Hoe 140 a new potent and long acting bradykinin‐antagonist: <i>in vitro</i> studies

British Journal of Pharmacology - Tập 102 Số 3 - Trang 769-773 - 1991
Franz J. Hock1, Klaus Wirth1, Udo Albus1, Wolfgang Linz1, H.J. Gerhards1, Gabriele Wiemer1, St. Henke1, Gerhard Breipohl1, Wilfried Α. König1, Jochen Knolle1, Bernward A. Schölkens1
1Hoechst AG, Pharmaceutical Division, General Pharmacology Research, P.O. Box 80 03 20, D-6230 Frankfurt/M. 80, F.R.G.

Tóm tắt

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, Thi5,8,d‐Phe7]BK. In receptor binding studies in guinea‐pig ileum preparations, Hoe 140 showed an IC50 of 1.07 × 10−9mol l−1 and a KI value of 7.98 × 10−10 mol l−1. In isolated organ preparations Hoe 140 and d‐Arg‐[Hyp2, Thi5,8, 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, Thi5,8, 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. 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). 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, Thi5,8, d‐Phe7]BK (10−7 mol l−1) showed a weaker antagonism. 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, Thi5,8, d‐Phe7]BK.

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British Journal of Pharmacology

Tập 102 Số 3

769-773

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