Kinin B₁and B₂receptors in the mouse

Abstract

A systematic study has been performed in various segments of the intestine and in the urinary bladder of the mouse to identify tissues that respond to kinins and possess B1 and (or) B2 receptors. The stomach was found to contain B1 and B2 functional sites that show pharmacological profiles compatible with B1 and B2 receptors, whereas the urinary bladder possesses only B2 sites. Myotropic responses mediated by B1 receptors show slow onset and reversibility compared with responses evoked by the activation of B2 receptors. The order of potency of agonists is bradykinin (BK) > or = [Hyp3]BK > [Aib7]BK on the B2 of both the stomach and urinary bladder, while desArg9-BK is inactive. The order of potency of agonists on the B1 receptor is [Lys]desArg9BK < or = desArg9BK, while BK and the other B2 agonists are inactive. B2 antagonists of the first generation, such as DArg[Hyp3,DPhe7]BK, act as partial agonists and show residual agonistic activities higher than 0.5, while HOE-140 shows high affinity and very little residual agonistic activity; WIN 64338 is almost inactive. On the B1 receptor, classical antagonists, such as [Leu8]desArg9BK and Lys[Leu8]desArg9BK, act as partial agonists. A modification of their structures has led to a new compound (R-715) that shows fairly high affinity (pA2 7.0) and little residual agonistic effect. This compound has been used for B1 receptor characterization in the stomach. Residual agonistic activities of both B2 and B1 antagonists appear to be mediated by B2 and B1 receptors, respectively. Data presented in this paper provide the pharmacological basis for sensitive and selective preparations to be used for studying B1 and B2 receptors in the mouse.

Kinin B1 and B2 receptors in pig vessels: characterization of two monoreceptor systems

“…1) and almost irreversible, such that only one concentration/response curve can be measured in each tissue. This is in accord with the observations made in other species (Nsa Allogho et al 1995;Meini et al 1996), where contractions elicited by B 1 receptor activation are prolonged compared with those induced by B 2 . The mechanism by which B 1 activation results in prolonged contractions is still unknown.…”

Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B 2 Kinin Receptor Gene Knockout Mice

“…The biological action of kinins is mediated by activation of at least 2 known subtypes of G-protein-coupled receptors, B 1 and B 2 . 8,26 The B 1 receptor is only weakly expressed under physiological conditions but is strongly induced under pathological conditions, such as inflammation or tissue injury, 27,28 and is sensitive to des-Arg 9 -bradykinin, a metabolite of bradykinin. B 2 receptors, which are constitutively expressed in most tissues, are sensitive to bradykinin and kallidin and are responsible for most known effects of bradykinin.…”

Kinin B 1 Receptor Antagonists Containing α-Methyl- l -Phenylalanine: In Vitro and In Vivo Antagonistic Activities

“…The present results confirm and further validate previous data obtained with a series of R 715 analogues in which the N-terminal residues DArg, DLys, Sar, Lys, or AcLys were used. 16 4 Therefore, R 892 can be considered a pure B 1 receptor antagonist and can be recommended for use in the mouse and possibly in other species (eg, the rat) that possess a B 1 receptor subtype whose major features are a high sensitivity to desArg 9 BK and the partial agonistic character of the classical B 1 antagonists. Antagonistic potency of R 892 is comparable to those of B 9858 and B 9958 designed by Stewart et al 26 who used a variety of unnatural amino acids such as Igl, Tic, Oic, and Cpg conjugated with a Lys-Lys extension of the N-terminal.…”

“…2 However, these peptide antagonists show some limitations, in part because of their susceptibility to enzymatic degradation by various tissue and plasma peptidases; they also have putative residual agonistic activities. This latter property has been observed inasmuch in vitro (on smooth muscle myotropic assays: the mouse stomach fundus, 4 the rat duodenum, 5 the rat ileum, 6 the rabbit stomach fundus, and the rat portal vein [F. Gobeil, personal observation]; on electrogenic assays: the dog colon mucosa, 7 the rat colon 8 ) as in vivo (eg, canine blood pressure 9,10 ). Use of these peptidic compounds may be the source of inconclusive interpretations, especially when experiments are performed on whole animals, and point to the need of new pharmacological tools for studying B 1 2) are thought to be the most efficient in vivo in the inactivation of peptides related to Lys-desArg 9 BK.…”