cyclovirobuxine-d and Arrhythmias--Cardiac

To search for compounds for the treatment of cardiovascular diseases through prodrug structural modifications of cyclovirobuxine D, a single efficient composition distilled from Box plant in China, which was used to treat angina and myocardial infarction.. According to prodrug design principle, a series of cyclovirobuxine D analogues were prepared, suc as succinate, phosphate and amino acid ester, and their biological activities were tested.. Seven new compounds were obtained and confirmed with 1H NMR, MS, and element analysis.. In pharmacology experiment, for treating arrhythmia induced by aconitine, succinate and amino acid ester of cyclovirobuxine D (I and VII) showed better activities than that of cyclovirobuxine D. The normal rhythm of the heart duration of I and VII were ( 11.53 +/- 7.62) min and (12.68 +/- 9.25) min, compared with 0.9% NaCl solution and cyclovirobuxine D, (2.36 +/- 1.68) min and (10.25 +/- 6.59) min (P < 0.01), respectively. Another pharmacology experiment, for treating arrhythmia induced by chloroform, the negative ratio of I and VII were 80% and 82%, compared with 0.9% NaCl solution and cyclovirobuxine D, 43% and 52% (P < 0.05), respectively. The difference between new compounds and cyclovirobuxine D was distinct.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Buxus; Chloroform; Drugs, Chinese Herbal; Female; Heart Rate; Male; Mice; Plants, Medicinal; Prodrugs; Random Allocation; Rats; Rats, Sprague-Dawley

To explore the possible mechanism of cyclovirobuxine D (CVB-D) in countering and inducing arrhythmia, by way of studying its electro-physiological effect on ventricular papillary muscles of rats in vitro.. The transmembrane potential of rat's isolated right ventricular papillary muscles were recorded using conventional glass micro-electrode technique.. (1) CVB-D in concentration of 13.3-63.3 micromol/L, showed prolonging effect on the action potential repolarization time, mainly the action potential duration 50 (APD50), APD70 and APD90, in dose-dependent manner, in concentration of 33.3-63.3 micromol/L, it could inhibit the resting potential, action potential amplitude (APA) and maximum depolarization velocity (Vmax) in dose-dependent manner. (2) CVB-D also showed time-dependent effect, the effect initiated 10 min after 20 micromol/L was perfused in ventricular muscle, the APD50, APD70 and APD90 were potentiated gradually along with prolongation of action time and reached the peak at 30-40 min, without any potentiation thereafter. (3) CVB-D could markedly prolong the effective refractory period (ERP) of action potential, increase the ratio of ERP/APD. (4) CVB-D in concentration of 33.3 micromol/L could induce frequent, multifocal spontaneous arrhythmia in some cells when the action time was longer than 45 min.. CVB-D has the action of anti-ventricular arrhythmia, the mechanism is correlated with the prolongation of APD and ERP of ventricular muscle as well as the increase of ERP/APD ratio, while it also has the effect of inducing arrhythmia, the mechanism might be concerned with excessive prolongation of APD and the inhibition on RP, APA and Vmax.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drugs, Chinese Herbal; Electrophysiologic Techniques, Cardiac; Heart Ventricles; In Vitro Techniques; Male; Myocytes, Cardiac; Papillary Muscles; Rats; Rats, Sprague-Dawley; Refractory Period, Electrophysiological; Ventricular Function

Cycloprotobuxine-A (CPB-A) 1-4 mg/kg (1/100-1/25 LD50) produced therapeutic and prophylactic effects which were found to be dose-dependent on experimental arrhythmias induced by BaCl2, aconitine and chloroform. Given at equitoxic doses, the anti-arrhythmic action of CPB-A was as potent as cyclovirobuxine-D (CVB-D) and amiodarone (Amio). However, its therapeutic index (LD50/ED50) was 1.8 times that of CVB-D and 1.2 times that of Amio. The most pronounced effects of CPB-A (0.3-30 mumol/L) on the electrophysiology of ventricular muscle of guinea pig were the lengthening of APD50, APD90 and ERP. This may contribute to its anti-arrhythmic action and suggests that CPB-A most likely belongs to class III anti-arrhythmic drugs (prolongation of APD). Perfused with the same concentration (3 mumol/L), CPB-A brought about more significant increases in APD50, APD90 and ERP than CVB-D and Amio did.

Topics: Action Potentials; Alkaloids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drugs, Chinese Herbal; Female; Guinea Pigs; Male; Mice; Rats; Rats, Inbred Strains; Ventricular Fibrillation

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; China; Drugs, Chinese Herbal; Guinea Pigs; Heart; In Vitro Techniques; Plant Extracts; Plants, Medicinal