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.

COMPARISON OF THE ANTI-FERTILITY AND SEX HORMONAL ACTIVITIES OF SEX HORMONES AND THEIR DERIVATIVES

1964 ◽  
Vol 47 (3) ◽  
pp. 444-456 ◽  
Author(s):  
P. A. Desaulles ◽  
C. Krähenbühl
Keyword(s):  
Sex Hormones ◽  
Relative Intensity ◽  
Sex Steroids ◽  
Inhibitory Action ◽  
Inhibitory Effect ◽  
The Other ◽  
Potent Effect ◽  
Other Hand ◽  
Activity Ratios ◽  
Blastocyst Implantation

ABSTRACT The following effects exerted by sex steroids were measured: androgenic, oestrogenic, and progestational effects; the inhibition action on gonadotrophic function in castrated animals; and the inhibitory action on ovulation and blastocyst implantation in intact animals. The steroids investigated consisted of oestradiol and its ethinyl and methoxyethinyl derivatives, oestrone, oestriol, testosterone, progesterone, and certain synthetic gestagens derived from nortestosterone, i. e. norethisterone, norethynodrel, and ethinyl-oestrenol. Oestradiol and its derivatives show potent anti-gonadotrophic activity, a relatively less potent anti-ovulatory effect, and a marked inhibitory action on implantation. Progesterone, on the other hand, which has only a very weak inhibitory effect on gonadotrophic function, shows an anti-ovulatory activity which, though inferior in absolute terms to that of oestradiol, is still appreciable, whereas it exerts almost no effect at all on implantation. With regard to its activity ratios, testosterone occupies a position mid-way between the two female hormones. Norethisterone, norethynodrel, and ethinyl-oestrenol have a more potent effect on gonadotrophic function than progesterone. The activity ratios for the effects of these three compounds on ovulation and implantation are comparable to those of oestradiol or progesterone, depending on the relative intensity of their oestrogenic and progestational action. The nature of the endocrine changes produced by these compounds are discussed with reference to the inhibition of ovulation and implantation.

Specific Inhibition of Platelet Agglutination and Aggregation by Aromatic Amidino Compounds

1978 ◽  
Vol 39 (02) ◽  
pp. 411-425 ◽  
Author(s):  
J D Geratz ◽  
R R Tidwell ◽  
K M Brinkhous ◽  
S F Mohammad ◽  
O Dann ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Human Plasma ◽  
Inhibitory Effect ◽  
The Other ◽  
Specific Inhibition ◽  
Test Systems ◽  
Other Hand ◽  
Bovine Plasma ◽  
Inhibitory Activities ◽  
High Concentrations

SummaryA series of aromatic amidino compounds were investigated for their inhibitory effect on platelet agglutination and platelet aggregation. Agglutination of fresh or fixed platelets was produced by bovine plasma or by human plasma in combination with ristocetin, while aggregation of fresh platelets was induced by ADP, thrombin or collagen. Highly effective inhibitors were found for both types of platelet clumping, but there was no parallelism between the inhibitory activities in the two test systems. 5-(5-amidino-2-benzimidazolyl)-2-(4-hydroxyben-zene)benzimidazole suppressed agglutination exclusively. Pentamidine, on the other hand, strongly blocked the aggregation reactions, but did not interfere with agglutination, even at high concentrations. Compounds which inhibited aggregation also prevented the liberation of serotonin from the platelets.

Adenine Nucleotide Metabolism of Human Platelets

1971 ◽  
Vol 25 (02) ◽  
pp. 223-233
Author(s):  
M Murakami ◽  
K Odake
Keyword(s):  
Adenine Nucleotide ◽  
Platelet Rich Plasma ◽  
Adenine Nucleotides ◽  
Human Platelets ◽  
Nucleotide Metabolism ◽  
The Other ◽  
Supernatant Fraction ◽  
Two Dimensional ◽  
Adenine Nucleotide Metabolism ◽  
Layer Chromatography

SummaryAfter platelet-rich plasma was incubated with radioactive adenine, radioactive adenine nucleotides in platelets were separated by two-dimensional thin-layer chromatography.Radioactive adenine was selectively incorporated into adenine nucleotides. Gradual decomposition of labelled nucleotides was observed after longer period of incubation. Radioactive ATP, ADP, AMP, IMP, and hypoxanthine were separated from PCA extract of platelets. On the other hand, radioactive adenine and hypoxanthine were separated from platelet-poor plasma.After thrombin treatment, radioactive ATP in platelets broke down rapidly, while radioactive ADP decreased more slowly. Radioactive AMP increased at first in the cellular and supernatant fractions, and then decreased gradually. The accumulation of radioactive hypoxanthine was observed in the supernatant fraction. Released radioactive ATP and ADP were 23% and 22% of the initial radioactive ATP and ADP in platelets, respectively.

