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

Abstract

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.

• Authors: H Dong, J Z Sheng, C M Lee, T M Wong
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 109 Issue 1 Pg. 113-9 (May 1993) ISSN: 0007-1188 [Print] England
• PMID: 8495235 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• Calcium Channel Blockers
• Cardiovascular Agents
• Isoquinolines
• Piperidines
• Tetrahydroisoquinolines
• CPU 23
• Potassium Chloride
• Diltiazem
• Nifedipine
• Calcium

Topics

• Action Potentials (drug effects)
• Anesthesia
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Blood Pressure (drug effects)
• Calcium (metabolism)
• Calcium Channel Blockers (pharmacology)
• Cardiovascular Agents (pharmacology)
• Coronary Vessels (physiology)
• Diltiazem (pharmacology)
• Female
• Guinea Pigs
• Heart Rate (drug effects)
• In Vitro Techniques
• Isoquinolines (pharmacology)
• Male
• Myocardial Contraction
• Myocardium (cytology)
• Nifedipine (pharmacology)
• Papillary Muscles (drug effects)
• Piperidines (pharmacology)
• Potassium Chloride (pharmacology)
• Rabbits
• Rats
• Rats, Sprague-Dawley
• Sinoatrial Node (drug effects)
• Tetrahydroisoquinolines