title: Pharmacological characterization of a new highly potent B2 receptor antagonist (HOE 140: D-Arg-[Hyp3,Thi5,D-Tic7,Qic8]bradykinin).
abstract: HOE 140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a new B2 antagonist, was compared to R-493 (D-Arg[Hyp3-D-Phe7,Leu8]bradykinin) with respect to inhibition of the responses of seven isolated smooth muscle preparations to bradykinin. R-493 was found to exert: (a) high antagonistic activity on the rabbit jugular vein (pA2 of 8.86), (b) moderate activity on the rabbit aorta, guinea-pig ileum, hamster urinary bladder and human urinary bladder (pA2 of 5.76, 6.77, 7.16 and 7.15, respectively) and (c) a stimulatory effect on the guinea-pig trachea. On the other hand, HOE 140 showed identical apparent affinities (8.36-9.12) on all preparations except the rabbit aorta where it was inactive and the guinea-pig trachea where the compound was an antagonist (pA2: 7.42) without agonistic effect. HOE 140 is specific and selective for B2 receptors since it was inactive against angiotensin II, substance P, neurokinin A, desArg9-bradykinin, noradrenaline or acetylcholine in the various preparations. R-493 inhibited the contractile effects of bradykinin competitively, while HOE 140 was not competitive even at low concentrations (7.7 x 10(-9) M). These results demonstrate that HOE 140 is a potent B2 antagonist with high affinity, specific for kinin receptors and selective for the B2 receptor type, but is non-competitive. HOE 140 is the first bradykinin receptor antagonist that acts as such on the guinea-pig trachea without showing any agonistic activity.
authors.affiliation: University of Sherbrooke, Quebec, Canada.
authors.forename: N E
authors.initials: NE
authors.lastname: Rhaleb
authors.forename: N
authors.initials: N
authors.lastname: Rouissi
authors.forename: D
authors.initials: D
authors.lastname: Jukic
authors.forename: D
authors.initials: D
authors.lastname: Regoli
authors.forename: S
authors.initials: S
authors.lastname: Henke
authors.forename: G
authors.initials: G
authors.lastname: Breipohl
authors.forename: J
authors.initials: J
authors.lastname: Knolle
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006224:Cricetinae; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D009842:Oligopeptides; C073117:bradykinin, Arg-Hyp(3)-Phe(7)-Leu(8)-; C065679:icatibant; D001920:Bradykinin