BRADYKININ RECEPTOR TYPES AND B-2 SUBTYPES

Bradykinin, desArg(9)BK, some agonist analogues and several antagonists have been tested in isolated organs in order to identify bradykinin B-2 receptor subtypes. The initial pharmacological characterization was made in the rabbit jugular vein and the guinea pig ileum, two widely used B-2 preparations which have shown marked differences in their sensitivities to both agonists and antagonists. The study has then been extended to peripheral tissues (stomach, colon, urinary bladder) of four species (the rat, guinea pig, rabbit and man) and to isolated vessels (rabbit jugular vein, rabbit vena cava, guinea pig pulmonary artery, rat portal vein) in order to determine if pharmacologic receptor subtypes may be related to species. It has been shown that B-2 receptors in rat and guinea pig tissues belong to a similar pharmacological entity, a receptor which is different from that mediating the responses of rabbit and human tissues. Agonists order of potency ([Hyp(3)]BK > BK > [Aib(7)]BK) obtained in the rabbit jugular vein is different from that found in the guinea pig ileum (BK less than or equal to [Aib(7)]BK > [Hyp(3)]BK). Affinities of competitive antagonists (for instance DArg[Hyp(3),DPhe(7),Leu(8)]BK) in rabbit tissues are higher than in guinea pig and rat tissues by at least 2 log units, while the non peptidic compound WIN 64338 is more active (also by two log units) in guinea pig than in human and rabbit tissues. The non competitive long-acting antagonist HOE 140 is very potent and equally active in the four species. Some antagonists (peptides without unnatural residues, peptides with unnatural residues, non peptides) have been shown to be specific for kinin receptors and selective for the B-2. Altogether, the present results a) confirm the existence of two B-2 receptor subtypes, b) suggest that receptor subtypes may be species dependent and c) indicate that the B-2 receptor subtype found in the rabbit is similar to that found in man.