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.

Reaction of Acetaldehyde with Human Platelets

1992 ◽  
Vol 67 (01) ◽  
pp. 126-130 ◽  
Author(s):  
Olivier Spertini ◽  
Jacques Hauert ◽  
Fedor Bachmann
Keyword(s):  
Platelet Aggregation ◽  
Inhibitory Action ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Shape Change ◽  
Reaction Medium ◽  
Human Platelets ◽  
Membrane Glycoproteins ◽  
Neutral Ph

SummaryPlatelet function defects observed in chronic alcoholics are not wholly explained by the inhibitory action of ethanol on platelet aggregation; they are not completely reproduced either in vivo by short-term ethanol perfusion into volunteers or in vitro by the addition of ethanol to platelet-rich plasma. As acetaldehyde (AcH) binds to many proteins and impairs cellular activities, we investigated the effect of this early degradation product of ethanol on platelets. AcH formed adducts with human platelets at neutral pH at 37° C which were stable to extensive washing, trichloracetic acid hydrolysis and heating at 100° C, and were not reduced by sodium borohydride. The amount of platelet adducts formed was a function of the incubation time and of the concentration of AcH in the reaction medium. At low AcH concentrations (<0.2 mM), platelet bound AcH was directly proportional to the concentration of AcH in the reaction medium. At higher concentrations (≥0.2 mM), AcH uptake by platelets tended to reach a plateau. The amount of adducts was also proportional to the number of exposures of platelets to pulses of 20 pM AcH.AcH adducts formation severely impaired platelet aggregation and shape change induced by ADP, collagen and thrombin. A positive correlation was established between platelet-bound AcH and inhibition of aggregation.SDS-PAGE analysis of AcH adducts at neutral pH demonstrated the binding of [14C]acetaldehyde to many platelet proteins. AcH adduct formation with membrane glycoproteins, cytoskeleton and enzymes might interfere with several steps of platelet activation and impair platelet aggregation.This in vitro study shows that AcH has a major inhibitory action on platelet aggregation and may account for the prolonged ex vivo inhibition of aggregation observed in chronic alcoholics even in the absence of alcoholemia.

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 ADP-Induced Responses in Human Platelets by Agents Elevating the Cyclic AMP Level: Comparison of Aggregation and Shape Change

1984 ◽  
Vol 52 (03) ◽  
pp. 333-335 ◽  
Author(s):  
Vider M Steen ◽  
Holm Holmsen
Keyword(s):  
Inhibitory Action ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
Shape Change ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Inhibitory Effects ◽  
Early Step ◽  
Stimulus Response ◽  
Sequential Relationship

SummaryThe inhibitory effect of cAMP-elevating agents on shape change and aggregation in human platelets was studied to improve the understanding of the sequential relationship between these two responses.Human platelet-rich plasma was preincubated for 2 min at 37° C with prostaglandin E1 or adenosine, agents known to elevate the intracellular level of cAMP. Their inhibitory effects on ADP-induced shape change and aggregation were determined both separately and simultaneously. The dose-inhibition patterns for shape change and aggregation were similar for both PGE1 and adenosine. There was no distinct difference between the inhibitory action of these two inhibitors.These observations suggest that elevation of the intracellular concentration of cAMP interferes with an early step in the stimulus-response coupling that is common for aggregation and shape change.

Mechanism of the Antiplatelet Action of Dipyridamole in Whole Blood: Modulation of Adenosine Concentration and Activity

1986 ◽  
Vol 55 (01) ◽  
pp. 012-018 ◽  
Author(s):  
Paolo Gresele ◽  
Jef Arnout ◽  
Hans Deckmyn ◽  
Jos Vermylen
Keyword(s):  
Platelet Aggregation ◽  
Adenosine Receptor ◽  
Whole Blood ◽  
Blood Cells ◽  
Inhibitory Action ◽  
Phosphodiesterase Inhibitor ◽  
Inhibitory Effect ◽  
Adenosine Concentration ◽  
Pharmacological Studies

