Inhibition of Human Platelet Aggregation by a Dibenzazepine Compound (GP 44296) and by N-(2,6-dichlorophenyl)-o-aminophenylacetic acid(GP 45840)

1971 ◽  
Vol 49 (5) ◽  
pp. 479-481 ◽  
Author(s):  
François Jobin ◽  
France T. Gagnon
Keyword(s):  
Platelet Aggregation ◽  
Human Platelet ◽  
Secondary Phase ◽  
Human Platelets ◽  
Primary Phase ◽  
Human Platelet Aggregation ◽  
Induced Aggregation

Studies of the aggregation of human platelets indicate that compounds GP 44296 and GP 45840 inhibit the secondary phase of ADP-induced aggregation and collagen-induced aggregation; GP 44296 also inhibits the primary phase of ADP-induced aggregation. Our results suggest that these compounds are more active on platelet behavior in vitro than phenylbutazone, oxyphenbutazone, and sulfinpyrazone.

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.

Effects of Ethanol on Pathways of Platelet Aggregation In Vitro

1988 ◽  
Vol 59 (03) ◽  
pp. 383-387 ◽  
Author(s):  
Margaret L Rand ◽  
Marian A Packham ◽  
Raelene L Kinlough-Rathbone ◽  
J Fraser Mustard
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Rich Plasma ◽  
Secondary Phase ◽  
Primary Phase ◽  
Rabbit Platelet ◽  
Membrane Phospholipids ◽  
Rabbit Platelets ◽  
Induced Aggregation

SummaryEthanol, at physiologically tolerable concentrations, did not affect the primary phase of ADP-induced aggregation of human or rabbit platelets, which is not associated with the secretion of granule contents. Potentiation by epinephrine of the primary phase of ADP-induced aggregation of rabbit platelets was also not inhibited by ethanol. However, ethanol did inhibit the secondary phase of ADP-induced aggregation which occurs with human platelets in citrated platelet-rich plasma and is dependent on the formation of thromboxane A2. Inhibition by ethanol of thromboxane production by stimulated platelets is likely due to inhibition of the mobilization of arachidonic acid from membrane phospholipids, as ethanol had little or no effect on aggregation and secretion induced by arachidonic acid or the thromboxane mimetic U46619. Rabbit platelet aggregation and secretion in response to low concentrations of collagen, thrombin, or PAF were inhibited by ethanol. Inhibition of the effects of thrombin and PAF was also observed with aspirin-treated platelets. Thus, in addition to inhibiting the mobilization of arachidonate for thromboxane formation that occurs with most agonists, ethanol can also inhibit aggregation and secretion through other effects on platelet responses.

Thromboxane A2-Stimulated Human Platelet Aggregation Is Potentiated By Epinephrine Acting VIA Alpha Adrenergic Receptors

1981 ◽  
Author(s):  
G J Johnson ◽  
G H R Rao ◽  
J G White
Keyword(s):  
Platelet Aggregation ◽  
Adrenergic Receptors ◽  
Human Platelet ◽  
Thromboxane A2 ◽  
Human Platelets ◽  
Adrenergic Agents ◽  
Alpha Adrenergic Receptors ◽  
Human Platelet Aggregation ◽  
Induced Aggregation

Epinephrine (E) potentiates arachidonate (A)-induced aggregation of human platelets. A-insensitive dog platelets (AIP), that form thromboxane A2 (T) but do not aggregate when stirred with A alone, aggregate when exposed to E + A. Therefore, we studied the effect of E on T-stimu- lated human platelet aggregation. AIP stirred with A formed T which was confirmed by TLC. 1/100 to 1/200 volume of AIP was removed 30 sec. after A, and transferred to gel- filtered, aspirin-incubated human platelets. Recipient platelet aggregation was proportional to the volume of AIP transferred. The addition of the thromboxane synthetase inhibitor, Azo Analog I, abolished the aggregating activity of AIP. Transfer of an aliquot of AIP that was inadequate to aggregate human gel-filtered, aspirin-incubated platelets resulted in irreversible aggregation in the presence of ≥0.5nM E. E potentiated aggregation when added 3 min. before but not 3 min. after aliquot transfer. T-stimulated aggregation was abolished by the T-antagonist, 13 azapro- stenoic acid (APA), but E added after APA and before T restored aggregation. E potentiation of T-stimulated aggregation was abolished by prior exposure to equimolar yohimbine, dihydroergocryptine and phentolamine, agents that bind to alpha2 adrenergic receptors, but not by prazosin an alpha1 antagonist. Higher concentrations of E reversed the inhibitory effects of the alpha2 adrenergic agents. All of these agents in higher concentrations (1-100μM) also blocked aggregation induced by T alone. Therefore T-induced platelet aggregation is potentiated by E, in concentrations attained in vivo, by a mechanism linked to platelet alpha adrenergic receptors. Platelet alpha2 receptors have a close functional relationship to the postulated T receptor. E may initiate platelet aggregation in vivo when T is formed in quantities inadequate to alone induce aggregation.

