Oral antinociception and oedema inhibition produced by NPC 18884, a non-peptidic bradykinin B-2 receptor antagonist

This study investigates the antinociceptive and the oedema inhibition prope rties of the novel non-peptide bradykinin (BK) B-2 receptor antagonist, NPC 18884. Given by i.p, or p.o, routes NPC 18884 produced graded and long-las ting (at least 2.5 h and 5.0 h, respectively, for i.p. and p.o. administrat ion) inhibition of acetic acid-induced abdominal constrictions in mice, wit h mean ID50 values of 8.3 nmol/kg and 439.9 nmol/kg. NPC 18884 also inhibit ed kaolin-induced abdominal constrictions (44 +/- 9% and 48 +/- 3% of inhib ition, for i.p. and po routes, respectively). Given by i.p. or p.o. routes NPC 18884 attenuated both phases of formalin-induced licking, as well as fo rmalin-induced oedema formation. At similar doses NPC 18884 produced signif icant inhibition of capsaicin-induced nociception. NPC 18884, like HOE 140 given i.p., prevented the nociception caused by BK with mean ID50 values of 0.85 nmol/kg and 0.44 nmol/kg, respectively. Given orally NPC 18884, but n ot HOE 140, caused graded inhibition of BK-induced nociception (mean ID50 v alue of 50 nmol/kg). In rats, NPC 18884 given i.p. prevented BK and carrageenan-induced hyperalg esia (mean ID50 values of 6 nmol/kg and 13 nmol/kg), without affecting the hyperalgesia induced by des-Arg(9)-bradykinin (DABK) or by prostaglandin E- 2 (PGE(2)). NPC 18884 given i.p. inhibited the mouse paw oedema induced by tyrosine(8)-bradykinin or by carrageenan, but had no effect on DABK-induced oedema in mice pre-treated with Escherichia coli endotoxin, or that induce d by PGE(2). Thus, the novel non-peptide BK B-2 receptor antagonist NPC 18884 produces r apid onset, potent and relatively long-lasting oral antinociceptive and oed ema inhibition properties. The anti-BK actions of NPC 18884 are quite selec tive towards the BK B-2 receptor-mediated responses.