Platelets, Thrombosis and Drugs

Mustard, J. F.; Packham, Marian A.

doi:10.2165/00003495-197509010-00003

Cited by 114 publications

(39 citation statements)

References 308 publications

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“…In addition, patients with elevated catecholamines such as in hypertension27 and coronary prone behavior pattern28 would be expected to be at greater risk of sudden death since catecholamines enhance human platelet aggregation. 29 These relationships are under investigation in our laboratory utilizing the present model in the hope that their significance in coronary disease may be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Platelet aggregation in partially obstructed vessels and its elimination with aspirin.

Folts¹,

Crowell²,

Rowe³

1976

Circulation

747

212

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SUMMARY In 35 open chest anesthetized dogs coronary and aortic blood flow were measured with electromagnetic flowmeters while aortic and distal coronary blood pressure and an epicardial ECG were recorded. A fixed amount of stenosis (60-80%) was produced in the coronary artery by an externally applied plastic cylinder. In 24 of the 35 dogs the coronary blood flow showed cyclical reductions to near zero, with a sudden spontaneous return to near control levels. During reduced flow the epicardial ECG showed ST-segment depression suggestive of ischemia, and ventricular premature beats were often noted. Six animals died acutely during episodes of reduced flow.MANY STUDIES OF MYOCARDIAL INFARCTION AND SUDDEN DEATH from coronary heart disease have been reported. The significance of acute occlusive thrombi as a precipitating cause is widely debated.' 2 Acute coronary occlusion by thrombi were found in 21%' to 88%4 of those infarcted hearts examined at autopsy. These data vary with the investigative technique and material examined. In many patients with coronary artery disease and sudden death no acute thrombus or other mechanism for producing acute coronary insufficiency is demonstrated at post mortem examination and an episode of transient ischemia precipitating arrhythmia is often postulated.Platelet aggregation is involved in the formation of arterial thrombi and is not prevented by coumarin or heparin anticoagulant therapy.5 Mechanical damage of platelets can induce platelet aggregation in vitro6 and thrombosis occurs in areas of turbulent flow.7 It has been postulated that the turbulent flow produced at the sites of atherosclerotic plaques may play a role in thrombus formation by inducing platelet aggregation.' It has also been postulated that sudden coronary death may result from platelet aggregates in the epicardial arteries of man.8'9We present experimental evidence here that a fixed stenosis in a narrowed coronary artery promotes periodic in vivo platelet aggregation which transiently increases obstruction and decreases coronary blood flow. The possible significance of these observations to coronary disease in man is discussed.Material and Methods Thirty-five healthy adult mongrel dogs of both sexes were anesthetized with morphine sulfate (3 mg/kg) followed one hour later by sodium pentobarbital (30 mg/kg). Respiration was maintained using a positive pressure respirator, and the heart was exposed through a left thoracotomy at the fifth intercostal space in the usual fashion. After 35 mg/kg of aspirin were given intravenously the cyclical reductions in coronary blood flow were abolished and the in vitro platelet aggregations were reduced from a control of 62.1 ± 15 units (Born technique) to an average of 23.7 ± 12 units. Histologic sections of the narrowed coronary artery obtained when coronary flow was reduced show an amorphous mass in the lumen which was thought to be a platelet aggregate. Perhaps a similar process of platelet aggregation occurs in the stenosed coronary arteries in man, producing acute coronary...

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Section: Discussionmentioning

confidence: 99%

Platelet aggregation in partially obstructed vessels and its elimination with aspirin.