Effects “in Vitro” of Some Cardiovascular Drugs and Other Agents on Human Platelet Aggregation

1973 ◽  
Vol 29 (01) ◽  
pp. 190-195 ◽  
Author(s):  
G Sacchetti ◽  
D Bellani ◽  
C Montanari ◽  
A Gibelli
Keyword(s):  
Platelet Aggregation ◽  
Mechanism Of Action ◽  
Human Platelet ◽  
Cardiovascular Drugs ◽  
Blocking Drug ◽  
Human Platelet Aggregation ◽  
Vitro Effect ◽  
Induced Aggregation

SummaryThe in vitro effect of the following substances on human platelet aggregation is studied: K 4423 (a ß-blocking drug), isoproterenol, phentolamine, papaverine, methamidoline (a myolytic agent).None of these substances causes aggregation. All inhibit aggregation induced by ADP or noradrenaline, except for phentolamine, which is active only on noradrenaline- induced aggregation.Hypothesis on the mechanism of action of the compounds tested are proposed.

Impairment of Human Platelet Aggregation and Serotonin Release Caused in Vitro by Echis Colorata Venom

1973 ◽  
Vol 30 (01) ◽  
pp. 191-198 ◽  
Author(s):  
Haim Biran ◽  
Alexander Dvilansky ◽  
Ilana Nathan ◽  
Avinoam Livne
Keyword(s):  
Platelet Aggregation ◽  
Functional Impairment ◽  
Human Platelet ◽  
Human Platelets ◽  
Endothelial Damage ◽  
Serotonin Release ◽  
Bleeding Tendency ◽  
Human Platelet Aggregation

SummaryAggregation of washed human platelets, induced by either ADP, thrombin or collagen, was decreased by Echis colorata venom (EVC). With ADP as an inducer, the inhibition of aggregation was proportional to the venom concentration, starting from 0.27 μg/ml and attaining full inhibition with venom concentration of 9 μg/ml. Higher concentrations were required for comparable venom effects when collagen or thrombin were used as inducers. Based on serotonin release measurements and platelet counting, it is concluded that the ECV-diminished aggregation is not due to platelet lysis. Thrombin-dependent serotonin release was inhibited by the venom to an extent proportional to the log ECV concentration at a range of 0.27 to 90 μg/ml. ECV effeces on serotonin release are apparently independent on its effects on aggregation, since similar results were obtained either with or without EDTA.Endothelial damage and defibrination are already known to be associated with the bleeding tendency caused by ECV. The present data disclose a functional impairment of platelets as an additional antihemostatic effect of this venom.

Human Platelet Aggregation Without Thromboxane (Tx) Formation

1981 ◽  
Author(s):  
J Westwick ◽  
J B Smith ◽  
V V Kakkar
Keyword(s):  
Platelet Aggregation ◽  
Human Platelet ◽  
Human Platelets ◽  
Synthesis Inhibitor ◽  
Thromboxane Receptor ◽  
Human Platelet Aggregation ◽  
Thromboxane Receptor Antagonist ◽  
Induced Aggregation ◽  
Carbocyclic Thromboxane A2

