Antiasthmatic effect of YM976, a novel PDE4 inhibitor, in guinea pigs

YM976 is a novel and specific phosphodiesterase 4 inhibitor. In our previou s report, we indicated that YM976 has less emetogenicity, a major adverse e ffect of PDE4 inhibitors, than rolipram. In the present study, we examined the antiasthmatic effects of YM976 in guinea pigs. YM976 orally administere d exhibited inhibition of antigen-induced bronchoconstriction, airway plasm a leakage, airway eosinophil infiltration, and airway hyperreactivity (AHR) , with ED50 values of 7.3, 5.7, 1.0, and 0.52 mg/kg, respectively. Rolipram also dose dependently suppressed these responses. Prednisolone suppressed eosinophil infiltration and AHR, whereas it failed to inhibit bronchoconstr iction and plasma leakage. Theophylline moderately suppressed bronchoconstr iction and edema, but neither eosinophil infiltration nor AHR. YM976 suppre ssed the peroxidase activity in the bronchoalveolar lavage fluid, and eleva ted the intracellular peroxidase activity and cAMP contents of infiltrated cells, suggesting that YM976 inhibited not only the infiltration but also t he activation of leukocytes. In vitro studies revealed that YM976 potently suppressed eosinophil activation (EC30 = 83 nM), and exerted a little relax ation on LTD4-precontracted tracheal smooth muscle (EC50 = 370 nM). Rolipra m exhibited a potent tracheal relaxation activity (EC50 = 50 nM). In vivo s tudies indicated that the inhibitory effect of YM976 on LTD4-induced bronch ospasm was marginal even at 30 mg/kg p.o., although rolipram significantly inhibited the bronchospasm at the same dose. These results suggested that Y M976, unlike rolipram, showed the inhibition of antigen-induced airway resp onses due to anti-inflammatory effects, but not to direct tracheal relaxati on. In conclusion, YM976 may have potential therapeutic value in the treatm ent of asthma through its antiinflammatory activities.