Pjs. Chiu et al., INHIBITION OF PLATELET-ADHESION AND AGGREGATION BY E4021, A TYPE-V PHOSPHODIESTERASE INHIBITOR, IN GUINEA-PIGS, Naunyn-Schmiedeberg's archives of pharmacology, 355(4), 1997, pp. 463-469
E4021 (sodium 1-[6-chloro-4-(3, zyl)-aminoquinazolin-2-yl]piperidine-4
-carboxylate sesquihydrate) is a highly selective and potent inhibitor
of type V phosphodiesterase(PDE5). The in vitro and in vivo effect of
E4021 on platelet function was evaluated, using echistatin, a potent
disintegrin, as a positive reference agent. E4021 inhibits aggregatory
response to collagen in washed human platelets (IC50 = 5 mu M, vs. 0.
14 mu M with echistatin). In the ex vivo-platelet aggregation assay us
ing whole blood from treated guinea pigs, E4021 (9 mg/kg i.v.) showed
a moderate inhibition (43%) against collagen (0.125 mu g/ml), whereas
echistatin (250 mu g/kg i.v.) exerted a 88% inhibition. The absence of
endothelium-derived factors (NO) may account for the moderate in vitr
o and ex vivo antiplatelet activity of E4021. In an in vivo model of r
eversible platelet aggregation elicited by collagen (100 mu g/kg i.v.)
, both E4021 and echistatin attenuated the intrapulmonary platelet acc
umulation in guinea pigs (-36% and -44%, respectively). In addition, E
4021 (9 mg/kg i.v.) and echistatin (250 mu g/kg i.v.) caused a similar
inhibition of platelet adhesion at sites of microfilament-induced vas
cular injury in guinea pigs (52% and 65%, respectively). The two agent
s in combination did not show additive effect, suggesting that E4021 i
nhibits platelet activation and impairs interactions of adhesion recep
tors with matrix proteins. E4021 caused a selective increase in cGMP c
oncentrations in the platelets isolated from treated guinea pigs; cAMP
was not affected. It is concluded that the antiplatelet activity of E
4021 is mediated through cGMP mechanism by virtue of selective inhibit
ion of PDE5 in the platelets.