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

Summary (±)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 Lt. 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 ix. 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 L v. The results indicate that (±)CP-96,345 is a specific and long-acting antagonist which crosses the blood-brain barrier to block the action of SP and NPK in the spinal cord. Furthermore, these findings are consistent with the hypothesis that receptors of the NK-1 subtype mediate the cardiovascular responses evoked by the spinal action of neurokinins.Correspondence to R. Couture at the above address