Effect of Indomethacin and Dazoxiben on Intravascular Platelet Aggregation in the Anaesthetized Rabbit

1986 ◽  
Vol 56 (01) ◽  
pp. 080-085 ◽  
Author(s):  
A C Honey ◽  
N Lad ◽  
D P Tuffin
Keyword(s):  
Platelet Aggregation ◽  
Plasma Levels ◽  
Thromboxane A2 ◽  
Adenosine Diphosphate ◽  
Thromboxane B2 ◽  
Bolus Intravenous Injection ◽  
Cyclic Endoperoxide ◽  
High Doses ◽  
Synthetic Capacity ◽  
Dose Dependent

Summary Collagen (10-40 μg kg−1), thrombin (1-10 units kg−1), adenosine diphosphate (ADP; 3-300 pμ kg−1), 1-0-hexadecyl Paf-acether and 1-0-octadecyl Paf-acether (1-300 ng kg−1) administered by bolus intravenous injection each caused dose-dependent thrombocytopoenia accompanied by marked hypotension in anaesthetized rabbits. Responses to ADP and the Paf-acether derivatives were transient in nature (3-8 min) whereas those induced by collagen and thrombin were always of longer duration (5-20 min) and frequently fatal at high doses. Responses to collagen, thrombin, and the Paf-acether derivatives were invariably accompanied by substantial, dose-related increases in plasma levels of thromboxane B2 in samples obtained 30 s after agonist administration, whereas following ADP, no change in plasma thromboxane B2 was detected at any dose level. Indomethacin (3.0 mg kg−1 by infusion) had no effect on responses to thrombin or Paf-acether, partially inhibited collagen-induced thrombocytopenia, and potentiated responses to ADP. In contrast, dazoxiben (10 mg kg−1 by infusion) partially but significantly inhibited responses to thrombin, whereas those induced by collagen, Paf-acether or ADP were unchanged. These results indicate that in this model of intravascular aggregation, whilst platelet responses to collagen and thrombin appear partially dependent on intact cyclic endoperoxide and thromboxane A2 synthetic capacity respectively, responses to ADP and Paf-acether are independent of arachidonate metabolism via cyclo-oxygenase despite measurably increased TXB2 formation in the latter case.

Mepacrine Blockade of Arachidonate-lnduced Washed Platelet Aggregation: Relationship to Mepacrine Inhibition of Platelet Cyclooxygenase

1983 ◽  
Vol 50 (04) ◽  
pp. 784-786 ◽  
Author(s):  
Amiram Raz
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Thromboxane A2 ◽  
Inhibitory Effect ◽  
Thromboxane B2 ◽  
Concomitant Increase ◽  
Dependent Inhibition ◽  
Dose Dependent Inhibition ◽  
Arachidonate Release ◽  
Dose Dependent

SummaryMepacrine, in addition to its established antilipolytic activity, was also found to inhibit the conversion of 14C-arachidonic acid to 14C-thromboxane B2 in human washed platelets. In the concentration range of 3.33-33 μM, mepacrine exerted a dose dependent inhibition of arachidonate conversion to thromboxane B2 in parallel to inhibition of arachidonate-induced platelet aggregation. Mepacrine inhibition of thromboxane formation was not accompanied by a concomitant increase in other cyclooxygenase products. Furthermore, mepacrine did not affect platelet transformation of added prostaglandin H2 to thromboxane A2 and other products. These results indicate that mepacrine inhibits the cyclooxygenase enzyme and not thromboxane synthase. In washed platelets, mepacrine inhibition of arachidonic acid conversion to thromboxane A2 appears to be a major factor in the overall inhibitory effect of the compound on the combined process of arachidonate release from cellular phospholipids and its conversion to proaggregatory products.

Effect of Vitamin E on Platelet Aggregation in Diabetes Mellitus

1984 ◽  
Vol 51 (03) ◽  
pp. 313-316 ◽  
Author(s):  
J Watanabe ◽  
F Umeda ◽  
H Wakasugi ◽  
H Ibayashi
Keyword(s):  
Vitamin E ◽  
Platelet Aggregation ◽  
Vascular Complications ◽  
Thromboxane A2 ◽  
Adenosine Diphosphate ◽  
Thromboxane B2 ◽  
Enhanced Production ◽  
Thromboxane Production ◽  
And Control ◽  
Platelet Thromboxane

SummaryVitamin E is known to be an inhibitor of platelet prostaglandin production and aggregation. The rate of platelet aggregation induced by adenosine diphosphate was significantly increased in diabetics with proliferative retinopathy and the enhanced production of thromboxane B2, a stable metabolite of thromboxane A2, was demonstrated in those patients. On the other hand, vitamin E in platelets was significantly reduced in diabetics compared with age matched controls. In addition, it was shown that vitamin E content in platelets examined in diabetic and control subjects inversely correlated with both the rate of platelet aggregation and thromboxane B2 production during aggregation. It is suggested that the reduced vitamin E levels in diabetic platelets can contribute to the mechanisms of the enhanced platelet thromboxane production and aggregation which relate to the development of vascular complications.

