IN-VITRO PHARMACOLOGICAL EFFECTS OF S-12370 (2-[4-BENZHYDRYLOXYPIPERIDINOETHYL]ISOXINDOLE - AN ANTIBRONCHOCONSTRICTOR AGENT) IN NORMAL AND SENSITIZED TISSUE

The effects of S 12370 (2-[4-benzhydryloxypiperidinoethyl]isoxindole), were studied in vitro. In guinea pig isolated tracheal rings, S 12370 induced a similar competitive inhibition of the contractile responses produced by acetylcholine, histamine and serotonin. However, it did n ot affect the contractions induced by leukotriene D-4 (LTD(4)), substa nce P and U 46619, a stable analogue of thromboxane A(2). S 12370 indu ced a concentration-dependent inhibition of the cholinergic component of the contraction induced by electrical field stimulation, whereas it did not influence the sustained nonadrenergic noncholinergic (NANC) e xcitatory response observed in guinea pig isolated bronchi. S 12370 di d not influence the relaxations induced by prostaglandin E(2), isopren aline and salbutamol, and did not modify the nonadrenergic noncholiner gic inhibitory response induced by electrical field stimulation. In is olated left atria, the negative inotropic effect of acetylcholine was competitively inhibited by S 12370. In binding experiments, S 12370 ex hibited similar affinity for M(1), M(2), M(3), M(4) muscarinic recepto rs and also recognized 5-HT2 serotonin and H-1 histamine receptor subt ypes. In ovalbumin-sensitized animals, the contractile response of iso lated tracheal rings produced by exposure to the allergen was not infl uenced by S 12370. Tracheal rings from sensitized animals preexposed i n vitro to the allergen developed a hyporesponsiveness to beta-adrenoc eptor stimulation. S 12370 prevented the inhibitory effect caused by o valbumin immune sensitization in the relaxation to isoprenaline. In ra t polymorphonuclear neutrophil (PMN) cells, S 12370 up to 10(-5) M did not inhibit the arachidonic acid metabolism. These results suggest th at in guinea pig tracheal smooth muscle, S 12370 is a competitive inhi bitor of muscarinic, serotonin and histamine receptors End can modulat e the beta-adrenergic dysfunction induced by immune sensitization. S 1 2370 may present some therapeutic interest in inflammatory airway dise ases.