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.
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