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

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Abstract
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.