2-Thiodiphosphate) (ADP-β-S) Is A Partial Agonist At The ADP Receptor Of Human Platelets

1981 ◽  
Author(s):  
N J Cusack ◽  
S M O Hourani
Keyword(s):  
Platelet Aggregation ◽  
Adenylate Cyclase ◽  
Human Platelet ◽  
Partial Agonist ◽  
Human Platelets ◽  
Simultaneous Addition ◽  
Prostaglandin Receptor ◽  
Human Platelet Aggregation ◽  
Adp Receptor ◽  
Stimulation Of

ADP induces human platelet aggregation and inhibits the stimulation of platelet adenylate cyclase by prostaglandin E1 (PGE1), but analogues of ADP in which the diphosphate group is modified retain only weak aggregating activity. However, ADP-β-S, an ADP analogue in which a terminal phosphate oxygen is replaced by sulphur, is known to be equipotent with ADP as an inhibitor of PGE1-stimulated adenylate cyclase in purified human platelet membranes. We therefore tested ADP-β-S on intact human platelets. ADP-β-S induced human platelet aggregation and inhibited PGE1-stimulated adenylate cyclase, but in botn cases was less potent than ADP and only achieved 75% and 50% respectively of the maximal effects of ADP. Aggregation induced by ADP-β-S was competitively inhibited by ATP (50 μM), a known ADP antagonist.Both these actions of ADP could be inhibited by the simultaneous addition of ADP-β-S (50 μM). Aggregation induced by a stable endoperoxide analogue (11 ,9 -epoxymethano PGH2), which acts at a prostaglandin receptor rather than at an ADP receptor, was not inhibited by the simultaneous addition of ADP-β-S (50 μM). The behaviour of ADP-β-S towards human platelets is therefore tnat of a partial agonist at the ADP receptor.

Inhibitory Effect of Staphylokinase on Platelet Aggregation

1993 ◽  
Vol 70 (05) ◽  
pp. 834-837 ◽  
Author(s):  
Akira Suehiro ◽  
Yoshio Oura ◽  
Motoo Ueda ◽  
Eizo Kakishita
Keyword(s):  
Platelet Aggregation ◽  
Human Platelet ◽  
Degradation Products ◽  
Platelet Rich Plasma ◽  
Inhibitory Effect ◽  
Effective Concentration ◽  
Inhibit Platelet Aggregation ◽  
Platelet Suspension ◽  
Washed Platelet ◽  
Human Platelet Aggregation

SummaryWe investigated the effect of staphylokinase (SAK), which has specific thrombolytic properties, on human platelet aggregation. Platelet aggregation induced with collagen was observed following preincubation of platelets in platelet-rich plasma (PRP) or washed platelet suspension (WP) with SAK at 37° C for 30 min. SAK inhibited platelet aggregation in PRP only at the highest examined concentration (1 x 10-4 g/ml). Although SAK did not inhibit platelet aggregation in WP which contained fibrinogen, it did when the platelets had been preincubated with SAK and plasminogen. The most effective concentration in WP was 1 x 10-6 g/ml. The effect could be inhibited by adding aprotinin or α2-antiplasmin. The highest generation of plasmin in the same preincubation fluid was detected at 1 x 10-6 g/ml SAK. We concluded that SAK can inhibit platelet aggregation in WP by generating plasmin and/or fibrinogen degradation products, but is only partially effective in PRP because of the existence of α2-antiplasmin.

Differential Ability of Agonists to Express Distinct Pools of Fibrinogen (Gpllb/llla) Receptors which Can Mediate the Aggregation of Human Platelets

1989 ◽  
Vol 62 (03) ◽  
pp. 955-961 ◽  
Author(s):  
Ian S Watts ◽  
Rebecca J Keery ◽  
Philip Lumley
Keyword(s):  
Platelet Aggregation ◽  
Human Platelet ◽  
Surface Membrane ◽  
Blood Platelet ◽  
Human Platelets ◽  
Membrane Glycoprotein ◽  
Platelet Surface ◽  
Human Platelet Aggregation ◽  
Differential Ability ◽  
Blood Platelet Aggregation

