ANTIPLATELET AND ANTIPROLIFERATIVE EFFECTS OF SCH-51866, A NOVEL TYPE-1 AND TYPE-5 PHOSPHODIESTERASE INHIBITOR

SCH 51866 is a potent and selective PDE1 and PDE5 inhibitor. The antip latelet, antiproliferative, and hemodynamic effects of SCH 51866 were compared with those of E4021, a highly selective PDE5 inhibitor. SCH 5 1866 inhibited PDE1 and PDE5 isozymes with a 50% inhibitory concentrat ion (IC50) of 70 and 60 nM, respectively. SCH 51866 and E4021 inhibite d washed human platelet aggregation induced by collagen with an IC50 o f 10 and 4 mu M, respectively, and attenuated (p < 0.05) the adhesion of (111)indium-labeled platelets to the nylon filament-injured rat aor ta. The doses of SCH 51866 and E4021 that inhibited platelet adhesion caused significant increases in platelet cyclic guanosine monophosphat e (cGMP; p < 0.05). SCH 51866 (1-10 mg/kg, p.o. twice daily) but not E 4021 (3-30 mg/kg, p.o. twice daily) inhibited neointima formation in t he carotid arteries of spontaneously hypertensive rats (SHRs) subjecte d to balloon angioplasty. Moreover, SCH 51866 (0.3-10 mg/kg, p.o.) eli cited dose-dependent reduction in blood pressure in SHRs, whereas E402 1 (3-30 mg/kg, p.o.) did not affect blood pressure in SHRs. In conclus ion, the data suggest that inhibition of PDE1 and PDE5 isozymes by SCH 51866 exerts antiplatelet and vascular protective effects. In compari son, inhibition of PDE5 alone by E4021 exhibited antiplatelet effects without affecting neointima formation.