Ibudilast modulates platelet-endothelium interaction mainly through cyclicGMP-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 g uanosine 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 enh anced cyclic GMP levels in the platelets cocultured with bovine aorta endot helial cells (ECs), In contrast, ibudilast enhanced cyclic AMP accumulation only at 100 mu M, either with or without ECs. The synergistic effect of ib udilast and EC on cyclic nucleotide accumulation also was demonstrated by t he inhibitory capability of the drug and the cells on platelet aggregation. The synergism between ibudilast and aspirin-pretreated ECs was more pronou nced than that between ibudilast and N-omega-nitro-L-arginine (L-NNA)-pretr eated ECs. Ibudilast affected neither ATP di-phosphohydrolase activity nor NO release from EC up to a concentration of 10 mu M. We conclude that ibudi last exhibits antiplatelet properties mainly by inhibiting PDES to potentia te antiplatelet function of endothelium-derived NO.