Potentiation of the antiplatelet action of @entity859 in whole blood by XXXX or dilazep and the @entity268 phosphodiesterase inhibitor, @entity70888 .

@entity1 @entity19350 @entity268 @entity2353 @entity859 @entity7308 @entity1423 @entity70889 @entity70888 @entity4341 @entity17828 @entity9392 @entity857 @entity70887
@entity859 ( @entity7308 , 10-50 microM), a potent inhibitor of @entity857 -induced @entity1 @entity1423 in platelet-rich plasma (PRP), does not inhibit aggregation in whole blood. However, the @entity7308 analogs, @entity70887 , @entity17828 and @entity19350 ( @entity19350 ) which are resistant to deamination ( @entity70887 ) or deamination and phosphorylation ( @entity17828 and @entity19350 ), inhibit aggregation in whole blood with IC50 values of 12 microM, 2.3 microM and 0.26 microM, respectively. The inhibitory effect of @entity19350 (200 nM) is potentiated by the platelet @entity268 phosphodiesterase (PDE) inhibitor @entity70888 (5 microM). Inhibition of the erythrocytic @entity2353 transport system by dilazep (1 microM) or @entity4341 (10 microM), or blockade of @entity7308 metabolism by @entity9392 (5 microM) plus @entity70889 (10 microM), evokes the antiaggregatory action of @entity7308 in whole blood (IC50 congruent to 2 microM). @entity70888 (5 microM) potentiates @entity7308 -mediated inhibition about 10-fold when @entity2353 transport or @entity7308 metabolism is blocked. @entity7308 (10 microM or 200 nM) is rapidly metabolized within 1 min in whole blood. When @entity2353 transport is inhibited by dilazep or @entity4341 , or when @entity7308 metabolism is blocked by @entity9392 and @entity70889 , 50-60% of the @entity7308 remains in the plasma after 5 min. These results show that the failure of @entity7308 to inhibit @entity1423 in whole blood results from its rapid uptake and metabolism by erythrocytes. More importantly, these data emphasize the key role of @entity2353 transport inhibition in the antiplatelet actions of @entity4341 and dilazep. In addition, superior therapeutic results may be obtained from the combination of blockade of @entity2353 transport system with inhibition of platelet @entity268 PDE.
