We have compared the in vivo activity of the
bradykinin B(2)
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
B(2) 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 B(2) receptors in guinea pig airways and in the vascular system. The greater efficacy of the antagonists in blocking airway compared with vascular
B(2) receptors after
topical administration suggests that they can block airway
B(2) receptors with little systemic effects.