ROLE OF NK-1 RECEPTOR IN CENTRAL CARDIOVASCULAR REGULATION IN RATS - STUDIES ON A NOVEL NONPEPTIDE ANTAGONIST, CP-96,345, OF SUBSTANCE-P NK-1 RECEPTOR

CP-96,345 [(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.21 octan-3-amine] was recently discovered to be a non-peptide substance P (SP) antagonist. We examined the effects of CP-96,345 on the central cardiovascular responses to tachykinin peptides in anesthetized rats. CP-96,345 (200 nmol, i.c.v.) inhibited the pressor responses to the NK-1 receptor-selective agonist GR 73632 (0.5 nmol, i.c.v.) and SP (7 nmol, i.c.v.). It also inhibited the increase in blood pressure elicited by neurokinin A (7 nmol, i.c.v.). However, it had no effect on the earlier pressor response induced by neuropeptide-gamma (1 nmol, i.c.v.) or by a selective NK-3 agonist senktide (1 nmol, i.c.v.). These findings suggest that SP (i.c.v.) induces pressor responses via the NK-1 receptor, and that the pressor response to neurokinin A may also be mediated by the NK-1 receptor in the brain.