Cardiovascular effects of CPU-23, a novel calcium channel blocker developed from a chinese medicinal herb
To develop novel therapeutic agents based on lead compounds isolated from Chinese medicinal herbs, a series of benzyl-tetrahydroisoquinolines have been synthesized and screened. CPU-23, the most potent compound identified in this series, was found to inhibit KCl-induced contraction of rat aorta and displace [3H]nitrendipine binding in rat cerebral cortical membranes with similar potency. It also induced hypotension and bradycardia in the rat in vivo. In the present study, the cardiovascular effects of CPU-23 were further investigated by using the patch-clamp, tension and haemodynamic measurements. CPU-23 (1-10 uM) dose-dependently inhibited inward Ba2currents of single smooth muscle cells isolated from the rat tail artery and reduced concentration-response curves for KC1 and phenylephrine in isolated rings in the presence of extracellular Ca2+, with PD2 values 5.70 and 4.85, respectively. CPU-23 (10-30 juM) also inhibited norepinephrine-induced contraction from 40% of control to 23% and 14% (p 0.01 for both) in the absence of extracellular Ca2+. The profile of hemodynamic action of CPU-23 was similar to diltiazem. It induced a rapid onset and long-lasting decrease in left ventricular systolic pressure, maximal velocity of pressure increase, systolic blood pressure, diastolic blood pressure and heart rate. These data indicate that CPU-23 is a novel calcium channel blocker, which exerts anti-hypertensive and cardiac depressant effects due to its blocking actions primarily on voltage-dependent calcium channels and partially on receptor-operated calcium channels and calcium release from intracellular stores.