Chronic verapamil treatment depresses automaticity and contractility in isolated cardiac tissues

Chronically administered verapamil can accumulate in cardiac tissues and may depress cardiac function despite low plasma concentration. To examine this, two groups of rabbits were injected intraperitoneally twice a day with either 1 mg/kg verapamil or saline for 28 days. Fourteen hours after the last dose, right atrial tissue and right ventricular papillary muscle were isolated. Plasma and myocardial tissue concentrations of verapamil were determined. Plasma samples contained no detectable amounts of verapamil, but the myocardium contained 2.1 +/- 0.6 (mean +/- SE) ng of verapamil per gram of wet tissue. Spontaneous action potentials recorded from the sinoatrial node in the verapamil-treated group showed decreases in the phase 0 and phase 4 depolarization rates, a slower pacemaker rate, and an attenuated response to epinephrine compared with the saline-treated group. Papillary muscle in the verapamil-treated group exhibited a significantly lower force of contraction and a depressed contractile response to epinephrine compared with the control group. There were no differences in rate or contractile responses the day after single injection with 2 mg/kg verapamil or saline twice a day. Myocardial verapamil concentration increased with the duration of treatment and with the doses given; myocardial verapamil concentration was 3.0 +/- 0.6 ng/g wet tissue in the group treated for 28 days with 2 mg/kg verapamil. Our study shows that chronic treatment of rabbits with verapamil decreases cardiac chronotropic and inotropic responses to adrenergic stimuli despite no detectable verapamil in plasma, and that accumulation of verapamil in the myocardium is probably associated with these effects.