Platelet Aggregation in Whole Blood: The Role of Thromboxane A2 and Adenosine Diphosphate

1985 ◽  
Vol 54 (03) ◽  
pp. 612-616 ◽  
Author(s):  
A J Carter ◽  
S Heptinstall
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Adenosine Diphosphate ◽  
Blood Platelet ◽  
Thromboxane B2 ◽  
Lipoxygenase Inhibitor ◽  
Thromboxane Synthase Inhibitor ◽  
Synthase Inhibitor

SummaryThe platelet aggregation that occurred in whole blood in response to several aggregating agents (collagen, arachidonic acid, adenosine diphosphate, adrenaline and thrombin) was measured using an Ultra-Flo 100 Whole Blood Platelet Counter. The amounts of thromboxane B2 produced were measured by radioimmunoassay. The effects of various inhibitors of thromboxane synthesis and the effects of apyrase, an enzyme that destroys adenosine diphosphate, were determined.Platelet aggregation was always accompanied by the production of thromboxane B2, and the amounts produced depended on the nature and concentration of the aggregating agent used. The various inhibitors of thromboxane synthesis - aspirin and flurbiprofen (cyclo-oxygenase inhibitors), BW755C (a cyclo-oxygenase and lipoxygenase inhibitor) and dazoxiben (a selective thromboxane synthase inhibitor) - did not markedly inhibit aggregation. Results obtained using apyrase showed that adenosine diphosphate contributed to the aggregation process, and that its role must be acknowledged when devising means of inhibiting platelet aggregation in vivo.

Collagen-Induced Platelet Aggregation: -Evidence Against the Essential Role of Platelet Adenosine Diphosphate

1979 ◽  
Vol 42 (04) ◽  
pp. 1193-1206 ◽  
Author(s):  
Barbara Nunn
Keyword(s):  
Platelet Aggregation ◽  
Time Course ◽  
Essential Role ◽  
Atp Release ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
High Doses ◽  
Induced Aggregation

SummaryThe hypothesis that platelet ADP is responsible for collagen-induced aggregation has been re-examined. It was found that the concentration of ADP obtaining in human PRP at the onset of aggregation was not sufficient to account for that aggregation. Furthermore, the time-course of collagen-induced release in human PRP was the same as that in sheep PRP where ADP does not cause release. These findings are not consistent with claims that ADP alone perpetuates a collagen-initiated release-aggregation-release sequence. The effects of high doses of collagen, which released 4-5 μM ADP, were not inhibited by 500 pM adenosine, a concentration that greatly reduced the effect of 300 μM ADP. Collagen caused aggregation in ADP-refractory PRP and in platelet suspensions unresponsive to 1 mM ADP. Thus human platelets can aggregate in response to collagen under circumstances in which they cannot respond to ADP. Apyrase inhibited aggregation and ATP release in platelet suspensions but not in human PRP. Evidence is presented that the means currently used to examine the role of ADP in aggregation require investigation.

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.

The vagus nerve in the thermoregulatory response to systemic inflammation

1997 ◽  
Vol 273 (1) ◽  
pp. R407-R413 ◽  
Author(s):  
A. A. Romanovsky ◽  
C. T. Simons ◽  
M. Szekely ◽  
V. A. Kulchitsky
Keyword(s):  
Intravenous Injection ◽  
Systemic Inflammation ◽  
Second Phase ◽  
Thermoregulatory Response ◽  
Cool Environment ◽  
Bolus Intravenous Injection ◽  
High Doses ◽  
Colonic Temperature ◽  
Dose Dependent ◽  
Higher Doses

