Digoxin toxicity: primary sites of drug action on the sympathetic nervous system

Increases and decreases in sympathetic nerve activity have been reported to accompany digitalis-induced arrhythmias. These effects may result from drug action on various sites such as the central nervous system, ganglia, chemoreceptor or baroreceptor afferent fibers or peripheral efferent nerve fibers. The relative importance of each possible site of drug action has not been clarified. To define the involvement of some of these sites, digoxin was administered intravenously to cats in order to study its effects on activity of preganglionic splanchnic or postganglionic inferior cardiac nerves in the presence or absence of chemoreceptor and baroreceptor reflexes. In cats with intact reflexes, arrhythmic doses of digoxin had diverse effects on postganglionic activity. In some cats digoxin increased activity and in others it decreased activity. In contrast, digoxin consistently caused large progressive increases in postganglionic activity when baroreceptors and chemoreceptors had been denervated. Digoxin inhibited preganglionic nerve activity only in cats with intact reflexes but had no effect in those without chemoreceptor and baroreceptor reflexes. Thus, the afferent component of the baroreceptor reflex is the apparent site of digoxin-induced inhibition. Digoxin produced increases in activity above control only in postganglionic nerves. This finding suggests that digoxin acts on the ganglion to increase sympathetic activity. Digoxin had no discernible effect on preganglionic activity when baroreceptor and chemoreceptor afferent input had been eliminated. To test further for any subliminal drug effect in the brain, effects of intravenously administered digoxin were observed on centrally evoked submaximal responses in the splanchnic nerve. Lethal doses of digoxin had no effect on responses evoked from the medulla or the hypothalamus. Therefore, these data are not consistent with the hypothesis that a primary site of drug action is in the central nervous system. Instead, the data suggest that neural effects of digoxin result primarily from drug actions within the peripheral autonomic nervous system on sites such as the ganglion and peripheral afferent components of the baroreceptor reflex.