It is not known whether PG endoperoxides have to be converted to TxA2 in order to induce aggregation and secretion We have examined this crucial question by measuring human platelet aggregation, 14C-5HT release and TxB2 formation induced by collagen, arachidonic acid (AA), adrenaline, U46619 and PGH2 in presence of either 1) 1-2-(4-carboxy-phenoxy) ethyl imidazole hydrochloride, a potent and selective thromboxane synthesis inhibitor (TSI) or a carbocyclic thromboxane A2 (CTA) - a so called thromboxane receptor antagonist. TSI, 1.5 to 75μM produced a dose related inhibition (IC50 5μM n=5) of Tx and elevation of PGE2 synthesis in adrenaline (8μM) and collagen (1.5μg/ml) stimulated platelets. When 14C-SHT labelled platelets were stimulated with 4.5μM adrenaline in the presence of 0, 2.5, 15 and 300μM TSI a 35±2.8, 27±0.5, 24.5±5.0% release of 14C-5HT release resulted and a 10014, 9612, 9711 and 9114% of control aggregation occurred. Similarly when human platelets were stimulated with 0.8mMAA a 51±1.4% (mean ±SE) release of 14C-5HT occurred, while in the presence of 15, 75 and 300μM of UK, a 42±0.4, 32±1, 33±3% of 14C-5HT release resulted. Aggregation induced by the PG endoperoxide analogue U46619 (lμM) was not inhibited by 300μM TSI or l00μM indomethacin, although 99.5% inhibition of Tx formation resulted, and 50 to 60% inhibition of 14C-5HT release was produced both by TSI and indomethacin. However CTA (l-3±M) produced a dose related inhibition of both aggregation and release induced by U46619. CTA (l-10μM) was found to produce superimposable dose related inhibition of collagen induced aggregation and secretion of platelets, whether the platelets were pretreated with 300μM TSI, or not.These results suggest that Tx formation is not necessary for human platelet aggregation, although is contributory to 14C-5HT release induced by collagen, adrenaline, AA and U46619.Also caution must be employed when CTA is used to elucidate the role of TxA2, as it appears to be an effective PG endoperoxide antagonist.

The Effect of Halofenate or Halofenate Free Acid on Human, Rat and Guinea Pig Platelet Aggregation

1976 ◽  
Vol 35 (02) ◽  
pp. 358-363 ◽  
Author(s):  
D.H Minsker ◽  
P.T Jordan ◽  
P Kling ◽  
A MacMillan ◽  
H.B Hucker ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Plasma Concentration ◽  
Guinea Pig ◽  
Plasma Levels ◽  
Human Platelet ◽  
Free Acid ◽  
Secondary Phase ◽  
Inhibitory Effects ◽  
Human Platelet Aggregation ◽  
Induced Aggregation

SummaryHalofenate free acid (HFA), the major metabolite of the hypolipemic agent halofenate, blocked the secondary phase of human platelet aggregation induced by ADP, epinephrine, or thrombin; higher concentrations of clohbrate free acid (CFA) were required to produce similar inhibitory effects on platelet aggregation. HFA and CFA inhibited collagen-induced aggregation of human, rat, or guinea pig platelets. Halofenate orally administered to rats caused inhibition of collagen-induced aggregation when plasma levels of HFA exceeded 300 μg/ml, a clinically achievable human plasma concentration. The platelet inhibitory effects of clofibrate administration were less than those observed with halofenate administration.

scholarly journals Effects of acetyl glyceryl ether phosphorylcholine on human platelet function in vitro

Blood ◽  
1981 ◽  
Vol 58 (5) ◽  
pp. 1027-1031 ◽  
Author(s):  
AJ Marcus ◽  
LB Safier ◽  
HL Ullman ◽  
KT Wong ◽  
MJ Broekman ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Initial Phase ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
Human Platelets ◽  
Strong Stimulus ◽  
Adp Release ◽  
Irreversible Aggregation ◽  
Induced Aggregation

Abstract AGEPC (PAF), at 1.9 x 10(-8) M or higher, induced concentration- dependent aggregation and release in human platelet-rich plasma. Comparative studies with arachidonate, collagen, ionophore, and ADP suggested that AGEPC was a strong stimulus for platelet aggregation and probably a moderate agonist for release, as well as a relatively weak inducer of TXA2 production. The initial phase of AGEPC-induced aggregation was independent of ADP release and TXA2 formation, since it was not inhibited by ASA, apyrase, or CP/CPK. Whereas irreversible aggregation always required ADP release, TXA2 formation was not essential in each instance. Thus, in several experiments, full aggregation responses took place in AGEPC-stimulated platelets that had been pretreated with ASA. AGEPC-induced release of 5-HT, beta - thromboglobulin and PF-4 occurred in parallel and were inhibited by both apyrase and ASA. Washed human platelets did not respond to exogenous AGEPC in the absence of ADP and did not appear to generate significant quantities of AGEPC upon stimulation with thrombin or ionophore.

