CARDIOVASCULAR EFFECTS OF CPU-23, A NOVEL L-TYPE CALCIUM-CHANNEL BLOCKER WITH A UNIQUE MOLECULAR-STRUCTURE

1 The cardiovascular effects of CPU-23 tyl-6,7-dimethoxy-1,2,3,4-tetra hydroisoquinoline), a cleavage product of tetrandrine, were investigat ed using the whole cell perforated patch-clamp technique, in vitro ten sion measurements and in vivo haemodynamic recordings. 2 CPU-23 (1 and 10 mu M) dose-dependently reduced concentration-response curves for K Cl and phenylephrine (PE) in the rat tail artery; inhibition of KCl-in duced contraction was much more potent than for PE. At the same concen trations, CPU-23 inhibited the inward Ba2+ currents in single smooth m uscle cells isolated from the rat tail artery, while CPU-23 (10 mu M) produced 95% vasorelaxation of the rat middle cerebral artery preconst ricted with BayK 8644. 3 CPU-23 (10 and 30 mu M) inhibited the noradre naline-induced phasic contraction of the rat tail artery in the absenc e of extracellular Ca2+ from 40% of control to 23% and 14%, respective ly (P<0.01) and tonic contraction of the artery after addition of Ca2 (2 mM) from 100% of control to 83% and 75%, respectively (P<0.01). In the presence of extracellular Ca2+ the PE-induced contraction was red uced by CPU-23 (30 and 100 mu M) to 27% and 37%, respectively. 4 The h aemodynamic profile of CPU-23 in the rat was very similar to diltiazem . At 5 mg kg(-1) CPU-23 induced a rapid onset and long-lasting decreas e in left ventricular systolic pressure (LVSP), maximal velocity of pr essure increase (dP/dt(max)), systolic blood pressure (SEP), diastolic blood pressure (DBP) and heart rate (HR). When haemodynamic actions o f CPU-23, verapamil, diltiazem and nifedipine were compared at equidep ressor doses, the order of potency for reducing LVSP and dP/dt(max) wa s verapamil > CPU-23 = diltiazem > nifedipine and the order of potency for decreasing HR was verapamil = CPU-23 = diltiazem > nifedipine. 5 These data indicate that CPU-23 is a novel calcium channel blocker wit h unique molecular structure, which exerts antihypertensive and cardia c depressant effects due primarily to its action on L-type voltage-gat ed calcium channels.