CP-96,345 ANTAGONISM OF NK(1) RECEPTORS AND SMOKE-INDUCED PROTEIN EXTRAVASATION IN RELATION TO ITS CARDIOVASCULAR EFFECTS

The effects of the non-peptide NK1 receptor antagonist, CP-96,345, on cardiovascular homeostasis were investigated in conscious and anaesthetized rats in vivo and on heart function and muscle tonicity of vessels in vitro. CP-96,345 and its enantiomer, CP-96,344, which does not exhibit NK1 receptor-blocking activity when tested at a concentration of 1 muM, significantly decreased blood pressure in conscious rats at a dose of 0.32 mg/kg i.v. CP-96,345 and CP-96,344 additionally reduced heart rate at doses of 1 and 3.2 mg/kg, respectively. Studies in anaesthetized rats showed that ganglionic blockade did not modify the decreases in blood pressure and heart rate elicited by CP-96,345. In the isolated guinea-pig heart, CP-96,345 and CP-96,344 exerted negative chronotropic effects at 10(-7) M; negative inotropic effects were observed at 10(-6) M. At 10(-5) M, both CP-96,345 and CP-96,344 decreased the amplitude of contraction of the rat portal vein, whereas at 10(-4) M, both compounds increased the frequency of contraction of this vessel. CP-96,345, at 5 x 10(-8) M, caused relaxation of precontracted pig coronary arteries. Since both CP-96,345 and CP-96,344 produced similar changes in haemodynamics and in the contractility of vascular and cardiac tissue, the cardiovascular effects of CP-96,345 are probably not related to NK1 receptor antagonism. As only the enantiomer with NK1 antagonistic activity inhibited cigarette smoke-induced plasma protein extravasation in rat trachea, CP-96,345 remains a useful tool for elucidating NK1 receptor-mediated responses, provided CP-96,344 is included as control.