Phosphodiesterase (
PDE)3 inhibitors exert potent antiplatelet effects through maintaining elevated intracellular cyclic
adenosine monophosphate levels, but do not prolong bleeding time. To resolve this discrepancy, we hypothesised that
PDE3 inhibitors effectively suppress shear-induced platelet
thrombus formation initiated by the interaction of the platelet receptor GPIb/V/IX with its
ligand,
von Willebrand factor (VWF), since arterial
thrombosis is more dependent on shear stress as compared with haemostatic plug formation. To test the hypothesis, we compared the in vitro effects of K-134 (a
PDE3 inhibitor),
tirofiban (a GPIIb/IIIa inhibitor) and
acetylsalicylic acid (ASA) on
ristocetin-induced platelet aggregation and platelet
thrombus formation on VWF or
collagen surfaces under flow conditions. K-134 inhibited GPIIb/IIIa-dependent platelet aggregation to the same extent as
tirofiban and more potently than ASA. Likewise, K-134 and
tirofiban effectively inhibited stable platelet
thrombus formation (platelet firm adhesion and subsequent aggregation) on the VWF or
collagen surface under high shear, but ASA only inhibited aggregation. Notably, inhibition by K-134 became evident only when a low concentration of
PGE1 was present. These inhibitors did not block shear-induced initial platelet contact with VWF via GPIb/V/IX. In contrast, under low shear, the inhibitory effects of K-134 on platelet aggregation on the
collagen surface were lower than
tirofiban or ASA. The observed shear-dependent suppression of platelet
thrombus formation by
PDE3 inhibitor in the presence of low levels of
adenylate cyclase stimulator may contribute to high therapeutic benefit with low risk of
bleeding.