INHIBITOR EFFECT OF APAFANT ON BRONCHOPULMONARY RESPONSES TO PLATELET-ACTIVATING-FACTOR AND TO ANTIGEN IN RATS

Apafant ropyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4] diazepine, CAS 105219-56-5, WEB 2086), as a specific platelet activating factor ( PAF) antagonist, inhibited PAF-induced increases of bronchial inflatio n pressure (Delta Pi), pulmonary artery perfusion pressure (Delta Pp) and microvascular permeability (wet-to-dry lung weight ratios), dose-d ependently in rats. Apafant also inhibited antigen-induced increase of Delta pi, Delta Pp and microvascular permeability in passively sensit ized rats. Ozagrel also inhibited PAF-and antigen-induced increase of Delta Pi, Delta Pp and microvascular permeability. Apafant almost comp letely inhibited the increase of intratracheal pressure and microvascu lar permeability, but incompletely inhibited the increase of pulmonary artery pressure. At 1 mu g/ml, the effects of ozagrel were almost com parable to that of apafant at the same concentration, but the inhibito ry effect on intratracheal pressure was less than that of apafant. Apa fant inhibited PAF-induced increase in perfusate of thromboxane (TX) B -2 and leukotrine C-4/D4E4 (LTs), and antigen-induced increase of TXB2 , LTs, PAF and histamine. Ozagrel also inhibited the PAF-induced incre ase of TXB2, but not the increase of LTs. Apafant inhibited antigen-in duced increase of TXB2 and LTs more strongly than PAF-induced increase . The order of inhibitory effects of apafant against generation and re lease of chemical mediators was TXB2, LTs, PAF and histamine. These fi ndings suggest that TXA(2), LTs and PAF may contribute to the increase of intratracheal pressure and microvascular permeability, and histami ne may contribute to the increase of vascular resistance in rats. Apaf ant may inhibit bronchopulmonary responses through PAF receptor antago nism In addition, apafant can be considered to be useful for the treat ment of some allergic diseases when the drug is employed in clinical u se.