Prostaglandins and human platelet aggregation. Implications for the anti-aggregating activity of thromboxane-synthase inhibitors |
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| Authors: | G Rajtar C Cerletti M N Castagnoli V Bertelé G de Gaetano |
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| Affiliation: | 1. Laboratory of Cardiovascular Clinical Pharmacology and Laboratory of Environmental Pharmacology and Toxicology, Istituto di Ricerche Farmacologiche “Mario Negri”, Via Eritrea 62, 20157 Milano, Italy;1. School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland;2. Irish Centre for Vascular Biology, Royal College of Surgeons in Ireland, Dublin, Ireland;3. School of Biological Sciences, University of Reading, Reading, United Kingdom;4. School of Medicine, Conway Institute, University College Dublin, Belfield, Dublin, Ireland;5. School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland;6. Department of Health Sciences and Technologies, ETH Zurich, Zurich, Switzerland;1. Department of Plant and Environmental Sciences, Faculty of Science, University of Copenhagen, Thorvaldsensvej 40, Frederiksberg DK-1871, Denmark;2. Copenhagen Plant Science Center, University of Copenhagen, Thorvaldsensvej 40, Frederiksberg DK-1871, Denmark;3. Department Life Sciences, Imperial College London, Sir Alexander Fleming Building, London SW7 2AZ, UK;4. Joint BioEnergy Institute and Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA;5. Carlsberg Research Laboratory, 100 Ny Carlsberg Vej, 1799 Copenhagen V, Denmark;6. Novo Nordisk, Novo Nordisk Park 1, 2760 Måløv, Denmark;7. School of BioSciences, The University of Melbourne, Victoria 3010, Australia;1. Section of Allergy and Immunology, Division of Infectious Diseases, Allergy and Immunology, Department of Internal Medicine, School of Medicine, Saint Louis University, St Louis, Mo;2. Department of Medicine, Nova Southeastern Allopathic Medical School, Fort Lauderdale, Fla;3. Department of Internal Medicine, School of Medicine, University of South Carolina, Columbia, SC;4. Department of Otolaryngology–Head and Neck Surgery, Pritzker School of Medicine, University of Chicago, Chicago, Ill;5. Allergy Section, Division of Immunology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, Ohio;6. Departments of Medicine and Pediatrics, Penn State University, Hershey, Pa;7. Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, School of Medicine, Stanford University, Stanford, Calif;8. Division of Allergy and Immunology, Department of Medicine, Queen’s University, Kingston, Ontario, Canada;9. Division of Allergy and Immunology, Department of Medicine, Mount Sinai West, New York, NY;10. Division of Allergy and Clinical Immunology, Department of Medicine, School of Medicine, John Hopkins University, Baltimore, Md;11. Section of Allergy and Immunology, Department of Pediatrics, Children’s Hospital Colorado, School of Medicine, University of Colorado, Aurora, Colo;12. Division of Allergic Diseases, Mayo Clinic, Rochester, Minn;13. Division of Allergy, Immunology and Pulmonary Medicine, Department of Pediatrics, School of Medicine, Washington University, St Louis, Mo;14. Division of Allergy and Immunology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Tex;15. Department of Allergy and Clinical Immunology, Respiratory Institute, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio;p. Center of Excellence in Asthma and Allergy, Hospital Medica Sur, Mexico City, Mexico;q. Division of Pulmonology Allergy and Immunology, Department of Pediatrics, The University of Tennessee Health Science Center, Memphis, Tenn;r. Division of Allergy and Immunology, Department of Pediatrics, School of Medicine, University of California, San Diego, Calif;s. Allergy and Asthma Medical Group and Research Center, San Diego, Calif;t. Division of Pulmonary & Critical Care Medicine and Allergic & Immunologic Diseases, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey–Rutgers New Jersey Medical School, New Brunswick, NJ;u. Pulmonary and Allergy Associates, Morristown, NJ;v. Division of Allergy, Asthma, and Clinical Immunology, Mayo Clinic in Arizona, Scottsdale, Ariz;w. Department of Pediatrics, Dartmouth-Hitchcock Medical Center, Lebanon, NH;x. Prevea Health, Green Bay, Wis;y. Allergy, Asthma and Sinus Center, Greenfield, Wis;z. Division of Allergy and Immunology, Nationwide Children''s Hospital, Columbus, Ohio;11. Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio;22. Division of Allergy and Immunology, Department of Pediatrics, The Elliot and Roslyn Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY;1. GeneCology Research Centre, School of Science and Engineering, University of the Sunshine Coast, Maroochydore, QLD 4558, Australia;2. Vietnam National University of Agriculture, Gia Lam, Ha Noi, Viet Nam;3. Research Institute for Aquaculture No.3, Nha Trang, Khanh Hoa, Viet Nam |
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| Abstract: | Selective pharmacological blockade of thromboxane-synthase in human platelets by dazoxiben resulted in the reorientation of cyclic-endoperoxides towards PGE2, PGD2 and PGF2 alpha. At concentrations which can be reached when thromboxane-synthase is inhibited, PGE2 (100-500 nM) exerted a marked, concentration-dependent pro-aggregatory effect. This required the formation of endogenous or the addition of exogenous endoperoxides and was prevented by PGD2 or 13-aza-prostanoic acid, a selective antagonist of PGH2/TxA2 receptors. The anti-aggregating effect of PGD2 was evident at concentrations lower than those obtained in dazoxiben-treated platelets. It is proposed that in the absence of TxA2 generation, a combination of endoperoxides and PGE2 may result in normal aggregation. The latter may be inhibited by PGD2. No interference of PGF2 alpha on platelet function could be shown. |
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