It has been suggested that central nervous system (CNS) neuroexcitation plays an important role in digitalis-induced
cardiac arrhythmias. To elucidate further the role of the CNS in digitalis-induced arrhythmias, the inotropic and toxic effects of a highly polar semisynthetic
cardiac glycoside, 3beta-O-(4 amino-4,6 dideoxy-beta-D-galactopyranosyl)-digitoxigenin (ASI-222) were compared to those of
digoxin and correlated with plasma and cerebrospinal fluid (CSF) concentrations of each
drug. Thirteen dogs anesthetized with
sodium pentobarbital were given repeated intravenous doses of
digoxin or
ASI-222.
Ventricular tachycardia was elicited at a mean dose of
digoxin of 0.12 mg/kg, compared with 0.09 mg/kg for
ASI-222 (not significant). Terminal
ventricular fibrillation occurred after 0.18 mg/kg of
digoxin, a value significantly larger than the
ASI-222 dose (0.14 mg/kg, P less than 0.05) required to produce lethal arrhythmias.
Digoxin produced a 21% increase in LV dP/dt at a plasma
digoxin concentration of 20.0 +/- 2 ng/ml (mean +/- SEM) 30 minutes after 0.05 mg/kg; the CSF
digoxin concentration at this time averaged 0.7 +/- 0.1 ng/ml. At death, the plasma
digoxin concentration was 88 +/- 16 ng/ml and CSF
digoxin concentration was 5.7 +/- 1.6 ng/ml.
ASI-222 produced a similar 25% increase in LV dP/dt 30 minutes after administration of 0.05 mg/kg, with a plasma concentration of 18 +/- 2 ng/ml as determined by a newly developed radioimmunoassay. The plasma
ASI-222 concentration at death, 95 +/- 18 ng/ml, was similar to that of
digoxin. However, CSF samples at 30 minutes and at death showed no detectable levels of
ASI-222. Thus, despite similar inotropic and toxic responses and similar plasma
drug concentrations compared to
digoxin,
ASI-222 was demonstrated to have limited if any access to the CNS as judged by CSF concentrations. These findings suggest that direct CNS stimulation does not play a primary part in the genesis of digitalis-induced
cardiac arrhythmias in this experimental model, or that CNS effects are mediated by an area or areas lacking an effective blood-brain barrier.