Experimentally, systemic inflammation induced by a bolus intravenous injection of lipopolysaccharide (LPS) may be accompanied by three different thermoregulatory responses: monophasic fever (the typical response to low doses of LPS), biphasic fever (medium doses), and hypothermia (high doses). In our recent study [Romanovsky, A. A., V. A. Kulchitsky, C. T. Simons, N. Sugimoto, and M. Szekely. Am. J. Physiol. (Regulatory Integrative Comp. Physiol.). In press], monophasic fever did not occur in subdiaphragmatically vagotomized rats. In the present work, we asked whether vagotomy affects the two other types of thermoregulatory response. Adult Wistar rats were vagotomized (or sham operated) and had an intravenous catheter implanted. On day 28 postvagotomy, the thermal responses to the intravenous injection of Escherichia coli LPS (0, 1, 10, 100, or 1,000 micrograms/kg) were tested in either a neutral (30 degrees C) or slightly cool (25 degrees C) environment. Three major results were obtained. 1) In the sham-operated rats, the 1 microgram/kg dose of LPS caused at 30 degrees C a monophasic fever with a maximal colonic temperature (Tc) rise of approximately 0.6 degree C; this response was abated (no Tc changes) in the vagotomized rats. 2) At 30 degrees C, all responses to higher doses of LPS (10-1,000 micrograms/kg) were represented by biphasic fevers (the higher the dose, the less pronounced the first and the more pronounced the second phase was); none of these biphasic fevers was altered in the vagotomized animals. 3) In response to the 1,000 micrograms/kg dose at 25 degrees C, hypothermia occurred: Tc changed by -0.5 +/- 0.1 degree C (nadir); this hypothermia was exaggerated (-1.1 +/- 0.1 degrees C) in the vagotomized rats. It is concluded that vagal afferentation may be important in the mediation of the response to minor amounts of circulating LPS, whereas the response to larger amounts is brought about mostly (if not exclusively) by nonvagal mechanisms. This difference may be explained by the dose-dependent mechanisms of the processing of exogenous pyrogens. Vagotomized animals also appear to be more sensitive to the hypothermizing action of LPS in a cool environment; the mechanisms of this phenomenon remain speculative.

A Study of Intravascular Platelet Aggregation in the Rat

1979 ◽  
Author(s):  
G. G. Duncan ◽  
G. M. Smith
Keyword(s):  
Arachidonic Acid ◽  
Platelet Count ◽  
Platelet Aggregation ◽  
Thromboxane A2 ◽  
Adenosine Diphosphate ◽  
Residual Response ◽  
Induced Aggregation ◽  
Anaesthetized Rat

Intravascular platelet aggregation can be studied by measuring the fall in the circulating platelet count induced by aggregating agents in anaesthetized animals. The Technicon Auto-counter was modified and connected via a double cannula to an anaesthetized rat to give a continuous count of the number of circulating platelets (1). Adenosine diphosphate (ADP), Collagen, Arachidonic acid (AA) and 5-Hydroxytryptamine (5-HT) were given at 15 minute intervals over a period of 2-3 hours. Aspirin (10 mg/Kg IV ) and Indomethacin (1-8 mg/Kg IV) partially inhibited collagen-induced aggregation and Indomethacin (2 mg/Kg IV) completely inhibited AA-induced aggregation. Adenosine (0.25 mg/min) inhibited the ADP-induced aggregation but did not inhibit aggregation produced by collagen or the residual response to collagen that remains after the addition of indomethacin.Reproducible responses to ADP and collagen were obtained but responses to AA and 5-HT were not reliable. Collagen-induced aggregation is thought to be mediated by the liberation of ADP, 5-HT and the formation of prostaglandin (PG ) endoperoxides and thromboxane A2. This study has shown that collagen-induced aggregation is reduced by inhibition of PG synthesis but the involvement of ADP or 5-HT could not be shown.

scholarly journals Prostaglandin Endoperoxides and Thromboxanes: Role in Platelets

1977 ◽  
Author(s):  
Bengt Samuelsson
Keyword(s):  
Smooth Muscle ◽  
Platelet Aggregation ◽  
Vascular Smooth Muscle ◽  
Thromboxane A2 ◽  
Human Platelets ◽  
Thromboxane B2 ◽  
Structural Work

Two groups of unstable (t1/2=5 min) endoperoxides, PGG and PGH compounds, have been isolated and shown to be precursors of the prostaglandins. The endoperoxides cause platelet aggregation and contract vascular and air-way smooth muscle.A new group of compounds(thromboxanes) derived from the endoperoxides has been discovered. A highly unstable(t1/2=30-40 sec) intermediate, thromboxane A2, between the endoperoxides and thromboxane B2 has been detected. Structural work indicates that it has a bicyclic oxane-oxetane structure. Thromboxane A2 is a potent aggregating agent with pronounced effects on vascular smooth muscle. Studies on the mechanisms of actions of the endoperoxides and thromboxanes in human platelets will be discussed.

