Effects Of Bay g 6575 On Platelets And On Vascular PGI2 Production

1981 ◽  
Author(s):  
D E MacIntyre ◽  
E W Salzman
Keyword(s):  
Vascular Tissue ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Duration Of Action ◽  
Antithrombotic Activity ◽  
Vascular Rings ◽  
And Control ◽  
Induced Aggregation

Bay g 6575 (1-[2-(β-naphthyloxy) ethyl]-3-methy1-2-pyrazolin-5-one) exerts a protective effect in several animal models of thrombosis. To elucidate its mechanism of action, we examined the effects of Bay g 6575 on platelets and on vascular PGI2 production. In vitro addition of Bay g 6575 (200 μM) to human citrated platelet rich plasma (PRP) did not inhibit aggregation induced by ADP or U44069, or augment inhibition of ADP-induced aggregation by PGD2, PGE1, PGI2 or papaverine. When added to isolated human or rat vascular rings, Bay g 6575 (200 μM) did not stimulate production of PGI2 or 6-oxo-PGF1α. Ex vivo studies one hour after administration of Baya g 6575 to rabbits (10 mg/kg, i.a.) or rats (100 mg/kg, p.o.) revealed no inhibition of ADP-induced aggregation or enhancement of the level of “circulating” PGI2 as measured by bio-immunoassay. When production of anti-aggregating activity by vascular rings from Bay g 6575 treated (B) and Control (C) rats were compared, in 6 of 8 experiments B inhibited more than C and B produced more 6-oxo-PGF1α than C (mean increase in B ± s.d.=74.3 ± 35.7%, range 42-135%). Production of antiaggregatory activity by “exhausted” C rings was enhanced by B>C platelet free plasma. In all cases, the inhibitor of aggregation produced by B and C rings acted on both human and rat PRP, and its effects could be reversed by anti-PGI1 antibodies that neutralize PGI2>6-oxo-PGE1>PGD2. When exogenous PGI2 was incubated with (exhausted) aspirin treated vascular rings, the duration of action of PGI2 was longer in the presence of B rings than C rings.Bay g 6575 has no direct effects on platelets or on vascular tissue. Its antithrombotic activity appears to be caused by regulation of PGI2 synthesis and metabolism, an effect mediated by factors, possibly Bay g 6575 metabolites, present in plasma after in vivo administration.

The pharmacology of L-670,596, a potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist

1989 ◽  
Vol 67 (9) ◽  
pp. 989-993 ◽  
Author(s):  
A. W. Ford-Hutchinson ◽  
Y. Girard ◽  
A. Lord ◽  
T. R. Jones ◽  
M. Cirino ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Guinea Pig ◽  
Receptor Antagonist ◽  
Competitive Inhibition ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Prostaglandin Endoperoxide ◽  
Induced Aggregation

L-670,596 ((−)6,8-difluoro-9-p-methylsulfonyl benzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid) has been shown to be a potent receptor antagonist as evidenced by the inhibition of the binding of 125I-labeled PTA-OH to human platelets (IC50, 5.5 × 10−9 M), inhibition of U-44069 induced aggregation of human platelet rich plasma (IC50, 1.1 × 10−7 M), and competitive inhibition of contractions of the guinea pig tracheal chain induced by U-44069 (pA2,9.0). The compound was also active in vivo as shown by inhibition of arachidonic acid and U-44069 induced bronchoconstriction in the guinea pig (ED50 values, 0.04 and 0.03 mg/kg i.v., respectively), U-44069 induced renal vasoconstriction in the pig (ED50, 0.02 mg/kg i.v.), and inhibition of ex vivo aggregation of rhesus monkey platelets to U-44069 (active 1–5 mg/kg p.o.). The selectivity of the compound was indicated by the failure to inhibit, first, ADP-induced human or primate platelet aggregation and, second, bronchoconstriction in the guinea pig in vivo and contraction of the guinea pig tracheal chain in vitro to a variety of agonists. It is concluded that L-670,596 is a potent, selective, orally active thromboxane A2/prostaglandin endoperoxide receptor antagonist.Key words: thromboxane A2, thromboxane antagonist, prostaglandin endoperoxides, platelet aggregation.

