Attempts to evaluate the role of kinins in airway inflammation in humans using the bradykinin receptor antagonist [DArg0-Hyp3-DPhe7]-bradykinin (NPC 567) were unsuccessful, possibly because of the low potency and poor stability of this compound. Recently, [DArg0-Hyp3-Thi5-DTic7-Oic8]- bradykinin (Hoe 140), a novel antagonist that seems to overcome these weaknesses, has been developed. The present study was performed to compare the potency and efficacy of Hoe 140 to those of NPC 567 and another antagonist, [DArg0-Hyp3-DPhe7-Ile8]-bradykinin (B7418), on kinin receptors on guinea pig tracheal epithelial cells. Radioligand binding studies showed the presence of two types of B2 kinin receptors on guinea pig tracheal epithelial cells: a high-affinity site with a K(d) of 0.44 nM and B(max) of 12.1 fmol/106 cells (4000 sites/cell), and a lower affinity site with a K(d) of 10 nM and B(max) of 16 fmol/106 cells (9600 sites/cell). Bradykinin-induced prostaglandin E2 production seemed to be associated primarily with the lower affinity site. All three B2 receptor antagonists displaced labeled bradykinin from both classes of binding sites and inhibited bradykinin-induced prostaglandin E2 production, but Hoe 140 was up to 40- fold more potent than NPC 567 and showed an affinity comparable to that of bradykinin for both binding sites. This higher potency of Hoe 140, and its stability against peptidases, suggests that this compound will be useful in evaluating the role of bradykinin in inflammatory diseases of the airways.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1 1993|
ASJC Scopus subject areas
- Molecular Medicine