The effect of a novel compound, 3-isobutyryl-2-isopropylpyrazolo [1, 5-a] pyridine (ibudilast, KC-404), on human platelet aggregation and its mechanism of action were investigated.
In vitro, KC-404 inhibited human platelet aggregation induced by ADP, collagen, adrenalin, platelet activating factor and arachidonic acid but not by ristocetin. Together, KC-404 and agents which increased cAMP (prostaglandin I2, prostaglandin E1 (PGE1), forskolin) or cGMP (3-morpholinosydnonimine (SIN-1)) produced synergistic inhibitory effects on platelet aggregation.
KC-404 inhibited human platelet cAMP phosphodiesterase (PDE) (IC50: 50μM) and cGMP-PDE (IC50: 5.2μM) activities. cAMP and cGMP concentration of human platelets were not increased by KC-404 itself. PGE1, an adenylate cyclase stimulator, increased cAMP content; KC-404 enhanced the effect of PGE1 on cAMP accumulation. SIN-1, which stimulates guanylate cyclase, increased cGMP content; KC-404 enhanced the effect of SIN-1 on cGMP accumulation.
These results suggest that effects of KC-404 on accumulation of cyclic nucleotides and inhibition of platelet aggregation are mediated via inhibition of platelet cyclic nucleotide phosphodiesterase activities.
