Selective type III phospodiesterase inhibitor as an antithrombotic agent.

In platelets, an increase in cAMP levels potently inhibits aggregation and release reactions. Cilostazol is an antiplatelet agent that increases intracellular cAMP levels by selective Type III phosphodiesterase (PDE) inhibition. The characteristics of cilostazol are presented in this review. Adenylate cyclase potentiator also shows strong inhibitory actions on platelet functions, but a number of reports suggest that the continuous use of an adenylate cyclase potentiator may lead to a reduction of drug efficacy. On the other hand, such an action has not been seen with cilostazol even after continuous administration of cilostazol (100 mg/kg) for two weeks in rats, which may be due to a feature of this drug, namely, inhibitory actions on PDE. Inhibitory actions of cilostazol on PDE are specific: strong inhibition (IC50 = 0.19 μM) against Type III PDE that comprises most of the PDE activities in platelets and weak inhibition against Type IV PDE that comprises most of the PDE activities in endothelial cells (ECs). This fact (i.e., specificity of cilostazol) brought about important results when the drug reacted in the presence of both platelets and blood vessels. A non-specific PDE inhibitor such as IBMX increases cAMP and decreases PGI2 synthesis in ECs, but such a phenomenon was not seen with cilostazol. The inhibitory actions of cilostazol on platelet functions were potently enhanced in the presence of PGI2. This phenomenon was reproduced in vivo, i.e., antiplatelet actions of cilostazol in vivo were approximately 50 times more potent than those in vitro. Cilostazol also strongly inhibits Type III PDE in vascular smooth muscle cells (SMCs) causing inhibition of SMC proliferation in vitro and inhibition of intimal hyperplasia in vivo. Therefore, it is considered that PDE III inhibitors such as cilostazol have great additional value as an antithrombotic agent.