title: In vitro platelet antiaggregatory properties of 4-methylcoumarins.
abstract: Platelets play a crucial role in physiological haemostasis. However, in coronary arteries damaged by atherosclerosis, enhanced platelet aggregation, with subsequent thrombus formation, is a precipitating factor in acute myocardial infarction. Current therapeutic approaches are able to reduce approximately one quarter of cardiovascular events, but they are associated with an increased risk of bleeding and in some resistant patients are not efficient. Some coumarins possess antiplatelet activity and, due to their additional antioxidant effects, may be promising drugs for use in combination with the present therapeutic agents. The aim of this study was to analyse a series of simple 4-methylcoumarins for their antiplatelet activity. Human plasma platelet suspensions were treated with different aggregation inducers [arachidonic acid (AA), collagen and ADP] in the presence of the 4-methylcoumarins. Complementary experiments were performed to explain the mechanism of action. 5,7-Dihydroxy-4-methylcoumarins, in particular those containing a lipophilic side chain at C-3, reached the activity of acetylsalicylic acid on AA-induced aggregation. Other tested coumarins were less active. Some of the tested compounds mildly inhibited either collagen- or ADP-induced aggregation. 5,7-Dihydroxy-4-methylcoumarins did not interfere with the function of thromboxane synthase, but were competitive antagonists of thromboxane A(2) receptors and inhibited cyclooxygenase-1 as well. 5,7-Dihydroxy-4-methylcoumarins appear to be promising candidates for the extension of the current spectrum of antiplatelet drugs.
authors.affiliation: Department of Pharmaceutical Botany and Ecology, Faculty of Pharmacy in Hradec Králové, Charles University in Prague, Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
authors.forename: Kateřina
authors.initials: K
authors.lastname: Macáková
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Řeháková
authors.forename: Přemysl
authors.initials: P
authors.lastname: Mladěnka
authors.forename: Jana
authors.initials: J
authors.lastname: Karlíčková
authors.forename: Tomáš
authors.initials: T
authors.lastname: Filipský
authors.forename: Michal
authors.initials: M
authors.lastname: Říha
authors.forename: Ashok K
authors.initials: AK
authors.lastname: Prasad
authors.forename: Virinder S
authors.initials: VS
authors.lastname: Parmar
authors.forename: Luděk
authors.initials: L
authors.lastname: Jahodář
authors.forename: Petr
authors.initials: P
authors.lastname: Pávek
authors.forename: Radomír
authors.initials: R
authors.lastname: Hrdina
authors.forename: Luciano
authors.initials: L
authors.lastname: Saso
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014468:Umbelliferones / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D003374:Coumarins; D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D014468:Umbelliferones; D016718:Arachidonic Acid; D000244:Adenosine Diphosphate; D003094:Collagen; D051545:Cyclooxygenase 1; D013930:Thromboxane-A Synthase; D001241:Aspirin; C506459:5,7-dihydroxy-4-methylcoumarin