The effect of
A02131-1 [3-(5'-hydroxymethyl-2'-furyl)-1-benzyl thieno (3,2-c)
pyrazole], a cGMP-specific
phosphodiesterase (PDE) inhibitor, on platelet function was investigated. The compound was found to inhibit the aggregation of and
adenosine triphosphate (
ATP) release from human platelet-rich plasma and washed platelets that were induced by aggregation inducing drugs such as
arachidonic acid (AA),
collagen,
U46619,
platelet-activating factor (PAF),
adenosine diphosphate (
ADP) and
A23187, and the inhibitory effect was concentration-dependent.
A02131-1 also disaggregated the performed platelet aggregates induced by these inducers.
Thromboxane B2 (TXB2) formations caused by
collagen, PAF,
ADP, and
A23187 were inhibited by
A02131-1 at concentrations that did not affect the AA-induced formation of TXB2 and
prostaglandin D2 (
PGD2).
A02131-1 suppressed both the generation of
inositol 1,4,5-triphosphate (IP3) and the increase of intracellular Ca2+ concentration stimulated by these aggregation inducers.
A02131-1 was shown to increase the cAMP and cGMP levels in platelets and the extent was found to be dependent on concentration as well as time.
A02131-1 increased the cAMP level much more slowly than the cGMP level. Activities of
adenylate cyclase,
guanylate cyclase, and
PDEs (type I and III) were not altered by
A02131-1. However, the activity of cGMP-specific PDE (type V) was inhibited by
A02131-1. The antiplatelet aggregation activity and the effect on raising cAMP level of
A02131-1 were both potentiated by
prostaglandin E1 (
PGE1). In the mouse tail
bleeding test,
A02131-1 was clearly shown to be more effective than
dipyridamole in prolonging the tail bleeding time of conscious mice. These data indicate that
A02131-1 is a cGMP-specific PDE (type V) inhibitor in human platelets.