Inhibitory action of (+/-)CP-96,345 on the cardiovascular responses to intrathecal substance P and neuropeptide K in the conscious freely moving rat.

Abstract

(+/-)CP-96,345, a nonpeptide and highly selective NK-1 receptor antagonist, was tested acutely and chronically as an inhibitor of the cardiovascular responses induced by the intrathecal (i.t.) injection of substance P (SP) and neuropeptide K (NPK) in the conscious rat. When given at T-9 spinal cord level, NPK (0.65, 3.25 and 6.5 nmol) and SP (6.5, 16.25 and 32.5 nmol) produced increases in mean arterial pressure and heart rate. The cardiovascular responses to NPK were greater in intensity and duration than those produced by SP. The prior i.t. injection of (+/-)CP-96,345 (0.65 and 6.5 nmol, 15 min earlier) inhibited in a dose-dependent manner the pressor response and the tachycardia induced by 6.5 nmol SP while 65 nmol of the antagonist was required to reduce the effects of 3.25 nmol NPK. However, both the SP and NPK-induced cardiovascular changes were blocked 2 days after the i.t. injection of 6.5 nmol (+/-)CP-96,345. Five days after a single i.t. injection of 6.5 nmol (+/-)CP-96,345, the cardiovascular response to SP remained unaffected while that of NPK was partially attenuated. Moreover, (+/-)CP-96,345 was active as an antagonist when given i.v. at the dose of 0.13 mg/kg. Conversely, (+/-)CP-96,345 failed to block the cardiovascular effect caused by the i.t. injection of 81 pmol bradykinin and did not produce any changes on resting blood pressure and heart rate when given alone either i.t. or i.v.(ABSTRACT TRUNCATED AT 250 WORDS)