Lu 23051, A New Potent Inhibitor Of Platelet Aggregation

1981 ◽  
Author(s):  
H D Lehmann ◽  
J Gries ◽  
D Lenke
Keyword(s):  
Platelet Aggregation ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Coronary Vessels ◽  
Inhibitory Effect ◽  
Spontaneously Hypertensive ◽  
Dependent Inhibition ◽  
Induced Aggregation

6- [p-(2-(Chiorpropionylamino)phenyl] -4.5-dihydro-5-methyl-3(2H)-pyridazinone, LU 23051, is primarily characterized by its strong inhibition of platelet aggregation under in vitro and in vivo conditions. In vitro there is a concentration-dependent inhibition of ADP and collagen induced aggregation in platelet rich plasma of man, rat and dog. The inhibitory concentration EC 33 % is 0.0010-0.030 mg/1 (man: ADP-0.030, col 1.-0.013 mg/l) depending on species and type of aggregation. When administered orally in ex vivo experiments on rats and dogs the substance is found to have a dose-dependent antiaggregatory effect in the range from 0.1-3.16 mg/kg. The ED 33 % is 0.27-0.63 mg/kg.-In addition after oral administration the substance has a good inhibitory effect in models being based on intravascular platelet aggregation. Thus, a dose of 1 mg/kg inhibits laser-induced aggregation in mesenteric venules of rats. Mortality after i.v. injection of collagen in mice is reduced by 50 % after a dose of 0.02 mg/kg. A dose of 0.039 mg/kg prolongs the bleeding time of rats by 50 %. The aggregation-inhibiting action is of long duration (0.1 mg/kg p.o.∼24 h). The substance does not interfere with clotting.Besides its effect on platelet aggregation LU 23051 acts as vasodilatator as well. Dilatation of coronary vessels by 100 % is seen in isolated guinea-pig hearts at a concentration of 0.1 mg/l. In spontaneously hypertensive rats the substance has an anti hypertensive effect. The ED 20 % is 0.36 mg/kg p.o.The combination of antiaggregatory and vasodilatatory effects opens up interesting aspects with respect to the pharmacotherapeutic use of the new substance

COMPARISON OF THE ANTITHROMBOTIC, ANTICLOTTING AND ANTIPLATELET AGGREGATORY ACTIVITIES OFLOW MOLECULAR WEIGHT RD HEPARIN WITH HEPARIN

1987 ◽  
Author(s):  
R L Fenichel ◽  
W Carmint ◽  
B Small ◽  
J Willis
Keyword(s):  
Human Platelet ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Subcutaneous Administration ◽  
Factor Xa ◽  
Duration Of Action ◽  
Antithrombotic Activity ◽  
Significant Difference ◽  
Initial Comparison

An initial comparison of in vitro plasma anti-factor Xa (anti Xa) and activated partial thromboplastin time (APTT) values of RD heparin with heparin based upon USP units shows increased anti Xa and decreased APTT activity of RD heparin. An ex vivo experiment in rabbits in which 100 USP units/kg of RD heparinand 200 USP units/kg of heparin, when given by the subcutaneous route, reflects the significantly increased anti Xa activity generated by RD heparin as wellas its longer duration of action. No significant difference in APTT activity was observed for the two heparins, but an increased anti Xa/APTT ratio (greaterthan two) was observed for the RD heparin. Heparin (10 yg/ml), but not RD heparin, potentiated adenosinediphosphate (ADP) induced platelet aggregation in human platelet rich plasma. Subcutaneous administration of RD heparin or heparin to rabbits over the dosage range of 0.75 to 1.75 mg/kg gives similar mean dose response lines for these heparins in the thrombosis-stasis model as measured by the extent of jugular vein clotting. Administration of these heparins to rabbits on a USP unitage basis shows a significantly greater antithrombotic effect for RD heparin at 120 and 160 USP units/kg. Moreover, this experiment indicates that if the optimum dosage of 120 USP units/kgfor RD heparin is exceeded then we begin to see an indication of loss of antithrombotic activity.

