title: Cationic amphiphilic drugs and platelet phospholipase A(2) (cPLA(2)).
abstract: The aim of the study was to verify and compare the effect of cationic amphiphilic drugs (CAD) from different pharmacological groups on activation of platelet phospholipase A2 (PLA2)--the essential enzyme of arachidonic pathway in blood platelets. Beta-adrenoceptor-blocking (BAB) drugs inhibited platelet aggregation in the rank order of potency: propranolol>alprenolol>metipranolol>atenolol. The higher the inhibition of arachidonic acid (AA) liberation by BAB drugs, the higher the inhibition of aggregation. Similarly did the H1-histamine antagonists bromadryl (BRO) and dithiaden (DIT) as well as the antimalarial chloroquine (CQ) show antiplatelet effect in vitro in the rank order of potency: DIT>BRO>CQ. Dose-dependent inhibition of aggregation was followed by the inhibition of AA liberation from membrane phospholipids of platelets stimulated either at the receptor site (thrombin) or by a stimulus bypassing membrane receptors (Ca2+ ionophore A23187). The rank order potency for inhibition of stimulated 3H-AA liberation from membrane phospholipids was: (a) for BAB drugs: propranolol>alprenolol>metipranolol, (b) for other drugs: DIT>BRO>CQ. The investigated drugs' interference with stimulated liberation of AA showed nonspecific inhibition of platelet cytosolic PLA2 (cPLA2) by these drugs at intracellular level. The results revealed that besides the inhibition of cyclooxygenase pathway and receptors for adenosine diphosphate (ADP) and glycoproteins Gp IIbIIIa, the interaction of drugs with cPLA2 may represent a further site for antiplatelet action.
authors.affiliation: Department of Cellular Pharmacology, Institute of Experimental Pharmacology, Slovak Academy of Sciences, Dúbravská 9, 842 16 Bratislava, Slovak Republic. exfarano@savba.sk
authors.forename: Rado
authors.initials: R
authors.lastname: Nosál
authors.forename: Viera
authors.initials: V
authors.lastname: Jancinová
mesh_terms: D000526:Alprenolol / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000097:blood; D001582:Benzothiepins / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology*; D002738:Chloroquine / Q000494:pharmacology; D004155:Diphenhydramine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D014290:Metipranolol / Q000494:pharmacology; D010741:Phospholipases A / Q000097:blood*; D054467:Phospholipases A2; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013501:Surface-Active Agents / Q000494:pharmacology*
chemical_list: D001582:Benzothiepins; D010975:Platelet Aggregation Inhibitors; D013501:Surface-Active Agents; D016718:Arachidonic Acid; C100170:dithiadene; D000526:Alprenolol; D002738:Chloroquine; D004155:Diphenhydramine; D011433:Propranolol; D010741:Phospholipases A; D054467:Phospholipases A2; C005715:embramine; D014290:Metipranolol