Mechanism of the antiarrhythmic action of verapamil.

We studied the antiarrhythmic mechanism of verapamil in anesthetized mongrel dogs. The animals were divided into seven groups, six of which were treated as follows: chlorpromazine, coenzyme Q10 and chlorpromazine, verapamil and chlorpromazine, lipid, carnitine and lipid, or verapamil and lipid; the seventh group received no drug treatment. In each group, the ventricular multiple response threshold (VMRT) was measured at 10 min intervals for 40 min. Thereafter, mitochondria were isolated from the myocardium and the mitochondrial Ca2+ binding activities were measured. Administration of chlorpromazine or lipid lowered VMRT and concomitantly decreased mitochondrial Ca2+ binding activity. Premedication with either coenzyme Q10 or carnitine prevented both the lowering of VMRT and the decrease in mitochondrial Ca2+ binding activity. Premedication with verapamil prevented the lowering of VMRT but not the decrease in Ca2+ binding activity. These results suggest that the decrease in mitochondrial Ca2+ binding activity is one important arrhythmogenic factor. Verapamil, which blocks the Ca2+ inward current, may act antiarrhythmically by counteracting the possible increase in the intracellular Ca2+ concentration induced by decreased mitochondrial Ca2+ binding activity.