Neurally mediated augmentation of arrhythmogenic properties of highly polar cardiac glycosides

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Abstract
To evaluate the possible advantages of digitalis derivatives unable to cross the blood-brain barrier [BBB], inotropic and arrhythmogenic responses to 3 highly polar ionizable cardenolides in 92 pentobarbital-anesthetized cats were studied. 3-.beta.-O-(4 amino-4,6-dideoxy-.beta.-D-galactopyranosyl)-digitoxigenin (ASI-222), digoxin-16''-.beta.-D-glucuronide [DG] and digitoxigenin-3-sulfate [DS] given by i.v. infusion at constant rate did not appear in the cerebrospinal fluid in amounts detectable by radioimmunoassay procedures sensitive to concentrations of 0.1 ng/ml. The therapeutic indices of ASI-222 (0.28), DG (0.47) and DS (0.35) were significantly poorer in each case than those of ouabain (0.15), digoxin (0.21) and digitoxin (0.19). A modulating role of the CNS in production of cardiac arrhythmias elicited by the ionizable cardenolides was supported by experiments showing that C-1 spinal cord transection increased the dose of these compounds required to produce ventricular tachycardia (VT) and at the same end point increased the degree of inhibition of monovalent cation active transport measured in myocardial samples in vitro. Transection of the neuraxis at the midcollicular level had no effect on the doses of ASI-222 or DG required to produce VT or on the degree of monovalent cation active transport inhibition at this end point. CNS centers between the midcollicular and C-1 spinal cord levels are apparently involved in modulation of arrhythmogenic responses to cardenolides, including derivatives with ionizable groups and limited BBB permeability.