Sevoflurane Inhibits Human Platelet Aggregation and Thromboxane A2Formation, Possibly by Suppression of Cyclooxygenase Activity

1996 ◽  
Vol 85 (6) ◽  
pp. 1447-1453. ◽  
Author(s):  
Hideo Hirakata ◽  
Fumitaka Ushikubi ◽  
Hiroshi Toda ◽  
Kumi Nakamura ◽  
Satoko Sai ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Human Platelet ◽  
Adenosine Diphosphate ◽  
Scatchard Analysis ◽  
Cyclooxygenase Activity ◽  
Human Platelet Aggregation ◽  
Induced Aggregation

Background Halothane increases bleeding time and suppresses platelet aggregation in vivo and in vitro. A previous study by the authors suggests that halothane inhibits platelet aggregation by reducing thromboxane (TX) A2 receptor-binding affinity. However, no studies of the effects of sevoflurane on platelet aggregation have been published. Methods The effects of sevoflurane, halothane, and isoflurane were examined at doses of 0.13-1.4 mM. Human platelet aggregation was induced by adenosine diphosphate, epinephrine, arachidonic acid, prostaglandin G2, and a TXA2 agonist ([+]-9, 11-epithia-11, 12-methano-TXA2, STA2) and measured by aggregometry. Platelet TXB2 levels were measured by radioimmunoassay, and the ligand-binding characteristics of the TXA2 receptors were examined by Scatchard analysis using a [3H]-labeled TXA2 receptor antagonist (5Z-7-(3-endo-([ring-4-[3H] phenyl) sulphonylamino-[2.2.1.] bicyclohept-2-exo-yl) heptenoic acid, [3H]S145). Results Isoflurane (0.28-0.84 mM) did not significantly affect platelet aggregation induced by adenosine diphosphate and epinephrine. Sevoflurane (0.13-0.91 mM) and halothane (0.49-1.25 mM) inhibited secondary platelet aggregation induced by adenosine diphosphate (1-10 microM) and epinephrine (1-10 microM) without altering primary aggregation. Sevoflurane (0.13 mM) also inhibited arachidonic acid-induced aggregation, but not that induced by prostaglandin G2 or STA2, although halothane (0.49 mM) inhibited the latter. Sevoflurane (3 mM) did not affect the binding of [3H]S145 to platelets, whereas halothane (3.3 mM) suppressed it strongly. Sevoflurane (0.26 mM) and halothane (0.98 mM) strongly suppressed TXB2 formation by arachidonic acid-stimulated platelets. Conclusions The findings that sevoflurane suppressed the effects of arachidonic acid, but not those of prostaglandin G2 and STA2, suggest strongly that sevoflurane inhibited TXA2 formation by suppressing cyclooxygenase activity. Halothane appeared to suppress both TXA2 formation and binding to its receptors. Sevoflurane has strong antiaggregatory effects at subanesthetic concentrations (greater than 0.13 mM; i.e., approximately 0.5 vol/%), whereas halothane has similar effects at somewhat greater anesthetic concentrations (0.49 mM; i.e., approximately 0.54 vol/%). Isoflurane at clinical concentration (0.84 mM; i.e., approximately 1.82 vol/%) does not affect platelet aggregation significantly.

scholarly journals Effects of acetyl glyceryl ether phosphorylcholine on human platelet function in vitro

Blood ◽  
1981 ◽  
Vol 58 (5) ◽  
pp. 1027-1031
Author(s):  
AJ Marcus ◽  
LB Safier ◽  
HL Ullman ◽  
KT Wong ◽  
MJ Broekman ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Initial Phase ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
Human Platelets ◽  
Strong Stimulus ◽  
Adp Release ◽  
Irreversible Aggregation ◽  
Induced Aggregation

AGEPC (PAF), at 1.9 x 10(-8) M or higher, induced concentration- dependent aggregation and release in human platelet-rich plasma. Comparative studies with arachidonate, collagen, ionophore, and ADP suggested that AGEPC was a strong stimulus for platelet aggregation and probably a moderate agonist for release, as well as a relatively weak inducer of TXA2 production. The initial phase of AGEPC-induced aggregation was independent of ADP release and TXA2 formation, since it was not inhibited by ASA, apyrase, or CP/CPK. Whereas irreversible aggregation always required ADP release, TXA2 formation was not essential in each instance. Thus, in several experiments, full aggregation responses took place in AGEPC-stimulated platelets that had been pretreated with ASA. AGEPC-induced release of 5-HT, beta - thromboglobulin and PF-4 occurred in parallel and were inhibited by both apyrase and ASA. Washed human platelets did not respond to exogenous AGEPC in the absence of ADP and did not appear to generate significant quantities of AGEPC upon stimulation with thrombin or ionophore.

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