SummaryWe have investigated the effect of two procedures that modify human platelet surface membrane glycoprotein (Gp) IIb and IIIa complexes upon whole blood platelet aggregation to a range of agonists. (A) Irreversible disruption of complexes by temporary (30 min) Ca2+-deprivation with EGTA at 37° C. (B) Binding of a monoclonal antibody M148 to the complex. EGTA exposure abolished aggregation to ADP, adrenaline and PAF. In contrast, full aggregation curves to collagen and U-46619 could still be established. EGTA exposure reduced M148 binding to platelets by 80%. Excess M148 abolished aggregation to ADP, PAF, collagen and U-46619. However, upon removal of unbound antibody from platelets full aggregation curves to collagen and U-46619 but not to ADP and PAF could be re-established. Thus human platelet aggregation to ADP, PAF and adrenaline appears absolutely dependent upon surface membrane GpIIb/IIIa complexes. In contrast, collagen and U-46619 cause expression of an additional distinct pool of Gp complexes inaccessible to EGTA and M148 in unstimulated platelets which is intimately involved in aggregation to these agonists.

Heparin Counteracts the Antiaggregating Effect of Prostacyclin by Potentiating Platelet Aggregation

1983 ◽  
Vol 49 (02) ◽  
pp. 081-083 ◽  
Author(s):  
Vittorio Bertelé ◽  
Maria Carla Roncaglioni ◽  
Maria Benedetta Donati ◽  
Giovanni de Gaetano
Keyword(s):  
Platelet Aggregation ◽  
Human Platelet ◽  
Specific Interaction ◽  
Inhibitory Effect ◽  
Effective Inhibitor ◽  
Inhibitory Potency ◽  
Human Platelet Aggregation

SummaryIt has recently been reported that heparin neutralizes the inhibitory effect of prostacyclin (PGI2) on human platelet aggregation. The mechanism of this interaction has not yet been unequivocally established. We present here evidence that heparin (Liquemin Roche) does not react directly with PGI2 but counteracts its inhibitory effect by potentiating platelet aggregation. In the absence of heparin, PGI2 was a less effective inhibitor of platelet aggregation induced by the combination of ADP and serotonin than by ADP alone. Moreover, the inhibitory effect of PGI2 was similarly reduced when increasing the concentrations of ADP (in the absence of heparin). The lack of a specific interaction between heparin and PGI2 is supported by the observation that, in the presence of heparin, other prostaglandins such as PGD2 and PGE1, and a non-prostanoid compound such as adenosine also appeared to lose their inhibitory potency. It is concluded that heparin opposes platelet aggregation inhibitory effect of PGI2 by enhancement of platelet aggregation.

Inhibition of Human and Rat Platelet Aggregation by Extracts of Mo-er (Auricularia auricula)

1982 ◽  
Vol 48 (02) ◽  
pp. 162-165 ◽  
Author(s):  
K C Agarwal ◽  
F X Russo ◽  
R E Parks
Keyword(s):  
Platelet Aggregation ◽  
Cyclic Amp ◽  
Human Platelet ◽  
Rapid Onset ◽  
Hot Water ◽  
Inhibitory Effects ◽  
Inhibition Of Platelet Aggregation ◽  
Auricularia Auricula ◽  
Human Platelet Aggregation ◽  
Induced Aggregation

SummaryHot water extracts of Mo-er (1 gm by 15 ml of water), an oriental food (Auricularia auricula), inhibit strongly both human and rat platelet ADP-induced aggregation. HPLC analysis of two varieties of Mo-er, A.auricula and A.polytricha (a black tree fungus), shows that they contain adenosine (Ado), 133 and 154 micrograms per gram of dry fungus, respectively. The inhibition of ADP-induced platelet aggregation by Mo-er extracts and by Ado was compared. Mo-er extracts caused a more rapid onset and a longer duration of inhibition than produced by equivalent amounts of Ado. Furthermore, Mo-er extract treated with adenosine deaminase to degrade the Ado retained the capacity to inhibit platelet aggregation. The inhibitory effects of Mo-er extracts on ADP-induced human platelet aggregation are greatly potentiated by the inhibitors of cyclic AMP phosphodiesterase such as oxagrelate (phthalazinol) and papaverine. The inhibition of platelet aggregation is only partially blocked by 2’,5’-dideoxy-adenosine (DDA), an inhibitor of platelet adenylate cyclase and 5’-deoxy, 5’-methylthioadenosine (MTA), an antagonist of Ado receptors. ADP-induced rat platelet aggregation is strongly inhibited by Mo-er extracts, but not by Ado. This inhibition is not reversed by either DDA or MTA. These findings indicate that Mo-er extracts contain an agent (or agents) in addition to Ado, that blocks platelet aggregation by a mechanism that does not involve the platelet cyclic AMP system.