SummaryDipyridamole inhibits platelet aggregation in whole blood at lower concentrations than in plasma. The blood cells responsible for increased effectiveness in blood are the erythrocytes. Using the impedance aggregometer we have carried out a series of pharmacological studies in vitro to elucidate the mechanism of action of dipyridamole in whole blood. Adenosine deaminase, an enzyme breaking down adenosine, reverses the inhibitory action of dipyridamole. Two different adenosine receptor antagonists, 5’-deoxy-5’-methylthioadenosine and theophylline, also partially neutralize the activity of dipyridamole in blood. Enprofylline, a phosphodiesterase inhibitor with almost no adenosine receptor antagonistic properties, potentiates the inhibition of platelet aggregation by dipyridamole. An inhibitory effect similar to that of dipyridamole can be obtained combining a pure adenosine uptake inhibitor (RE 102 BS) with a pure phosphodiesterase inhibitor (MX-MB 82 or enprofylline). Mixing the blood during preincubation with dipyridamole increases the degree of inhibition. Lowering the haematocrit slightly reduces the effectiveness.Although we did not carry out direct measurements of adenosine levels, the results of our pharmacological studies clearly show that dipyridamole inhibits platelet aggregation in whole blood by blocking the reuptake of adenosine formed from precursors released by red blood cells following microtrauma. Its slight phosphodiesterase inhibitory action potentiates the effects of adenosine on platelets.

scholarly journals Selective Inhibition of Platelet Agglutination and Aggregation by Aromatic Amidino Compounds

1977 ◽  
Author(s):  
J. D. Geratz ◽  
R. R. Tidwell ◽  
K. M. Brinkhous ◽  
S. F. Mohammad
Keyword(s):  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
The Other ◽  
Future Studies ◽  
Bovine Plasma ◽  
Inhibitory Activities ◽  
High Concentrations ◽  
Ristocetin Cofactor ◽  
Specific Inhibitors

A series of aromatic amidino compounds were investigated for their inhibitory effect on platelet agglutination and platelet aggregation. Agglutination of fresh or fixed human platelets was produced by bovine plasma or by human plasma in combination with ristocetin, while aggregation of fresh platelets was induced by ADP, thrombin or collagen. Highly effective inhibitors were found for both types of platelet clumping, but there was no parallelism between the inhibitory activities in the two test systems.5-(5-Amidino-2-benzimidazolyl)-2-(4-hydroxybenzene)benzimidazole suppressed agglutination exclusively. Pentamidine, on the other hand, strongly blocked the aggregation reactions, but did not interfere with agglutination, even at high concentrations. Compounds which inhibited aggregation also prevented the liberation of serotonin from the platelets.This investigation has led to the identification of new specific inhibitors of platelet agglutination and aggregation which can serve an important role in future studies of the two processes. The exact mode of interaction between ami dines and platelets is still being explored.. In the case of agglutination, inhibition most likely occurred at the level of binding of ristocetin cofactor to the platelet membrane. In the case of aggregation, however, interference could have taken place at the membranes or in the cytoplasm and could have been enzymatic or non-enzymatic in nature.

scholarly journals Nucleotide and Serotonin Metabolism in Platelets With Defective Secondary Aggregation

Blood ◽  
1974 ◽  
Vol 44 (6) ◽  
pp. 789-800 ◽  
Author(s):  
F. I. Pareti ◽  
H. J. Day ◽  
D. C. B. Mills
Keyword(s):  
Platelet Aggregation ◽  
Adenine Nucleotide ◽  
Platelet Rich Plasma ◽  
Adenine Nucleotides ◽  
Rapid Rate ◽  
Serotonin Metabolism ◽  
Release Reaction ◽  
Atp Breakdown ◽  
Platelet Defects ◽  
Adenine Nucleotide Pool

Abstract Ten patients with qualitative platelet defects have been investigated. All of the patients had impairment of secondary platelet aggregation induced by ADP, epinephrine, and collagen, and a defective release reaction. In seven patients from four families, the abnormality was consistent with the lack of a metabolically inert adenine nucleotide pool. Four of these patients, from two families, were albinos. Platelets from all of these patients had lower than normal amounts of adenine nucleotides and 5HT; the ability of these platelets to incorporate the amine was reduced and 5HT was metabolized at an abnormally rapid rate in platelet-rich plasma. It was not possible to distinguish the defect present in the albinos from that in the normally pigmented patients. Three other patients had normal amounts of platelet adenine nucleotides and 5HT; platelet aggregation and the release of adenine nucleotides induced by collagen were impaired. Metabolic ATP breakdown, during collagen aggregation, was also decreased. This defect is similar to that induced in normal platelets by aspirin. Studies on intracellular synthesis of cyclic 3'5' AMP in both groups of patients showed that the platelets were normally responsive to PGE1 and the antagonism of PGE1 by ADP and by epinephrine was also normal.

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