Effects of gaseous anesthetics and ultrashort and short-acting barbiturates on human blood platelet free cytosolic calcium: relevance to their effects on platelet aggregation

1992 ◽  
Vol 70 (8) ◽  
pp. 1161-1166 ◽  
Author(s):  
R. B. Philp ◽  
P. Arora ◽  
D. J. McIver
Keyword(s):  
Nitrous Oxide ◽  
Platelet Aggregation ◽  
Adenosine Diphosphate ◽  
Blood Platelet ◽  
Cytosolic Calcium ◽  
Common Mechanism ◽  
Myristate Acetate ◽  
Elevated Pressures ◽  
Human Blood Platelet ◽  
High Doses

The effects of elevated pressures (to 6 atmospheres absolute (ATA)) of nitrous oxide (N2O) and of xenon (Xe), and barbiturates on platelet free cytosolic calcium ([Ca2+]i) and platelet aggregation were studied. N2O inhibited the ADP-induced rise in [Ca2+]i whereas Xe had no effect. Neither affected basal levels. Pentobarbital and methohexital had little effect on basal or stimulated levels in the presence or "absence" of extracellular Ca2+; but both, at concentrations > 10−4 M, inhibited platelet aggregation induced by adenosine diphosphate. Thiopental increased basal and stimulated [Ca2+]i when extracellular Ca2+ was present, but not when it was absent, and displayed a bimodal effect with low and high doses being more active than intermediate ones. It also potentiated aggregation. Methitural displayed similar, but nonsignificant, effects. These patterns held for all agents whether or not acetylsalicylic acid was present. Pentobarbital and methohexital inhibited phorbol myristate acetate aggregation in low extracellular calcium and no potentiation was seen with thiopental. In the absence of extracellular Ca2+, no potentiation was observed in stimulated platelets. Potentiation of aggregation previously reported for Xe does not involve increased Ca2+ uptake and did not occur in the absence of extracellular Ca2+. A common mechanism of action for these agents cannot be inferred from their effects on platelet aggregation or [Ca2+]i, as their pharmacological profiles differ markedly. It is evident that their inhibitory properties in this cell are not dependent on extracellular Ca2+, whereas the potentiation observed with pentobarbital, and formerly with Xe, is so dependent.Key words: platelets, aggregation, calcium, anesthetics, narcotic gases.

scholarly journals Deficiency of intact thrombospondin and membrane glycoprotein Ia in platelets with defective collagen-induced aggregation and spontaneous loss of disorder

Blood ◽  
1988 ◽  
Vol 71 (4) ◽  
pp. 1074-1078 ◽  
Author(s):  
B Kehrel ◽  
L Balleisen ◽  
R Kokott ◽  
R Mesters ◽  
W Stenzinger ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Type I Collagen ◽  
Adenosine Diphosphate ◽  
Membrane Glycoprotein ◽  
Type I ◽  
Bleeding Tendency ◽  
Clot Retraction ◽  
Spontaneous Disappearance ◽  
High Doses ◽  
Induced Aggregation

Platelets from a patient with a severe lifelong bleeding tendency, which later spontaneously disappeared, lacked intact thrombospondin and glycoprotein (GP) Ia. Before disappearance of the bleeding disorder, results of coagulation studies and platelet aggregation in response to adenosine diphosphate (ADP), arachidonic acid, thrombin, A23187, epinephrine, and ristocetin were normal. In contrast, aggregation only occurred in the presence of collagen or wheat germ agglutinin at unusually high doses of these agonists. The platelets adhered normally to purified bovine and human type I collagen, and they did not spread in the presence of methylated type I collagen. No collagen-induced clot retraction was observed. Two-dimensional gel electrophoretic analyses of platelet proteins and immunologic studies showed that intact thrombospondin and GP Ia were absent. Aggregation in response to collagen could be restored by adding thrombospondin. Disappearance of the bleeding tendency occurred at the onset of menopause; subsequent analyses revealed that thrombospondin and GP Ia were present in platelets and that collagen-induced platelet aggregation was normal. These results suggest that both thrombospondin and GP Ia are essential in collagen-induced platelet aggregation. The spontaneous disappearance of the bleeding tendency may have been related to hormonal influences.

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