IN-VITRO EFFECTS OF HOE-140 IN HUMAN BRONCHIAL AND VASCULAR TISSUE

Bradykinin is a potent inflammatory mediator which may be involved in various airway diseases. A selective and patent antagonist of the brad ykinin B-2 receptor has recently been discovered (HOE 140: D-Arg-[Hyp( 3),Thi(5),D-Tic(7),Oic(8)]bradykinin) The purpose of this study was to evaluate the potency of this compound in isolated human tissue (bronc hus, pulmonary artery endothelium, umbilical artery and vein smooth mu scle). Bradykinin induced contractions of the isolated human bronchus and umbilical artery and vein (the umbilical vessels were pretreated w ith indomethacin and L-nitro-arginine to inhibit prostaglandin and nit ric oxide synthesis). It provoked an endotherium-dependent relaxation in the human pulmonary artery. HOE 140 was a non-competitive antagonis t in human bronchial tissue (pK(B): 8.19 +/- 0.30) and a competitive o ne in vascular tissue (pA(2): 7.97 +/- 0.12, 8.16 +/- 0.16 and 8.00 +/ - 0.11 in human pulmonary artery, umbilical artery and vein respective ly). The effect of HOE 140 was selective as it did not influence the u mbilical vein contractile response to serotonin and histamine. HOE 140 up to 3 x 10(-6) M was devoid of residual agonistic activity in the v arious human preparations studied. Furthermore, although the effects o f HOE 140 were fully reversible, in isolated bronchial airways and umb ilical veins, HOE 140 (10(-6) M) still possessed activity 1 h after be ing washed out in both tissues. Our results indicate that HOE 140 is a potent and potentially long-acting antagonist of the human bradykinin B-2 receptor.