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- 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. 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.
Dong
H
H
Department of Physiology, Faculty of Medicine, University of Hong Kong.
Sheng
J Z
JZ
Lee
C M
CM
Wong
T M
TM
D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D003331:Coronary Vessels / Q000502:physiology; D004110:Diltiazem / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000166:cytology; D009543:Nifedipine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012849:Sinoatrial Node / Q000187:drug effects; D044005:Tetrahydroisoquinolines
D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D002317:Cardiovascular Agents; D007546:Isoquinolines; D010880:Piperidines; D044005:Tetrahydroisoquinolines; C077683:CPU 23; D011189:Potassium Chloride; D004110:Diltiazem; D009543:Nifedipine; D002118:Calcium