New, long‐acting, potent bradykinin antagonists

1 Three new bradykinin (BK) antagonists, d‐Arg0‐Hyp3‐Thi5‐d‐Tic7‐Oic8‐BK (compound I), d‐Arg0‐Hyp3‐d‐Tic7‐Oic8‐BK (compound II), and Arg(Tos)1‐Hyp3‐Thi5‐d‐Tic7‐Oic8‐BK (compound III), were tested against the effects of BK in 9 bioassay preparations including visceral smooth muscles, vasoconstriction, plasma protein extravasation, release of prostaglandin E2, bronchoconstriction, and stimulation of afferent C‐fibre nociceptors. In some of these tests the effects of the new compounds were compared with those of the antagonist d‐Arg0‐Hyp2‐Thi5,8‐d‐Phe7‐BK (compound IV), described by Stewart & Vavrek (1987). 2 For all bioassays the general rank order of potency of the compounds was found to be I > II > III ≫ IV. The new antagonists were long‐acting; in some bioassays their effects outlasted the duration of the experiment. 3 The inhibitory effects of the new BK antagonists were specific for BK; actions of noradrenaline, angiotensin II, acetylcholine or histamine were unaffected by the antagonists. They did not stimulate the release of histamine or prostaglandins. An agonistic effect was observed only with very high concentrations of compounds I and II in the plasma protein extravasation test. 4 The long duration of action of the new BK antagonists is probably due to a high and long‐lasting affinity to the BK receptors. A high resistance of the antagonists to enzymatic destruction may be another reason. 5 The new BK antagonists will be valuable tools for the investigation of the pathophysiological role of BK. In addition they may offer a potential for therapeutic applications.