Analysis of the antagonistic actions of HOE 140 and other novel bradykinin analogues on the guinea-pig ileum

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Abstract

The type of antagonism exhibited by three novel bradykinin (BK) antagonists, D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]BK (HOE 140, compound I), D-Arg-[Hyp3, D-Tic7, Oic8]BK (compound II) and [Arg(Tos)1, Hyp3, Thi5, D-Tic7, Oic8]BK (compound III), was compared with that of a conventional antagonist, D-Arg-[Hyp2, Thi5,8, D-Phe7]BK (compound IV), on the guinea-pig ileum. The novel compounds induced rightward displacements of cumulative concentration-response curves to BK, accompanied by a progressive reduction of the maximum effect (Emax) without a significant decrease in the slope, whereas no reduction of Emax was observed with compound IV. Actions of substance P on the guinea-pig ileum and of vasopressin on the rat uterus remained completely unaffected. It is concluded that as the novel BK analogues show competitive as well as non-competitive inhibition in the guinea-pig ileum, but the inhibition is reversible and specific, they are dual antagonists.

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      Although the profile of antagonism displayed by Hoe 140 is highly dependent upon the species and tissue used for assay, most studies have shown that it is predominantly an insurmountable antagonist. Thus, Hoe 140 is an insurmountable antagonist against responses to bradykinin in guinea pig ileum (Griesbacher and Lembeck, 1992), rabbit jugular vein (Rhaleb et al., 1992; Félétou et al., 1994; Marceau et al., 1994), and guinea pig trachea (Field et al., 1992; Trifilieff et al., 1993). By contrast, Hoe 140 causes surmountable antagonism in the human umbilical vein (Marceau et al., 1994).

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