Calcium antagonistic and antiarrhythmic actions of CPU-23 a substituted tetrahydroisoquinoline.

摘要

1. The effects of CPU-23 (1-(1-[(6-methoxyl)-naphth-2-yl])-propyl-2-(1-piperidine)-acetyl-6 ,7- dimethyoxy-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 Ca(2+)-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 2.5-5 mg kg-1 it even abolished VF, which was accompanied by 100% survival.(ABSTRACT TRUNCATED AT 250 WORDS)