INHIBITION OF PLATELET-ADHESION AND AGGREGATION BY E4021, A TYPE-V PHOSPHODIESTERASE INHIBITOR, IN GUINEA-PIGS

Citation
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
Citations number
45
Categorie Soggetti
Pharmacology & Pharmacy
ISSN journal
00281298
Volume
355
Issue
4
Year of publication
1997
Pages
463 - 469
Database
ISI
SICI code
0028-1298(1997)355:4<463:IOPAAB>2.0.ZU;2-N
Abstract
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.