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

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PEPTIDE EPTOR amiya

6,345, OF S U B S T A N C E P t :l. Saito, Y. Nakayama, K. Hond~

cology, Faculty of Pharmaceutic~ 4-01, Japan.

, Fukuoka

,~cently, CP-96,345 [(2S, 3S)-cis-2-(diphenylm~ phenylmethyl)-N,~thyl]-l-azabicyclo [2.2.2] octan-3-amine] was dis discovered ptide antagonist of NK-1 receptor (1). In this study, stuc we e)

yphenyl))tent non,= effect of ~-96,345 on the central cardiovascular respons 3onses of ta .=ptides in ethane anesthetized rats. Experiments on cardiovascu car( ses were rformed as described previously (2,3). We examined exami whE ~,345 acts a specific antagonist of NK-1 receptor by in vitro bioassa~ 45 (1-100 4) caused parallel shifts of the right of the concentration conc~ t curve of bstance P (SP)-induced vasodilation in the guinea pig aort ,'eptor). At ncentrations that block the NK-1 receptor (1( '100 nM), CP-96,345 did not tagonize neurokinin A (NKA)-induced contraction in the rat vas deferens(NNK-2 anta( rece ,'eptor). Intracerebroventricular injections (i.c.v.) of tachykinins caused dosedc pendent increases in blood pressure and hea~ de heart rate in anesthetized rrats. Pr{etreatment with CP-96,345 (200 nmol, i.c.v.) inhibited inhib the pressor response~ 3onses to the,= NK-l-selective agonist GR73632 (0.5 nmol, i.c.v.) and SP (7 nmol, i.c.v.). It also inhilibited the increase in blood pressure elicited by NKA NI. (7 nmol, i.c.v.). HowevE Iowever, it hadd no effect on the earlier pressor response induced induc~ by neuropeptide y (1 nmol, nr i.c.v.), or by a selective NK-3 agonist senktide (1 nmol, i.c.v.). These results res suggest that SP (i.c.v.) caused ,'aused pressor responses Via the NK-1 receptor, and1that the pressor response to NKA is also mediated by the NK-1 receptor in the brain. br However, we were unable )le to determine whether a specific receptor subtype for neuropeptide y exists inq the brain. CP-96,345 was a generous gift from Pfizer Pf (U.S.A.), and GR73632 from "om Glaxo (UK). (1) McLean, S., et al., (1991 991 ) Science, 251 : 437-439. (2) Takano, Y., et al., (1990) 90) Brain Res., 528: 231-237. (3) Takano, Y., et al., (1992 92) Neurosci. Letters, in press.