Ibudilast modulates platelet-endothelium interaction mainly through cyclic GMP-dependent mechanism

3-isobutyryl-2-isopropylpyrazolo[1,5-a]pyridine(ibudilast) has been widely used in Japanese clinics for its antiasthmatic and antithrombotic effects. We investigated the mechanisms involved in the antiplatelet effects of the agent, specifically focusing on platelet-endothelium interaction. Ibudilast inhibits both phosphodiesterase (PDE) 3 and 5, the two major PDE isoforms of human platelets, with an IC50 of 31 and 2.2 mu M, respectively. Cyclic guanosine monophosphate (GMP) accumulation in washed human platelets exposed to ibudilast alone increased significantly only at high concentrations of the agent (100 mu M), whereas greater than or equal to 1 mu M ibudilast enhanced cyclic GMP levels in the platelets cocultured with bovine aorta endothelial cells (ECs), In contrast, ibudilast enhanced cyclic AMP accumulation only at 100 mu M, either with or without ECs. The synergistic effect of ibudilast and EC on cyclic nucleotide accumulation also was demonstrated by the inhibitory capability of the drug and the cells on platelet aggregation. The synergism between ibudilast and aspirin-pretreated ECs was more pronounced than that between ibudilast and N-omega-nitro-L-arginine (L-NNA)-pretreated ECs. Ibudilast affected neither ATP di-phosphohydrolase activity nor NO release from EC up to a concentration of 10 mu M. We conclude that ibudilast exhibits antiplatelet properties mainly by inhibiting PDES to potentiate antiplatelet function of endothelium-derived NO.