INHIBITORY EFFECT OF SIN 1 ON PLATELET FUNCTION:POSSIBLE INTEREFRENCE WITH PHOSPHOLIPASE C AND FIBRINOGEN BINDING

The mode of action of SIN 1, the main metabolite of an antianginal drug (Molsidomine) was investigated in vitro on huma platelet functions. SIN 1 inhibited dose dependently platelet activation as reflected by aggregation and release of serotonin induced by arachidonic acid, prostaglandin endoperoxydes analogues (U 46619, U 44069), collagen, and ADP (figst and second wave). The maximal inhibition was reached at 10⁻⁵ M. The thromboxane (TX) synthesis was inconsis^antly impaired even at high concentrations of SIN 1 (10⁴ M) suggesting a discrepancy between the inhibitory effect on platelet activation and TX formation. The main cofactor of ADP-stimulated aggregation is fibrinogen ; SIN 1 dose-dependently inhibited the fibrinogen binding to platelets thereby explaining it antiaggregatory properties.

In order to further investigate the mechanism of action of this drug on platelet activation we tested SIN 1 on the thrombin-induced phg^phosinositide metabolism and protein phosphorylation on ³²P-prelabelled isolated platelets.P-phosphatidate (PA) formation was greatly inhibited. Phosphorylations of the myosin light chain (P20) and of 43 kDa protein (P43) were also reduced. These effects were accompanied by an inhibition of serotoninrelease, TXB₂ synthsei^, and platelet aggregation.

SIN rl_would seem to act on early biochemical events and more especially at thelevel of the membrane phospholipase C.