THERAPEUTIC AND REFLEXOGENIC EFFECT OF DIGITALIS

Project: Research project

Project Details

Description

Aminosugar digitalis compounds are polar and do not traverse
lipid barriers or biological membranes. They differ in actions
from neutral sugar digitalis in that aminocardenolides have a
greater cardiac inotropic potency, are more potent inhibitors of
Na+, K+-ATPase, produce more marked lengthening of A-V nodal
refractory period (AVRP), have a higher therapeutic index and a
different pattern of cardiac toxicity, and interact differently with
reflexogenic systems to alter autonomic nervous system activity
at the heart, apparently causing only withdrawal of sympathetic
nervous tone. We hypothesize that the aminocardenolides,
because of high polarity, are incapable of interacting with certain
cellular sites covered by membrane lipid barriers. In contrast,
neutral cardenolides are able to reach these sites. The
aminocardenolides therefore produce a different spectrum of
cardiovascular and neural events than noted with neutral sugar
digitalis agents. To test this hypothesis, we propose four areas of investigation: 1)
Effects on Cardiac Autonomic Nerve Activity.
Aminocardenolides differ from traditional digitalis agents in their
ability to lengthen AVRP; we conclude from indirect evidence
that they do solely by the withdrawal of sympathetic nervous
tone, as opposed to digoxin and ouabain which influence
sympathetic tone and vagal activity. We seek to confirm our
conclusion by directly measuring and comparing sympathetic and
vagal nervous activity produced by infusion of an
aminocardenolide or neutral cardenolide throughout the
therapeutic and toxic dose range. 2) Actions on Reflexogenic
Receptor Areas. Because an aminocardenolide appears to
lengthen A-V refractory period solely by withdrawal of cardiac
sympathetic nervous tone rather than additionally augmenting
vagal tone, we will identify the site(s) of reflex receptor
interaction of an aminocardenolide compared to those sites
involved in the actions of digoxin and ouabain. This will be
examined by experiments which systematically exclude all but
these sites. Local, discrete administration of the cardenolides
will also be made into these specific sites. Additionally, afferent
neural traffic from specific sites will be examined. Since
sympathetic nervous tone to various organs may be differentially
affected by these glycosides, we shall monitor nerve activity to
several regions. 3) Effects on A-V Transmission. Since we have
evidence that an aminocardenolide, ASI-222 produces
therapeutically important and greater increases in AVRP than
digoxin at fractions of the arrhythmic dose, we shall study the
nature of its actions and those of two closely related congeners
and the site of the cardiac conduction system involved. the
ability of agents to reduce ventricular rate in a model of atrial
fibrillation will also be determined. 4) Therapeutic and Toxic
Actions in Chronically Treated Conscious Dogs. Cardiac inotropic
and A-V nodal effects of chronic administration of these
cardenolides in conscious dogs may be unlike those noted acutely
in anesthetized dogs and may occur at different doses. Their
toxic effects in conscious dogs may also be different. Further study of the actions of these polar agents will create a
better understanding of automatic nervous reflexes and the
properties of digitalis analogs necessary for selective reflex
receptor interactions. Beyond basic mechanism considerations,
aminocardenolides are of obvious and direct clinical significance
since they may prove to be safer and more effective than
presently available cardiac glycosides.
StatusNot started