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J Electrocardiol. 1981 Jul;14(3):219-24.

Mechanism of chlorpromazine-induced arrhythmia -- arrhythmia and mitochondrial dysfunction.

Abstract

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.

PMID:
6167651
[Indexed for MEDLINE]

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