ETHANOL INHIBITS RABBIT PLATELET RESPONSES TO COLLAGEN IN VITRO BUT DOES NOT AFFECT RABBIT PLATELET ADHERENCE TO DE-ENDOTHELIALIZED A0RTAE IN VIVO

1987 ◽  
Author(s):  
M L Rand ◽  
H M Groves ◽  
R L Kinlough-Rathbone ◽  
M A Packham ◽  
J F Mustard
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Platelet Adherence ◽  
Induced Aggregation

Epidemiological studies indicate that moderate consumption of alcohol is associated with a reduced risk of coronary heart disease, but it is not known whether inhibition of platelet functions by ethanol is involved. We studied the effects of ethanol on rabbit platelet responses to collagen in vitro and in vivo. Addition of ethanol (4 mg/ml) to suspensions of washed platelets prelabelled with [14c]serotonin inhibited aggregation and secretion in response to low (0.4 μg/ml) concentrations of acid soluble collagen (14% secretion without ethanol, 3% secretion with ethanol). With a higher concentration of collagen (1.25 μg/ml), 4 mg/ml ethanol had no inhibitory effect. The inhibitory effect of ethanol on collagen-induced aggregation was also observed in citrated platelet-rich plasma (c-PRP) to which ethanol was added in vitro and in c-PRP from rabbits given ethanol acutely by gavage (3.5 g/kg) 30 min before blood sampling. The accumulation of [51cr]-labeled platelets on the subendothelium of rabbit aortae de-endothelialized with balloon catheters was measured in vivo in rabbits given ethanol (blood ethanol concentration at time of vessel wall injury: 4.1 ± 0.2 mg/ml, mean ± S.E., n=6). Ten min after de-endothelialization, there was no difference between the number of platelets adherent per square mm of injured aorta of control rabbits (39,400 ± 2,600, mean ± S.E., n=6) and intoxicated rabbits (36,800 ± 3,700, mean ± S.E., n=6). Thus, although ethanol inhibits platelet aggregation and secretion in response to collagen in vitro and ex vivo, it does not alter platelet adherence to the subendothelium, including its constituent collagen, in vivo. Therefore, it is unlikely that ethanol exerts its beneficial effects against coronary heart disease by altering the initial adherence of platelets to injured vessel walls.

Dipyridamole Inhibits Platelet Aggregation in Whole Blood

1983 ◽  
Vol 50 (04) ◽  
pp. 852-856 ◽  
Author(s):  
P Gresele ◽  
C Zoja ◽  
H Deckmyn ◽  
J Arnout ◽  
J Vermylen ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Whole Blood ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Significant Negative Correlation ◽  
Significant Inhibition ◽  
Oral Drug ◽  
Human Blood Samples ◽  
Induced Aggregation

SummaryDipyridamole possesses antithrombotic properties in the animal and in man but it does not inhibit platelet aggregation in plasma. We evaluated the effect of dipyridamole ex vivo and in vitro on platelet aggregation induced by collagen and adenosine- 5’-diphosphate (ADP) in human whole blood with an impedance aggregometer. Two hundred mg dipyridamole induced a significant inhibition of both ADP- and collagen-induced aggregation in human blood samples taken 2 hr after oral drug intake. Administration of the drug for four days, 400 mg/day, further increased the antiplatelet effect. A significant negative correlation was found between collagen-induced platelet aggregation in whole blood and dipyridamole levels in plasma (p <0.001). A statistically significant inhibition of both collagen (p <0.0025) and ADP-induced (p <0.005) platelet aggregation was also obtained by incubating whole blood in vitro for 2 min at 37° C with dipyridamole (3.9 μM). No such effects were seen in platelet-rich plasma, even after enrichment with leukocytes. Low-dose adenosine enhanced in vitro inhibition in whole blood.Our results demonstrate that dipyridamole impedes platelet aggregation in whole blood by an interaction with red blood cells, probably involving adenosine.

Effects Of Pentoxifylline, Penbutolol, Prenylamine, Clofibric Acid And Nicotinic Acid On The Release Of Prostacyclin-(PGI2-) Like Activity From Rat Aorta In Vivo And In Vitro

1981 ◽  
Author(s):  
K U Weithmann ◽  
A G Hoechst
Keyword(s):  
Cyclic Amp ◽  
Nicotinic Acid ◽  
Ex Vivo ◽  
Synergistic Effects ◽  
Rat Aorta ◽  
Clofibric Acid ◽  
Vessel Walls ◽  
Induced Aggregation

