Antagonists for kinin B1 and B2 receptors in the mouse

Contractile responses to B1 and B2 receptor agonists have been demonstrated in the mouse stomach; the mouse urinary bladder responds only to B2 receptor agonists. These tissues were used in this study to investigate the antagonistic effect of four B2 receptor antagonists, namely, DArg[Hyp3,DPhe7,Leu8]BK (BK, bradykinin), HOE-140, WIN 64338, and FR-173657 (B2 receptor antagonists), as well as three B1 kinin receptor antagonists; [Leu8]desArg9BK, Lys[Leu8]desArg9BK, and AcLys[D beta Nal7,Ile8]desArg9BK, were investigated. Results shown indicate that DArg[Hyp3,DPhe7,Leu8]BK is a partial agonist, while HOE-140 and FR-173657 are pure antagonists, devoid of direct myotropic effects, and quite selective for the B2 receptor. WIN 64338 was essentially inactive on both B1 and B2 receptors. The myotropic effect of DArg[Hyp3,DPhe7,Leu8]BK is blocked by HOE-140. Similarly, Lys[Leu8]desArg9BK and [Leu8]desArg9BK are B1 receptor partial agonists whose activities are blocked by AcLys[D beta Nal7,Ile8]desArg9BK (code name R 715), a fairly pure B1 receptor antagonist. Both HOE-140 and FR-173657 are long-acting, slowly reversible compounds that exert a noncompetitive type of antagonism, while R 715 is rapidly reversible and, thus, possibly competitive. Data presented in this paper provide a pharmacological characterization of B1 and B2 receptor antagonists in the mouse and underline the positive features of FR-173657 as a potent and selective B2 receptor antagonist, as well as the potency and purity of R 715 as a B1 receptor antagonist in the mouse.