Folts¹,

Crowell²,

Rowe³

1976

Circulation

747

212

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“…Considerable attention has focused on a pharmacological means of decreasing the in vivo platelet reactivity through inhibition of arachidonic acid metabolism. Thus, the nonsteroidal antiinflammatory agents (e.g., aspirin) which block the synthesis of PGH2 (8-11) (and hence TXA2) are currently being evaluated for their effectiveness in the treatment of thromboembolic disorders (12)(13)(14)(15)(16)(17). An alternative and potentially more specific means of inhibiting arachidonic acid-induced platelet aggregation would involve the development of compounds that selectively block the interaction of TXA2 and PGH2 with the platelet receptor(s).…”

mentioning

confidence: 99%

13-Azaprostanoic acid: a specific antagonist of the human blood platelet thromboxane/endoperoxide receptor.

Breton¹,

Venton²,

Enke³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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A newly synthesized 13-aza derivative of prostanoic acid (13-APA) specifically inhibited human platelet aggregation induced by arachidonic acid, prostaglandin H2, or the stable endoperoxide analog (15S)hyhroxy-9a,11a-epoxymethano)prosta-5Z,13E-dienoic acid. 13-APA also inhibited [14C]serotonin release in response to arachidonic acid, ADP, or thrombin but did not inhibit primar aregation induced by ADP or tirombin. 13-APA completely blocked prostaglandin H2-induced aggregation in indomethacin-treated resuspended platelets but did not inhibit thromboxane synthesis. We therefore conclude that 13APA acts as a direct antagonist of the platelet thromboxane/endoperoxide receptor. The aggregation of human blood platelets by arachidonic acid is mediated through the production of highly reactive intermediates, thromboxane A2 (TXA2) and prostaglandin H2 (PGH2) (1-7). Considerable attention has focused on a pharmacological means of decreasing the in vivo platelet reactivity through inhibition of arachidonic acid metabolism. Thus, the nonsteroidal antiinflammatory agents (e.g., aspirin) which block the synthesis of PGH2 (8-11) (and hence TXA2) are currently being evaluated for their effectiveness in the treatment of thromboembolic disorders (12)(13)(14)(15)(16)(17). An alternative and potentially more specific means of inhibiting arachidonic acid-induced platelet aggregation would involve the development of compounds that selectively block the interaction of TXA2 and PGH2 with the platelet receptor(s). Recently, Fitzpatrick et al. (18) reported that 9,11-epoxyiminoprosta-5,13-dienoic acid antagonizes TXA2 stimulation of platelet aggregation. However, it was also demonstrated that 9,11-iminoprostadienoic acid exhibited activity inconsistent with selective TXA2 receptor antagonism-e.g., 9,11-iminoprostadienoic acid inhibited prostacyclin (PGI2) synthesis in rabbit lung microsomes and BALB 3T3 cells and stimulated coronary smooth muscle. To date then, no specific antagonist of the TXA2 or PGH2 receptor has been reported.We have previously demonstrated that nitrogen-substituted derivatives of prostanoic acid are potent and specific inhibitors of arachidonic acid-induced aggregation (ref. 19, §). The inhibitory activity of the 13-azaprostanoate series was found to be highly sensitive to the stereochemistry of the 5-membered ring and the length of the amino side chain. Any deviation from the natural prostaglandin carbon skeletal arrangement resulted in decreased potency. In the present report, we provide evidence that 13-azaprostanoic acid (13-APA) inhibits arachadonic acid-induced aggregation by directly antagonizing the action of TXA2 or PGH2 at the receptor level.MATERIALS AND METHODS 13-APA was synthesized as described (19). Human blood, collected into sodium citrate (0.38% final concentration), was obtained from apparently healthy donors who had not received medication for 4 days prior to the study. Platelet-rich plasma (PRP) was prepared by centrifugation of the whole blood at 167 X g for 15 min, and the pla...

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“…The interactions between platelets and blood vessel walls are important in the development of thrombosis and cardiovascular disease such as myocardial infarction, stroke, and arteriosclerosis. [23][24][25] Once blood vessels are damaged, platelet aggregation occurs rapidly to form hemostatic plugs or arterial thrombi at the sites of vessel injury or in regions where blood flow is disturbed. These thrombi are the source of thromboembolic complications of arteriosclerosis, heart attacks, stroke, and peripheral vascular disease.…”

Section: Discussionmentioning

confidence: 99%

Antithrombotic and Antiallergic Activities of Daidzein, a Metabolite of Puerarin and Daidzin Produced by Human Intestinal Microflora.

