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Effect of bradykinin antagonists on bradykinin‐induced plasma extravasation, venoconstriction, prostaglandin E2 release, nociceptor stimulation and contraction of the iris sphincter muscle in the rabbit

1 The inhibition of the bradykinin‐induced plasma extravasation by six bradykinin (Bk) antagonists was tested on rabbit skin. All of them showed inhibitory effects without an agonistic action in the doses used. B4310 (Lys‐Lys‐3‐Hyp‐5,8‐Thi‐7‐DPhe‐Bk) was the most active antagonist and was therefore used in the subsequent experiments. 2 B4310 (5–500 nm) antagonized the bradykinin‐induced reduction of the venous outflow from the rabbit isolated ear in a dose‐dependent manner without affecting the arterial vasoconstriction induced by angiotensin II. 3 The bradykinin‐induced release of prostaglandin E2 (PGE2) from the perfused rabbit ear was reduced by 63% when B4310 (800 nm) was infused before, during and after the bradykinin injection. 4 Bradykinin was injected into the ear artery of anaesthetized rabbits and the reflex hypotensive response was used as indicator of the nociception. The response was antagonized by a local infusion of B4310 (50 and 500 nm). The antagonism was dose‐dependent and reversible. The parallel shift of the dose‐response curve to bradykinin suggests a competitive inhibition. However, B4310 did not antagonize acetylcholine‐induced nociceptor stimulation. 5 B4310 inhibited bradykinin‐induced stimulation of the trigeminal nerve which results in a substance P‐mediated contraction of the iris sphincter muscle. A pA2 of 7.59 was calculated. B4310 did not inhibit capsaicin‐induced contractions. 6 It is concluded that B4310 inhibits specifically five different actions of bradykinin which are related to its possible pathophysiological role.