Antagonists for kinin B-1 and B-2 receptors in the mouse

Contractile responses to B-1 and B-2 receptor agonists have been demonstrated in the mouse stomach; the mouse urinary bladder responds only to B-2 receptor agonists. These tissues were used in this study to investigate the antagonistic effect of four B-2 receptor antagonists, namely, DArg[Hyp(3),DPhe(7),Leu(8)]BK (BK, bradykinin), HOE-140, WIN 64338, and FR-173657 (B-2 receptor antagonists), as well as three B-1 kinin receptor antagonists; [Leu(8)]desArg(9)BK, Lys[Leu(8)]desArg(9)BK, and AcLys[D beta Nal(7),Ile(8)]desArg(9)BK, were investigated. Results shown indicate that DArg[Hyp(3),DPhe(7),Leu(8)]BK is a partial agonist, while HOE-140 and FR-173657 are pure antagonists, devoid of direct myotropic effects, and quite selective for the B-2 receptor. WIN 64338 was essentially inactive on both B-1 and B-2 receptors. The myotropic effect of DArg[Hyp(3),DPhe(7),Leu(8)]BK is blocked by HOE-140. Similarly, Lys[Leu(8)]desArg(9)BK and [Leu(8)]desArg(9)BK are B-1 receptor partial agonists whose activities are blocked by AcLys[D beta Nal(7),Ile(8)]desArg(9)BK (code name R 715), a fairly pure B-1 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 B-1 and B-2 receptor antagonists in the mouse and underline the positive features of FR-173657 as a potent and selective B-2 receptor antagonist, as well as the potency and purity of R 715 as a B-1 receptor antagonist in the mouse.