The
phosphodiesterase (PDE) inhibitors
AY-31,390,
milrinone and
pelrinone (AY-28,768) were analyzed in human platelet aggregatory systems and in a rabbit arteriovenous shunt model to delineate their activity.
AY-31,390 showed a remarkably potent capacity to inhibit human antithrombotic platelet aggregation.
AY-31,390 inhibited
arachidonic acid,
U46619,
collagen,
epinephrine (second phase) and
adenosine diphosphate (second phase) induced platelet aggregation (PA) with IC50 values of 0.18, 0.21, 0.54, 0.43 and 0.20 microM, respectively.
Milrinone, although less potent than
AY-31,390, inhibited PA with IC50 values of 2.1, 2.0, 5.4, 3.7 and 4.1 microM and
pelrinone's IC50 values were 2.8, 6.6, 13.3, 18.6 and 11.8 microM, respectively. Platelets which were incubated with
AY-31,390,
milrinone or
pelrinone, washed with
Hanks' balanced salt solution and then resuspended in platelet poor plasma, lost their inhibitory activity in
collagen and
arachidonic acid PA systems. These results suggested that
AY-31,390,
milrinone and
pelrinone did not bind tightly to cAMP PDE. If human platelet-rich plasma was pretreated with
adenosine deaminase, an
enzyme that degrades
adenosine, the inhibitory effect of
milrinone and to a lesser extent
pelrinone was reversed.
AY-31,390 did not produce a loss of activity with
adenosine deaminase in the
arachidonic acid system and only a small loss in the
collagen system.
Adenosine did not appear to be a meaningful factor in AY-31,390's inhibitory activity.
Pelrinone,
milrinone to a greater extent, and
AY-31,390 to the greatest extent were effective inhibitors of white
thrombus formation in the in vivo rabbit arteriovenous shunt model. These PDE III inhibitors were potent deterrants of platelet aggregation and white
thrombus formation; these agents would be expected to be efficacious therapeutic antithrombotics.