Aortas from rats, treated with 5-20 mg/kg of pentoxifylline (pof), penbutolol, prenylamine, clofibric acid or nicotinic acid showed, ex vivo, a significantly higher release of acid labile PGI2-like anti-aggregatory activity compared to controls. This activity could be suppressed by pre-treatment with 2 mg/kg Indomethacin. When incubated with rat aortas in vitro, pof showed a similar stimulatory effect on PGI2-like release, whereas clofibric-and nicotinic acid had no significant effect in this system. Pof and all other drugs mentioned above in therapeutical concentrations had virtually no effect on induced aggregation of human platelets in vitro. However, in the presence of small amounts PGI2 in vitro, inhibition of aggregation and platelet cyclic AMP are enhanced synergistically above the effects of PGI2 and pof individually.We conclude from these experiments that therapeutic doses of all drugs in our study stimulate in vivo the release of PGI2-like activity from vessel walls, thus inhibiting platelet aggregation in vivo. The primary site of action of pof seems to be the vessel wall, whereas the effect of clofibric acid and nicotinic acid on the vessel walls seem to be secondary. The elevation of platelet cyclic AMP levels which generally parallels PGI2-induced inhibition of aggregation might be further enhanced by pof known as an inhibitor of platelet cyclic AMP phosphodiesterase, thus explaining the observed synergistic effects between PGI2 and pof.

scholarly journals Effects of Sodium Nitroprusside on Platelet Adhesion, Subsequent Aggregation and Vasoconstriction

1977 ◽  
Author(s):  
H.R. Baumgartner
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Sodium Nitroprusside ◽  
Platelet Adhesion ◽  
Ex Vivo ◽  
Balloon Catheter ◽  
Strong Inhibitor ◽  
Induced Aggregation

Sodium nitroprusside (SNP), a potent vasodilator, has shown beneficial effects in acute myocardial infarction. Since platelets may play an important role in the pathogenesis of myocardial infarction, the effect of SNP on their interaction with rabbit aorta subendothelium was investigated in vivo and under controlled blood flow conditions ex vivo and in vitro.One iliac artery and the abdominal aorta were denuded of endothelium by balloon catheter injury during infusion of glucose, SNP at 6 or 12 μg/kg/min in groups of 12, 6 and 7 rabbits respectively. The aorta and their branches were perfuse-fixed under controlled pressure 10 min after denudation. Morphometric evaluation showed dose-dependent and significant (2p < 0.01 or 0.001) inhibition of platelet spreading, adhesion and aggregation. The latter was abolished at the higher dose of SNP. Denudation and subsequent platelet adhesion caused strong vasoconstriction (2p < 0.001) which was inhibited by SNP (2p < 0.01).By exposure of subendothelium to either citrated blood or native blood in a flow chamber (2000 sec-1 shear rate) strong inhibition of spreading and adhesion-induced aggregation was again demonstrated at 6 and 12 μg/kg/min SNP. In vitro, adhesion-induced aggregation was completely abolished after the addition of SNP to rabbit (at 20 μg/ml) or human blood (2 μg/ml). 1 μg/ml PGE1 was needed to induce a similar inhibitory effect.Thus SNP is a strong inhibitor of platelet function and of injury + platelet induced vasoconstriction. These findings may explain its beneficial effect in acute myocardial infarction.

Inhibition of Human Platelet Aggregation by the Proteolytic Effect of Streptokinase (SK). Role of the Factor VIII Related Antigen

1975 ◽  
Author(s):  
R. Castillo ◽  
S. Maragall ◽  
J. A. Guisasola ◽  
F. Casals ◽  
C. Ruiz ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Platelet Rich Plasma ◽  
Gel Filtration ◽  
Inhibitory Effect ◽  
Factor Viii Related Antigen ◽  
Human Factor Viii ◽  
Induced Aggregation

Defective ADP-induced platelet aggregation has been observed in patients treated with streptokinase. This same effect appears “in vitro” when adding SK to platelet rich plasma (PRP). Classic hemophilia and normal platelet poor plasmas (PPP) treated with SK inhibit the aggregation of washed platelets; plasmin-treated normal human serum also shows an inhibitory effect on platelet aggregation. However, von Willebrand SK-treated plasmas do not inhibit the aggregation of washed platelets. The same results appear when plasmas are previously treated with a rabbit antibody to human factor VIII.This confirms that the antiaggregating effect is mainly linked to the digested factor VIII related antigen.The inhibition of ADP-induced platelet aggregation has been proved in gel filtration-isolated and washed platelets from SK-treated PRP.Defective ristocetin-induced platelet aggregation has also been observed- This action does not appear in washed platelets from SK-treated PRP in presence of normal PPP, but it does in presence of SK-treated PPP, which suggests that the inhibition of the ristocetin-induced aggregation is due to the lack of factor VIII and not to the factor VIII-related products.Heparin, either “in vivo” or “in vitro”, has corrected the antiaggregating effect of SK.

