CPU 86017 suppresses tachyarrhythmias induced by ouabain and myocardial infarction: Concentrations in plasma and different areas of the heart in dogs

CPU 86017 (p-chlorobenzyl-tetrahydroberberine) a derivative of berberine, possesses an antiarrhythmic effect against arrhythmias in animal models. Two canine arrhythmia models were established by i.v. infusion of ouabain and two-stage ligation of coronary artery to generate sustained ventricular tachyarrhythmias in dogs. In the ouabain model CPU 86017 was infused at 0.96 mg/kg divided into two doses of 0.36 and 0.6mg/kg; tachycardia was completely suppressed and reversed to control sinus rhythm. The canine heart was infarcted by two-stage ligation of the anterior coronary artery and cardiac tachycardia occurred 20h after coronary ligation. A total dose of 0.5, 0.7, and 1.0 mg/kg i.v. infusion of CPU 86017 was effective to suppress arrhythmic scores (0-7 score system) from the untreated 5.2+/-0.7 to 3.8+/-0.5, (P<0.05), 3.9+1.9 (P<0.05) and 2.6+2.0(P<0.01), respectively, and i.v. amiodarone 5mg/kg reduced arrhythmic scores to 2.3+/-11.3 (P<0.01). There was a counterclockwise hysteresis loop of the pharmacokinetic/pharmacodynamic relationship in both models attributed to a small Keo value. Concentrations were not different in the outer, middle, and inner layers of the left ventricle, but higher in the working myocardium against the SA node and AV node. They were also different in the myocardial levels in the infarcted, risk, and noninfarcted regions where concentrations were 0.267+/-0.09 mug/ml, 0.948+/-0.399 mug/ml, and 1.371+/-0.433 mug/ml, respectively. By continuous infusion of high doses in ouabain-receiving dogs the PR interval and QTc (QTc=QT/(R-R)) were prolonged by 27.5% and 24.5%, respectively (P<0.001). The accumulation in the myocardium of CPU 86017 was evident against the rapid decrease in plasma levels. The toxicity to the heart by high doses of CPU 86017 is principally due to cardiac block and cardiac arrest rather than torsade de pointes. (C) 2003 Wiley-Liss, Inc.