Differences between peptide and nonpeptide B-2 bradykinin receptor antagonists in blocking bronchoconstriction and hypotension induced by bradykinin in anesthetized guinea pigs

We have compared the in vivo activity of the bradykinin B-2 receptor peptid e antagonists MEN 11270 and Icatibant versus the nonpeptide antagonist FR 1 73657, after intravenous (i.v.) and intratracheal (i.t.) administration, on the bradykinin (BK) induced bronchoconstriction and hypotension in anesthe tized guinea pigs. We have also assessed the affinity of these antagonists for B2 receptors in guinea pig lung membranes by radioligand binding and th e metabolic stability of peptide antagonists in guinea pig plasma and tissu e homogenates. The i.v. administration of MEN 11270, Icatibant, or FR 17365 7 induced a dose-dependent (10-100 nmol/kg) inhibition of both hypotension and bronchoconstriction induced by bradykinin (10 nmol/kg i.v.). The inhibi tory effect of MEN 11270 and Icatibant was comparable both in terms of pote ncy 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 dep endently inhibited both bronchoconstriction and hypotension, whereas FR 173 657 (10-100 nmol/kg) reduced bronchoconstriction without affecting hypotens ion. 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 indicate d that, in vivo, the peptide antagonists are more potent and longer lasting than FR 173657 acting on bradykinin B-2 receptors in guinea pig airways an d in the vascular system. The greater efficacy of the antagonists in blocki ng airway compared with vascular B-2 receptors after topical administration suggests that they can block airway B-2 receptors with little systemic eff ects.