title: Characterization of bradykinin B(2) receptor antagonists in human and rat urinary bladder.
abstract: The effect of three selective bradykinin B(2) receptor antagonists, MEN11270 (H-DArg-Arg-Pro-Hyp-Gly-Thi-c(Dab-DTic-Oic-Arg)c(7gamma-1 0alpha)), Icatibant (H-DArg-Arg-Pro-Hyp-Gly-Thi-Ser-DTic-Oic-Arg-OH), and FR173567 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-[2, 4-dichloro-3-[(2-methyl-8-quinolinyl) oxymethyl] phenyl]-N-methylaminocarbonylmethyl]acrylamide) was evaluated in the human and rat urinary bladder in vitro and in vivo in anaesthetized rats. Bradykinin evoked a concentration-dependent contraction of human (pD(2)=7.2) and rat (pD(2)=7.7) detrusor muscle strips. In human preparations, all the antagonists tested produced a rightward-shift in the concentration-response curve for bradykinin. Schild plot analysis yielded pK(B) values of 8.4, 8.4 and 8.6 for MEN11270, Icatibant, and FR173567, respectively. In the rat preparations the three antagonists (at 100 nM concentration), produced a shift to the right which gave apparent pA(2) values of 8. 2, 8.0 and 8.1 for MEN11270, Icatibant, and FR173567, respectively. In anaesthetized rats, both MEN11270 and Icatibant (1-10 nmol/kg i.v. ) dose dependently reduced the bradykinin (100 nmol/kg i.v.)-induced urinary bladder contraction, their effect being prompt and long-lasting. In contrast, FR173567 (100 nmol/kg i.v.) produced a partial and short-lasting inhibition of bradykinin-induced bladder contractions. The present findings indicate that all the antagonists tested recognize with similar potencies the bradykinin B(2) receptors expressed in the detrusor muscle of both humans and rats. MEN11270 and Icatibant possess a higher potency and longer duration of action in vivo than FR173657, suggesting that the activity of this non-peptide antagonist in vivo is hampered by factors unrelated to its affinity for bradykinin B(2) receptors.
authors.affiliation: Pharmacology Department, Menarini Ricerche, via Rismondo 12 A, 50135, Florence, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Meini
authors.forename: R
authors.initials: R
authors.lastname: Patacchini
authors.forename: S
authors.initials: S
authors.lastname: Giuliani
authors.forename: M
authors.initials: M
authors.lastname: Lazzeri
authors.forename: D
authors.initials: D
authors.lastname: Turini
authors.forename: C A
authors.initials: CA
authors.lastname: Maggi
authors.forename: A
authors.initials: A
authors.lastname: Lecci
mesh_terms: D000368:Aged; D000771:Anesthesia, Intravenous; D018686:Anesthetics, Intravenous; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043782:Receptor, Bradykinin B2; D014520:Urethane; D001743:Urinary Bladder / Q000187:drug effects*
chemical_list: D018686:Anesthetics, Intravenous; D065168:Bradykinin Receptor Antagonists; C105311:FR 173657; C119318:MEN 11270; D009842:Oligopeptides; D010456:Peptides, Cyclic; D011804:Quinolines; D043782:Receptor, Bradykinin B2; D014520:Urethane; C065679:icatibant; D001920:Bradykinin