Characterization of bradykinin B-2 receptor antagonists in human and rat urinary bladder

The effect of three selective bradykinin B-2 receptor antagonists, MEN11270 (H-DArg-Arg-Pro-Hyp-Gly-Thi-c(Dab-DTic-Oic- Arg)c(7 gamma-10 alpha)), Icat ibant( 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) oxy methyl] phenyl]-N-methylaminocarbonylmethyl] acrylamide) was evaluated in t he 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 t he rat preparations the three antagonists (at 100 nM concentration), produc ed 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 rat s, both MEN11270 and Icatibant (1-10 nmol/kg i.v.) dose dependently reduced the bradykinin (100 nmol/kg i.v.)-induced urinary bladder contraction, the ir effect being prompt and long-lasting. In contrast, FR173567 (100 nmol/kg i.v.) produced a partial and short-lasting inhibition of bradykinin-induce d bladder contractions. The present findings indicate that all the antagoni sts tested recognize with similar potencies the bradykinin B-2 receptors ex pressed in the detrusor muscle of both humans and rats. MEN11270 and Icatib ant possess a higher potency and longer duration of action in vivo than FR1 73657, suggesting that the activity of this non-peptide antagonist in vivo is hampered by factors unrelated to its affinity for bradykinin B-2 recepto rs. (C) 2000 Elsevier Science B.V. All rights reserved.