Effects of the antithrombitic agent PCA 4230 on agonist-induced Ca2+ entry and Ca2+ release in human platelets.
We have studied the effects of the antithrombitic agent PCA 4230 on the entry of Mn2+, used here as a Ca2+ surrogate for Ca2+ channels, and on the release of Ca2+ from the intracellular stores in stimulated human platelets loaded with fura-2. PCA 4230 prevented receptor-operated calcium entry activated by thrombin, ADP and collagen with no modification of the Ca2+ release from the intracellular stores. PCA 4230 also inhibited cytochrome P-450-mediated O-dealkylase activity with the same concentration-dependence as the thrombin-induced Mn2+ entry. These results suggest that the inhibitory effects of PCA 4230 on Ca2+ influx may be due to its interaction with cytochrome P-450, which has been proposed recently to be involved in the activation of receptor-operated Ca2+ channels. In addition, PCA 4230 inhibited both PAF-induced Ca2+ entry and Ca2+ release, behaving as a PAF-antagonist. All these effects contribute to explain the antithrombitic action of PCA 4230.
Alonso
M T
MT
Departamento de Bioquímica y Biología Molecular y Fisiología, Facultad de Medicina, Universidad de Valladolid, Spain.
Villalobos
C
C
Sanchez
A
A
D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D004095:Dihydropyridines / Q000494:pharmacology*; D016257:Fura-2; D006801:Humans; D007211:Indoles; D008345:Manganese / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D013917:Thrombin / Q000037:antagonists & inhibitors
D015220:Calcium Channels; D065607:Cytochrome P-450 Enzyme Inhibitors; D004095:Dihydropyridines; D007211:Indoles; D010972:Platelet Activating Factor; C073664:PCA 4230; D008345:Manganese; D003577:Cytochrome P-450 Enzyme System; D013917:Thrombin; C048960:indo-1; D002118:Calcium; D016257:Fura-2