Cardiovascular effects of CP-96,345, a non-peptide blocker of tachykinin NK1 receptors

CP-96,345, a non-peptide, selective tachykinin NK1 receptor blocker and its inactive enantiomer, CP-96,344, inhibit ligand binding of phenylalkylamine but not dihydropyridine Ca2+ channel antagonists. Whether these Ca2+ channel antagonist properties of CP-96,345 and CP-96,344 can be expressed as cardiovascular effects in vitro and in vivo is unknown. The cardiovascular effects of CP-96,345 and CP-96,344 in isolated vascular smooth muscle and in anesthetized dogs were compared to those of verapamil and nifedipine, phenylalkylamine and dihydropyridine Ca2+ channel antagonists, respectively. CP-96,345, CP-96,344, verapamil and nifedipine inhibited Ca(2+)-induced contractions in rat isolated portal vein with pD2' values of 5.9, 5.8, 6.8 and 8.1, respectively. In closed chest, anesthetized, spinal-pithed dogs, CP-96,345 caused dose-related hypotension and depressed heart rate. In open chest, anesthetized beagles at equihypotensive doses, CP-96,345, 1 mg/kg, CP-96,344, 1 mg/kg and verapamil, 0.5 mg/kg caused significant negative chronotropic, dromotropic and inotropic effects that were not observed with nifedipine, 0.01 mg/kg or nitroglycerin, 0.02 mg/kg. We conclude that the cardiovascular effects of CP-96,345 and its isomer are due to 'verapamil-like' Ca2+ channel antagonism and are not related to blockade of NK1 receptors.