CP-96,345 antagonism of NK1 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 microM, 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.
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001798:Blood Proteins / Q000187:drug effects; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000209:etiology; D006168:Guinea Pigs; D006439:Hemodynamics / Q000187:drug effects; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009200:Myocardial Contraction / Q000187:drug effects*; D010947:Plants, Toxic; D051381:Rats; D017207:Rats, Sprague-Dawley; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D018039:Receptors, Tachykinin; D012906:Smoke / Q000009:adverse effects*; D013373:Substance P / Q000037:antagonists & inhibitors*; D013552:Swine; D014026:Nicotiana; D014132:Trachea / Q000187:drug effects
D001713:Biphenyl Compounds; D001798:Blood Proteins; D017981:Receptors, Neurotransmitter; D018039:Receptors, Tachykinin; D012906:Smoke; D013373:Substance P; C066892:CP 96345