This study examined the role of cardiac
beta-adrenergic receptors and cardiac sympathetic and vagal nerves in the
cardiotoxicity of 3-beta-0-(4-amino-4,6-dideoxy-beta-D-glucopyranosyl)
digitoxigenin hydrochloride (ASI-254). Vagally intact dogs received a constant rate
intravenous infusion of either
digoxin or
ASI-254 in the presence and absence of
practolol.
Practolol pretreatment increased the dose of
digoxin required to produce arrhythmias and markedly altered the pattern of toxicity, but did not alter the lethal dose. The terminal event was cardiac standstill rather than
ventricular fibrillation as seen in
digoxin control dogs.
Practolol did not alter the toxic dose of
ASI-254 and produced little change in the pattern of
cardiotoxicity; both control and
practolol-treated dogs died in cardiac standstill. Surgical
sympathectomy did not alter the toxic dose of
ASI-254, the character of toxicity, or the lethal dose compared to neurally intact dogs. However, vagal innervation may play a role in determining the type of
cardiotoxicity produced by
ASI-254.
Vagotomy alone did not alter the toxic or the lethal dose of
ASI-254;
vagotomy did, however, alter the character of
cardiotoxicity and terminal event. Our results indicate that
ASI-254 infused intravenously does not interact with sites, central or peripheral, which activate the sympathetic nervous system.
ASI-254 administered into the lateral ventricles produced signs of increased cardiac sympathetic nervous system activity.
Tachycardia and arrhythmias produced by ICV
ASI-254 appear to be neurally mediated since ganglionic blockade blunted these effects. These results suggest that
ASI-254 is capable of interacting with central sympathetic nervous system structures, but in contrast to
digoxin, access to these structures from
intravenous administration is limited.