Hoe 140 a new potent and long acting bradykinin‐antagonist: in vitro studies

Abstract

1 Hoe 140 (d-Arg-[Hyp³, Thi⁵, d-Tic⁷, Oic⁸]bradykinin) is a new bradykinin (BK)-antagonist. It was tested in several in vitro assays and compared with d-Arg-[Hyp², Thi^5,8,d-Phe⁷]BK. 2 In receptor binding studies in guinea-pig ileum preparations, Hoe 140 showed an IC₅₀ of 1.07 × 10⁻⁹mol l⁻¹ and a K_I value of 7.98 × 10⁻¹⁰ mol l⁻¹. 3 In isolated organ preparations Hoe 140 and d-Arg-[Hyp², Thi^5,8, d-Phe⁷]BK inhibited bradykinin-induced contractions concentration dependently, with IC₅₀-values in the guinea-pig ileum preparation of 1.1 × 10⁻⁸ mol l⁻¹ and 3 × 10⁻⁵ mol l⁻¹, respectively. pA₂ values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC₅₀ value was 4.9 × 10⁻⁹ mol l⁻¹ for Hoe 140. d-Arg-[Hyp², Thi^5,8, d-Phe⁷]BK showed an IC₅₀ of 4.0 × 10⁻⁶ mol l⁻¹. The IC₅₀ values in the guinea-pig isolated pulmonary artery were 5.4 × 10⁻⁹ mol l⁻¹ and 6.4 × 10⁻⁶ mol l⁻¹, respectively. In the rabbit aorta no inhibitory effects on Des-Arg⁹-BK induced contractions were observed. 4 In cultured bovine endothelial cells, Hoe 140 antagonized (IC₅₀ = 10⁻⁸ mol l⁻¹) bradykinin-induced endothelium-derived relaxing factor (EDRF) release and the bradykinin-induced increase in cytosolic free calcium (IC₅₀ = 10⁻⁹ mol l⁻¹). 5 Hoe 140 (10⁻⁷ mol l⁻¹) totally suppressed the bradykinin-induced (10⁻⁸ to 10⁻⁴mol l⁻¹) prostacyclin (PGI₂) release from cultured endothelial cells of bovine aorta. d-Arg-[Hyp², Thi^5,8, d-Phe⁷]BK (10⁻⁷ mol l⁻¹) showed a weaker antagonism. 6 Taken together these results show that Hoe 140 is a highly potent bradykinin antagonist. It was two to three orders of magnitude more potent than d-Arg-[Hyp², Thi^5,8, d-Phe⁷]BK.