The Central Nervous System as a Site of Action for the Coronary Vasoconstrictor Effect of Digoxin

Abstract

A B S T R A C T Digitalis is known to have a vasoconstrictor effect in the coronary circulation. Recent studies have demonstrated that the coronary vasoconstrictor effects of acetylstrophanthidin and digoxin are neurally mediated via alpha adrenergic fibers. In the present study, experiments were done in 20 dogs anesthetized with chloralose and urethane to study the central nervous system as a possible site of action for this vasoconstrictor effect of digoxin. After the intravenous administration of 1.0 mg digoxin, cerebrospinal fluid concentrations of digoxin rose to a peak of 2.3±0.4 (SEM) ng/ml at 15 min, temporally corresponding to the peak in coronary vascular resistance change of + 20.0± 2.5% of control in the paced canine heart. Submicrogram digoxin injections into the lateral cerebral ventricle produced a significant increase in coronary vascular resistance, the latter injection producing a peak increase in coronary vascular resistance of 12.4±11.2% of control. Cross-perfusion experiments, where the isolated head of the operative dog was perfused from a donor dog receiving digoxin, thus keeping digoxin levels in the remainder of the operative dog very low, showed a similar degree of coronary vasoconstriction. Thus, the central nervous system appears to be an important site of action for the early coronary vasoconstrictor effect of digoxin.

Accumulation of Radioactive Cardiac Glycosides by Various Brain Regions in Relation to the Dysrhythmogenic Effect

“…Recently, Garan et al (1974) determined the CSF and plasma concentrations of digoxin following intravenous injection. They found that the highest CSF value was 2.3 ng/ml (2.9 pmol/ml) with a CSF/plasma ratio of about 0.05.…”

“…By simultaneously recording sympathetic and phrenic nerve activity together with the ECG, the above workers demonstrated a relationship between the enhanced neuronal activity and cardiac disorders following systemic injection of digitalis. We felt that these studies of Gillis (1969) and recent claims of Garan, Smith & Powell (1974) were sufficiently impressive to require careful evaluation of the CNS as a possible site of digitalis-induced dysrhythmia. Thus, we undertook a systematic evaluation to determine: (1) the rate of appearance of systemically administered cardiac glycosides, namely ouabain and digitoxin, in the cerebrospinal fluid (CSF); (2) the uptake of these cardiac glycosides in various brain areas; and (3) the effect of these cardiac glycosides upon the ionic composition of the CSF.…”

Effect of ouabain on total vascular capacity in the dog.

“…2 and 3 and our previous work (9)(10)(11). The work by Garan et al (12) suggests that the central nervous system is the site of action of the increase in arterial resistance after digitalis administration. The alpha adrenergically mediated increase in transhepatic resistance with ouabain may also be mediated through the central nervous system, although, recently published data by Lorenz et al (13) suggest that ouabain may release norepinephrine from neuronal stores in isolated venous segments.…”

Contrasting effects of digitalis and dobutamine on baroreflex sympathetic control in normal humans.

“…Twenty-two male subjects (age 22±t1 year, mean+SEM) were studied in three treatment groups: digitalis group (n=8; subjects 1-8), dobutamine group (n=8; subjects [9][10][11][12][13][14][15][16], and placebo group (n=6; subjects [17][18][19][20][21][22]. All subjects were studied without sedation in the supine, postabsorptive state and were free of cardiovascular or other systemic diseases based on medical history and physical examination.…”