Vol. 296, Issue 3, 1051-1057, March 2001

Differences between Peptide and Nonpeptide B₂ Bradykinin Receptor Antagonists in Blocking Bronchoconstriction and Hypotension Induced by Bradykinin in Anesthetized Guinea Pigs

Manuela Tramontana, Alessandro Lecci, Stefania Meini, Xavier Montserrat, Jaume Pascual, Sandro Giuliani, Laura Quartara and Carlo Alberto Maggi

Departments of Pharmacology (M.T., A.L., S.M., S.G., C.A.M.) and Chemistry (L.Q.), Menarini Ricerche S.p.A., Florence, Italy; and Department of Chemistry, Laboratorios Menarini, Badalona, Spain (X.M., J.P)

We have compared the in vivo activity of the bradykinin B₂ receptor peptide antagonists MEN 11270 and Icatibant versus the nonpeptide antagonist FR 173657, after intravenous (i.v.) and intratracheal (i.t.) administration, on the bradykinin (BK)-induced bronchoconstriction and hypotension in anesthetized guinea pigs. We have also assessed the affinity of these antagonists for B₂ receptors in guinea pig lung membranes by radioligand binding and the metabolic stability of peptide antagonists in guinea pig plasma and tissue homogenates. The i.v. administration of MEN 11270, Icatibant, or FR 173657 induced a dose-dependent (10-100 nmol/kg) inhibition of both hypotension and bronchoconstriction induced by bradykinin (10 nmol/kg i.v.). The inhibitory effect of MEN 11270 and Icatibant was comparable both in terms of potency and time course, whereas FR 173657 was less potent and shorter acting. After i.t. administration MEN 11270 and Icatibant (10-100 nmol/kg) dose dependently inhibited both bronchoconstriction and hypotension, whereas FR 173657 (10-100 nmol/kg) reduced bronchoconstriction without affecting hypotension. The antibronchoconstrictor effect of MEN 11270 was more prolonged than that of Icatibant and FR 173657, whereas no differences were found between the peptide antagonists in inhibiting hypotension. These findings indicated that, in vivo, the peptide antagonists are more potent and longer lasting than FR 173657 acting on bradykinin B₂ receptors in guinea pig airways and in the vascular system. The greater efficacy of the antagonists in blocking airway compared with vascular B₂ receptors after topical administration suggests that they can block airway B₂ receptors with little systemic effects.