scholarly journals Antithrombotic Activity of a Potent, New Agent, 6,7-Dichloro-1,2,3,5-Tetrahydroimidazo[2,1-B] Quinazolin-2-One Hydrochloride Monohydrate

1977 ◽  
Author(s):  
J. S. Fleming ◽  
J. P. Buyniski
Keyword(s):  
Platelet Aggregation ◽  
Animal Models ◽  
Ex Vivo ◽  
Platelet Rich Plasma ◽  
Oral Dosage ◽  
Antithrombotic Agent ◽  
Duration Of Action ◽  
Antithrombotic Activity ◽  
Small Vessels ◽  
Hydrochloride Monohydrate

A potent, new anti-thrombotic agent, 6 ,7-dichloro-l,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-2-one hydrochloride monohydrate (BL-4162A) has been evaluated for activity against induced platelet aggregation in a series of in vitro and ex vivo experiments using platelet rich plasma (PRP) from various species including man. In addition, the compound’s potential utility as an antithrombotic agent has been tested in various in vivo animal models including two models of induced thrombosis involving both large and small vessels. Aggregometry was employed to test the ability of BL-4162A to inhibit platelet aggregation induced by aggregating agents such as ADP, collagen, thrombin and antigen-antibody complexes. The compound’s antithrombotic activity was evaluated in small vessels using the biolaser-rabbit ear chamber technique while the effect of BL-4162A on large vessel thrombosis was assessed against electrically-induced carotid artery thrombosis in dogs. Results indicate that BL-4162A inhibits platelet aggregation in the range of 0.08 to 0.68 pg/ml. Platelet antiaggregating activity was also observed in ex vivo aggregometry studies in dogs and rats at oral doses in the range of 1 to 10 mg/kg. Of particular interest, is the fact that BL-4162A effectively inhibited thrombosis in both animal models employed over the same oral dosage range. Results of the above investigations as well as an appreciable duration of action suggest that BL-4162A may be an important candidate for clinical evaluation in thromboembolism.

The Interaction Of Platelet Active Drugs With Prostacyclin In Vitro And Against Biolaser Induced Intravascular Thrombosis

1981 ◽  
Author(s):  
J S Fleming ◽  
B T Cornish ◽  
J O Buchanan ◽  
J P Buyniski
Keyword(s):  
Platelet Aggregation ◽  
Arachidonic Acid Metabolism ◽  
In Vivo Model ◽  
Additive Interaction ◽  
Antithrombotic Activity ◽  
Intravascular Thrombosis ◽  
Low Levels ◽  
Induced Aggregation

Prostacyclin and thromboxane A2, two of the physiologically most important end products of arachidonic acid metabolism, represent a basic control system which modulates platelet function. Decreased vascular prostacyclin is believed to play a role in the increased thrombotic tendency associated with various clinical diseases including diabetes and atherosclerosis. Compounds which either enhance the formation or release of prostacyclin or potentiate the activity of low levels of prostacyclin may be therapeutically useful in ameliorating this associated pathology. We have studied various inhibitors of platelet aggregation for their ability to potentiate the activity of low levels of prostacyclin both in vitro and in an in vivo model of experimental thrombosis. Anagrelide, aspirin, dipyridamole, sulfinpyrazone and ticlopidine all demonstrated interaction with prostacyclin in vitro against collagen-induced platelet aggregation. More limited interactions were observed against ADP-induced aggregation. Using isobolographic analysis most combinations demonstrated additive interaction. However, pronounced supra-additive interaction was observed vs. both aggregating agents in the case of prostacyclin (0.1-1 ng/ml) - anagrelide (8-90 ng/ml) combinations. Dramatic enhancement of the effects of prostacyclin on biolaser-induced thrombosis was also seen in anagrelide (0.5 mg/kg po) pretreated animals. Other inhibitors of platelet aggregation used in combination with prostacyclin produced less spectacular results. These findings suggest that aside from inherent antiaggregatory and antithrombotic activity, certain platelet active drugs may produce equally important effects by virtue of their ability to interact with prostacyclin in a clinically beneficial manner.

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