Prostaglandins (PG) Inhibit Human Platelet Aggregation by PG Receptor Antagonism as well as Adenylate Cyclase Stimulation

1979 ◽  
Author(s):  
D.E. MacIntyre ◽  
E.W. Salzman
Keyword(s):  
Platelet Aggregation ◽  
Adenylate Cyclase ◽  
Human Platelet ◽  
High Ratio ◽  
Receptor Antagonism ◽  
Human Platelet Aggregation ◽  
Alkyl Groups ◽  
Low Concentrations ◽  
Alkyl Substitution ◽  
Adenylate Cyclase Stimulation

11-Deoxy and/or 15 or 16 alkyl substitution confer platelet aggregating activity to bis-enoic PG's: e.g., 11-deoxy-PGE2 (threshold (T)-5μM); ll-deoxy-15(S)-15-methyl-PGE2 (T=0.1μM);ll-deoxy-15(S)-16-methyl-PGE2(T=0.1μM). Responses induced by such PG’s mimic those induced by PGH2 and PGH2 analogues (e.g., U44069). N0164 competitively inhibits aggregation induced by PG’s and suppresses “secondary” responses induced by low concentrations of ADP or arachidonic acid, suggesting involvement of a specific PG stimulatory receptor in platelet aggregation. We compared non-aggregatory PG’s as inhibitors of pri mary aggregation induced by ADP or U44069. PG’s containing 11-deoxy and/or 16-alkyl groups selectively inhibited aggregation induced by U44069. Mean I50 values (n-4) against ADP and U44069 respectively were PGA2 (>100μM; 0.3μM); PGB2 (>100μM; 5μM); PGD2 (6nM; 2nM); PGE1(10nM; 5nM); 11-deoxy PGE1 (60μM; 2μM); ll-deoxy-15-(R)-16-methyl (100μM; 2μM); 13,14-dihydro-16-methyl-PGE2 methyl ester(750nM; 15nM). A low ADP: 406 I50 ratio (e.g., PGD2) indicates that inhibition is mainly due to adenylate cyclase stim ulation, and a high ratio (e.g., PGA2) that inhibition is mainly due to PG receptor antagonism. We have demonstrated a PG stimulatory receptor on the platelet, and its involvement in “secondary” aggregation. PG’s inhibit aggregation by combining with this receptor and/or by stimulating adenylate cyclase.

scholarly journals Human platelet aggregation by murine monoclonal antiplatelet antibodies is subtype-dependent

Blood ◽  
1993 ◽  
Vol 81 (7) ◽  
pp. 1792-1800 ◽  
Author(s):  
S De Reys ◽  
C Blom ◽  
B Lepoudre ◽  
PJ Declerck ◽  
M De Ley ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Platelet Aggregation ◽  
Platelet Activation ◽  
Human Platelet ◽  
Human Platelets ◽  
Antigen Recognition ◽  
Metabolic Inhibitors ◽  
Antigen Binding ◽  
Human Platelet Aggregation ◽  
Murine Monoclonal Antibodies

Abstract Twenty murine monoclonal antibodies (MoAbs) generated against different human platelet antigens induced clumping of human platelets in plasma and buffer. Whereas one MoAb could agglutinate platelets, clumping for 19 MoAbs was blocked by metabolic inhibitors, indicating that these induce platelet activation. Fifteen MoAbs were of IgG1, two of IgG2a, and two of IgG2b subtype. F(ab')2 fragments of these did not evoke an aggregatory response, but specifically inhibited aggregations by and binding of their respective intact MoAbs to platelets. Single-platelet counting technology indicated that the MoAbs bind through their antigen- binding and Fc domains mainly to the surface of the same platelet, rather than cause interplatelet-binding. Despite these similarities, the mechanism of action was nevertheless subtype-dependent. Aggregation induced by all IgG1 antibodies could consistently be prevented by blocking the Fc gamma II-receptor, whereas aggregations induced by all IgG2 antibodies still occurred with blocked Fc-receptor, provided functional complement was present. We therefore conclude that platelet activation by MoAb-binding is initiated by antigen recognition followed by an Fc domain-dependent step, which involves the Fc gamma II-receptor for IgG1-type MoAbs and complement-binding for IgG2-type MoAbs. Thus, antibodies of different subtypes can aggregate platelets via different pathways.

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