Role of NK-1 receptor in central cardiovascular regulation in rats: studies on a novel non-peptide antagonist, CP-96,345, of substance P NK-1 receptor.

CP-96,345[(2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)- methyl]-1-azabicyclo [2.2.2] octan-3-amine] was recently discovered to be a nonpeptide 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 of 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 (l 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.