flavin-adenine-dinucleotide and Arrhythmias--Cardiac

In this study, we investigated the mechanism of the arrhythmogenic action of chlorpromazine (CPZ). Thirty-two anesthetized mongrel dogs were used. In each, the chest was opened and a stimulating electrode was attached to the apex of the left ventricle and the ventricular multiple response threshold (VMRT) was measured. The carotid artery was cannulated to measure aortic pressure. The dogs were divided into four groups, and the time course of VMRT, blood pressure, and heart rate were determined. All groups were placed under observation for 30 min after CPZ infusion. In the control group, only saline (2ml/kg) was infused; CPZ group: CPZ (Img/kg) was infused 10 min after saline (2ml/kg) infusion; CoQ10 group: Coenzyme Q10 (CoQ10) (5mg/kg) was infused 10 min before CPZ (Img/kg) infusion; FAD group: Flavin-adenine-dinucleotide (FAD) (2mg/kg) was infused 10 min before CPZ (Img/kg) infusion. In each group, myocardial mitochondria were prepared 30 min after CPZ infusion. The mitochondrial functions, respiratory control index, AdP/O, State III rate of oxygen consumption, and activities of two segments of the electron-transport chain (NADH leads to CoQ leads to cyt.c and cyt.c leads to cyt.a,a3 leads to O2) were measured separately. Ca++--binding activity of the mitochondria was also determined. CPZ administration decreased VMRT and blood pressure, and caused mitochondrial dysfunction which derived from a disturbance in the first segment of the electron transport chain. Decreased Ca++--binding activity was observed when mitochondrial function was disturbed. CoQ10 prevented significantly the decrease in VMRT and the disturbance of mitochondrial function induced by CPZ, but did not prevent the hypotensive effect of CPZ. FAD prevented not only the decrease in VMRT and the disturbance of mitochondrial function, but also the hypotensive effect of CPZ. These results suggest that the decrease in VMRT is closely related to mitochondrial dysfunction induced by CPZ. Moreover, it is suggested that the arrhythmogenic effect of CPZ is derived from the decreased mitochondrial Ca++--binding activity.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Cardiac Complexes, Premature; Chlorpromazine; Coenzymes; Dogs; Electric Stimulation; Female; Flavin-Adenine Dinucleotide; Heart Ventricles; Hemodynamics; Humans; Male; Mitochondria, Heart; Ubiquinone

To investigate the mechanism of chlorpromazine(CPZ)-induced ventricular arrhythmia, the changes in ventricular fibrillation threshold (VFT) were followed after intravenous injection of CPZ (1 mg/Kg) in dogs. Following injection, VFT was decreased to 56.6 +/- 5.4% (mean +/- SE) of the initial level. Since flavin-adenine-dinucleotide (FAD) combines specifically with CPZ in vitro, we investigate whether or not prior treatment with FAD prevents the CPZ effect. With FAD (2 mg/Kg), the CPZ-induced decrease in VFT was significantly cancelled (92.2 +/- 4.2% of the initial level). Mitochondria isolated from canine heart after CPZ injection showed a significant decrease in respiratory control index and ADP/O. Effects of CPZ on canine heart mitochondria were also well cancelled by prior administration of FAD. The findings suggest that the arrhythmogenic action of CPZ might be associated in part with impaired function of heart mitochondria. These results also suggest that FAD might be useful in the treatment of the cardiac disturbances associated with overdosage of CPZ.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Chlorpromazine; Dogs; Flavin-Adenine Dinucleotide; Mitochondria, Heart; Ventricular Fibrillation

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Bradycardia; Dextrans; Electrocardiography; Energy Metabolism; Flavin-Adenine Dinucleotide; Glycogen; Lysine; Microcirculation; Mitochondria, Muscle; Molecular Weight; Myocardium; NAD; Oxidative Phosphorylation; Oxygen Consumption; Phosphorus; Phosphorylases; Rabbits; Stimulation, Chemical; Succinates; Vasopressins

Topics: Aerosols; Arrhythmias, Cardiac; Asphyxia; Asthma; Flavin-Adenine Dinucleotide; Humans; Isoproterenol