Choo

Park

Yoon

et al. 2002

Biological & Pharmaceutical Bulletin

101

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The rhizome of Pueraria lobata (family Leguminosae) is frequently used for the liver diseases, strokes, and allergy as a crude substance taken orally in Asian countries as a traditional ingredient of polyprescriptions.1) Some isoflavones, puerarin, and daidzin, were isolated from the rhizome of Pueraria lobata as the main component.2,3) Among them, daidzin has acetaldehyde dehydrogenase and cAMP phosphoesterase inhibitory and antispasmatic activities, [4][5][6] and puerarin has hypoglycemic and coronary artery blood flow increasing activity. 7,8) Most herbal medicines are administered orally and their components are inevitably brought into contact with intestinal microflora in the alimentary tract. Most components are metabolized by the intestinal bacteria before absorption from the gastrointestinal tract.9) Related to the metabolism of puerarin and daidzin, Yasuda et al. reported that daidzein and its conjugates were found in the urine of rats orally administered puerarin and daidzin. 10,11) We also reported that puerarin and daidzin are transformed to daidzein and calycosin by human intestinal microflora. Based on these findings, we thought that these compounds could be metabolized to their aglycones by intestinal bacteria before absorption into the blood and expression of their pharmacological actions. However, the relationship between the pharmacological actions, such as antithrombotic and antiallergic effects, and the metabolism of these compounds by human intestinal microflora was not completely clarified.Therefore we investigated the antithrombotic and antiallergic activities of puerarin, daidzin, and daidzein, which is a metabolite of puerarin and daidzin produced by human intestinal microflora. MATERIALS AND METHODSMaterials Adenosine 5Ј-diphosphate (ADP), epinephrine, collagen, bovine serum albumin, prothrombin, thromboplastin, thrombin, hyaluronidase from bovine testis, p-nitrophenyl N-acetyl-b -D-glucosaminide, anti-dinitrophenol (DNP)-IgE, DNP-bovine serum albumin (BSA), Evans blue, hyaluronic acid potassium salts, azelastine, xanthine oxidase (XOD), 2,2-diphenyl-1-picrylhydrzyl (DPPH), and disodium cromoglycate (DSCG) were purchased from Sigma Chemical (U.S.A.). Puerarin and daidzin were isolated from the rhizome of P. lobata according to the method of Kakegawa et al.,[12][13][14] and daidzein was isolated according to our previous method.15) The other chemicals were of analytical reagent grade.Animals Sprague-Dawley rats (male, 180-220 g) and ICR mice (male, 20-24 g) were purchased from Sam Yook Animal Co. (Korea) and acclimatized for 1 week at a temperature of 22Ϯ1°C and humidity of 55Ϯ5% with free access to a commercial pellet diet (Samyang Co., Korea) and drinking water before the experiments. Animal experiments were carried out in accordance with international guidelines.Preparation of Platelets Blood from rats was collected by cardiac puncture into a plastic flask containing 2.2% sodium citrate (1 : 9 v/v). Platelet-rich plasma (PRP) was prepared by centrifugation of the blood at 120ϫg for 1...

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Platelets, Thrombosis and Drugs

Cited by 114 publications

References 308 publications

Platelet aggregation in partially obstructed vessels and its elimination with aspirin.

Platelet aggregation in partially obstructed vessels and its elimination with aspirin.

13-Azaprostanoic acid: a specific antagonist of the human blood platelet thromboxane/endoperoxide receptor.

Antithrombotic and Antiallergic Activities of Daidzein, a Metabolite of Puerarin and Daidzin Produced by Human Intestinal Microflora.

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