Evaluation of the effects of anti-thromboxane agents in platelet–vessel wall interaction

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• 作者：Buccellati ; Carola ; Ciceri ; Paola ; Ballerio ; Rossana ; Casagrande ; Cesare ; Folco ; Giancarlo ; et. al.
• 关键词：Thromboxane A₂ ; Prostacyclin ; Platelet ; Vascular tissue ; Picotamide ; (Rabbit)
• 刊名：European Journal of Pharmacology
• 出版年：2002
• 出版时间：May 17, 2002
• 年：2002
• 卷：443
• 期：1-3
• 页码：133-141
• 全文大小：356 K

文摘

We evaluated the capacity of anti-aggregating agents to influence thromboxane A₂ and prostacyclin formation, arachidonic acid-endoperoxide redirection, platelet aggregation and vessel tone, in isolated rabbit aorta incubated with homologous platelets. Picotamide (N,N′bis(3-pyridinylmethyl)-4-methoxy-isophthalamide), the only dual thromboxane A₂-synthase inhibitor/receptor antagonist in clinical use, inhibited arachidonic acid-induced platelet aggregation with low potency, increased 180-fold by aorta presence. It inhibited thromboxane A₂ formation in platelets and, in aorta presence, increased prostacyclin formation. Ozagrel (OKY-046, (E)-3-(4-(1-imidazolylmethyl)phenyl)-2-propenoic acid), a pure thromboxane A₂-synthase inhibitor, behaved similarly to picotamide, although the aorta caused a higher (600-fold) shift. The potency of the antagonist SQ 29,548 (1S-(1α,2β(5Z),3β,4α))-7-(3((2-((phenylamino)carbonyl)hydrazino)methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid) was unaffected by aorta. In coincubation experiments, arachidonic acid-challenge increased thromboxane A₂-dependent vessel tone; picotamide increased prostacyclin and reduced thromboxane A₂ formation and vasoconstriction. Ozagrel mimicked picotamide; aspirin (acetylsalicylic acid) reduced aorta contractility, thromboxane A₂ and prostacyclin formation. SQ 29,548 reduced vasoconstriction without affecting eicosanoids. We demonstrate the importance of redirection of eicosanoids in the mechanism of action of thromboxane A₂ inhibitors/antagonists within platelet–vascular wall interactions. These findings bear relevance in the development of novel anti-thrombotic drugs.