CALCIUM ANTAGONISTIC AND ANTIARRHYTHMIC ACTIONS OF CPU-23, A SUBSTITUTED TETRAHYDROISOQUINOLINE

1 The effects of CPU-23 (1-{1[(6-methoxyl)-naphth-2-yl]}-propyl-2-(1-piperidine)-acetyl-6,7-dimethy-oxy-1,2,3,4-tetra-hydroisoquinoline) were studied on mechanical and electrical activities, and intracellular free calcium ([Ca2+]i) of isolated cardiac tissues in order to investigate its spectrum and mechanisms of action in the heart. Its antiarrhythmic and haemodynamic effects in pentobarbitone-anaesthetized rats subjected to coronary artery ligation were also evaluated. 2 CPU-23 at 10(-6)-10(-4) M Markedly inhibited slow action potential characteristics in guinea-pig papillary muscles and pace-maker action potential of rabbit sinoatrial node. It affected fast action potential only at 10(-4) M. None of the effects of (CPU-23 was reversed by washout for up to 2 h. 3 Like nifedipine and diltiazem, CPU-23 decreased the heart rate of the isolated perfused heart of the rat. However, in contrast to these two classical calcium antagonists which dose-dependently inhibited the force of contraction, CPU-23 inhibited and stimulated the force of contraction at 10(-7) -3 x 10(-6) M and 10(-5) m, respectively. 4 CPU-23 at 10(-6)-10(-5) M inhibited the KCl-induced [Ca2+]i increase in the Ca2+ medium, but did not affect the caffeine-induced [Ca2+]i increase in the Ca2+-free medium in isolated ventricular myocytes. 5 CPU-23 at 1-5 mg kg-1 reduced dose-dependently ventricular arrhythmias including ventricular ectopic beats, VT and VF as well as mortality during coronary artery ligation. At 15-5 mg kg-1 it even abolished VF, which was accompanied by 100% survival. 6 It is suggested that CPU-23 has calcium antagonistic properties in cardiac tissues. It selectively blocks the transmembrane influx of extracellular Ca2+ through Ca2+ channels, thus reducing the heart rate and developed tension, altering the slow action potential characteristics and producing antiarrhythmic effect against ischaemic arrhythmias.