PAF and thrombin actions in platelets are selectively affected by a new 1,4-dihydropyridine derivative.
In the present study we described the effects of a new 1,4-dihydropyridine derivative with antithrombotic activity on phosphoinositide turnover in washed platelets stimulated by either platelet-activating factor or thrombin. In 32P-labeled rabbit platelets, both PAF and thrombin evoked a transient loss of [32P]phosphatidylinositol 4,5-bisphosphate (PIP2) and, thereafter, labeling increased over the control value. Concomitantly, a progressive formation of phosphatidic acid was observed. In [3H]arachidonate labeled platelets, both agonists elicited an increase in diacylglycerol (DAG) levels and arachidonate release. Pretreatment of platelets with the new dihydropyridine derivative (PCA-4230) prevents, in a dose-dependent fashion, the PAF-evoked variations in phosphoinositide turnover and DAG production. However, thrombin-induced variations were rather enhanced by PCA-4230. With respect to arachidonate release and platelet aggregation, the drug was again selective against PAF and thrombin. Although PCA-4230 shows some PAF antagonistic activity, its effects on PAF-evoked responses did not seem only due to an antagonism at receptor level. In view of the present results, the drug is not only able to discern the pathways of platelet activation by which PAF and thrombin exert their action, but it also affects selectively the enhanced phosphoinositide turnover and arachidonate release evoked by thrombin. Thereafter, PCA-4230 is a suitable tool to explore the mechanisms of action of the natural agonists.
Catalán
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RE
Departamento de Biología Molecular, Centro de Biología Molecular, Severo Ochoa, (CSIC-UAM), Madrid, Spain.
Martínez
A M
AM
Aragonés
M D
MD
Garde
E
E
Lombardía
M
M
Ortega
P
P
D000818:Animals; D016718:Arachidonic Acid / Q000302:isolation & purification; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D004075:Diglycerides / Q000302:isolation & purification; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000302:isolation & purification / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000502:physiology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors
D004075:Diglycerides; D004095:Dihydropyridines; D010716:Phosphatidylinositols; D010972:Platelet Activating Factor; C073664:PCA 4230; D016718:Arachidonic Acid; C038806:1,4-dihydropyridine; D010738:Type C Phospholipases; D013917:Thrombin