title: In vitro effects of HOE 140 in human bronchial and vascular tissue.
abstract: Bradykinin is a potent inflammatory mediator which may be involved in various airway diseases. A selective and potent antagonist of the bradykinin B2 receptor has recently been discovered (HOE 140: D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin). The purpose of this study was to evaluate the potency of this compound in isolated human tissue (bronchus, pulmonary artery endothelium, umbilical artery and vein smooth muscle). Bradykinin induced contractions of the isolated human bronchus and umbilical artery and vein (the umbilical vessels were pretreated with indomethacin and L-nitro-arginine to inhibit prostaglandin and nitric oxide synthesis). It provoked an endothelium-dependent relaxation in the human pulmonary artery. HOE 140 was a non-competitive antagonist in human bronchial tissue (pKB: 8.19 +/- 0.30) and a competitive one in vascular tissue (pA2: 7.97 +/- 0.12, 8.16 +/- 0.16 and 8.00 +/- 0.11 in human pulmonary artery, umbilical artery and vein respectively). The effect of HOE 140 was selective as it did not influence the umbilical vein contractile response to serotonin and histamine. HOE 140 up to 3 x 10(-6) M was devoid of residual agonistic activity in the various human preparations studied. Furthermore, although the effects of HOE 140 were fully reversible, in isolated bronchial airways and umbilical veins, HOE 140 (10(-6) M) still possessed activity 1 h after being washed out in both tissues. Our results indicate that HOE 140 is a potent and potentially long-acting antagonist of the human bradykinin B2 receptor.
authors.affiliation: Laboratoire de Pharmacologie, Faculté de Médecine Paris-Ouest, France.
authors.forename: M
authors.initials: M
authors.lastname: Félétou
authors.forename: C A
authors.initials: CA
authors.lastname: Martin
authors.forename: M
authors.initials: M
authors.lastname: Molimard
authors.forename: E
authors.initials: E
authors.lastname: Naline
authors.forename: M
authors.initials: M
authors.lastname: Germain
authors.forename: C
authors.initials: C
authors.lastname: Thurieau
authors.forename: J L
authors.initials: JL
authors.lastname: Fauchère
authors.forename: E
authors.initials: E
authors.lastname: Canet
authors.forename: C
authors.initials: C
authors.lastname: Advenier
mesh_terms: D001665:Binding Sites; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D014469:Umbilical Arteries / Q000187:drug effects / Q000378:metabolism; D014471:Umbilical Veins / Q000187:drug effects / Q000378:metabolism
chemical_list: C065679:icatibant; D001920:Bradykinin