Effects of bretylium on rat cardiac muscle: the electrophysiological effects and its uptake and binding in normal and immunosympathectomized rat hearts.

Bretylium produced electrophysiological effects on both rat atrium and ventricle in vitro at concentrations ranging from 2 times 10- minus 5 to 10- minus three M. Those effects included lengthening of action potential duration and effective refractory period; increasing effective refractory period/action potential duration; decreasing dv/dt of phase zero of the action potential and suppressing the action potential amplitude and overshoot. These effects, which could serve as a basis for the antiarrhythmic action of bretylium, were observed also in hearts from immunosympathectomized rats confirming a direct effect of this drug on the electrical properties of the cardiac muscle cells. In vivo and in vitro exposure of the myocardium to 14-C-bretylium showed that this drug is concentrated in cardiac ventricle and that this concentrating ability of the heart may be responsible for attaining effective antiarrhythmic concentrations in the myocardium at low plasma concentrations of the drug. Uptake of bretylium by the sympathetic nerves never amounted to more than 15% of the total bretylium binding by the cardiac ventricle and this neuronal uptake became insignificant compared to total bretylium uptake at concentrations greater than 10- minus 6 M. Subcellular distribution of the bretylium bound to the cardiac ventricle from immunosympathectomized rats suggested a binding to plasma membranes. Efflux studies indicate that this binding was tight, although reversible. These results indicate that underlying the antiarrhythmic effects of bretylium is an accumulation of the drug by cardiac muscle cells and a direct effect of the drug on the electrical properties of the cardiac muscle membrane independent of any action on the adrenergic neuron.